You're using an outdated browser. Please upgrade to a modern browser for the best experience.
Immune Control of Avian Influenza Virus Infection: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Ravi Pratap Barnwal.

The avian influenza A virus (AIV) is naturally prevalent in aquatic birds, infecting different avian species and transmitting from birds to humans. Both AIVs, the H5N1 and H7N9 viruses, have the potential to infect humans, causing an acute influenza disease syndrome in humans, and are a possible pandemic threat. AIV H5N1 is highly pathogenic, whereas AIV H7N9 has comparatively low pathogenicity.

  • avian influenza virus
  • innate immunity
  • adaptive immunity
  • diagnosis
  • vaccine development

1. Introduction

Influenza viruses (IVs) of types A and B lead to seasonal influenza epidemics, but only type A is linked to pandemics. The two main viral surface proteins that cause protective host antibody responses are haemagglutinin (HA) and neuraminidase (NA), which are categorized into 18 HA and 11 NA subtypes based on an antigenic investigation. The IV is an eight-segmented single-stranded RNA virus. Mutations cause genetic and antigenic variations in RNA viruses, just as in other viruses. The virus’s segmented RNA genome allows it to produce a variation through genetic reassortment. The predominant human H1N1 IV acquired a novel HA and polymerase basic 1 (PB1) gene of avian origin, resulting in a virus with a new subtype: H2N2 in 1957 and H3N2 in 1968. This led to the pandemics of 1957 and 1968 [1]. AIVs belong to the category of type A viruses because they can infect humans and animals. Type A viruses are a significant danger to public health, as they can cause an influenza pandemic. AIVs are carried by wild birds in their intestines. Thus, the birds shed these viruses in saliva, feces and nasal secretions. AIVs are found naturally in aquatic birds. Except for H17N10 and H18N11, which are found in bats, all the subtypes are prevalent in aquatic birds [2]. AIVs are classified according to their potential to cause disease in chickens. AIVs can be low pathogenic AIVs (LPAIV) or high pathogenic AIVs (HPAIV). LPAIVs only cause mild illness in domestic birds, whereas acute influenza symptoms are manifested in the case of HPAIVs, which may also cause internal organ damage, affect the respiratory tract and increase poultry mortalities [3]. LPAIV is the main cause of upper respiratory tract (URT) infections with variable degrees of sinus, conjunctival and tracheal irritation. Influenza H5 and H7 subtypes arise from non-pathogenic influenza viruses belonging to the category of HPAIVs [2]. H5N1, H7N2, H7N3, H7N7, H9N2, H7N9, H5N6, H6N1, H10N7 and H10N8 are AIVs known to infect humans. [2,4][2][4]. Only mild clinical symptoms are observed in infections with H7N2, H7N3, H7N7, and H6N1 [4]. However, some AIVs, such as H5N1 and H7N9, can cause severe influenza disease and have high human mortality rates [5]. The reason behind this is the truancy of preexisting AIV-specific antibodies, although antibodies against both viruses can be identified during the development of illness [2].
The H5N1 AIV continues to spread zoonotically among people, causing severe illness and posing a pandemic threat [6], and Early in 2009, a novel H1N1 variety (H1N1v) virus of a swine origin initially surfaced; it is currently a pandemic [7]. This contradicted the conventional belief that an influenza pandemic is brought on by the advent of a virus with a unique HA subtype. Except for those over 60 years old, there is minimal preexisting cross-reacting humoral immunity in the community, and the new H1N1 virus is antigenically distinct from the prevalent human H1N1 virus [8]. As a result, the human population is already endemic to a universal strain of the influenza subtype H1N1. To put an end to the COVID-19 crisis, several mitigation measures, including face masks, social distancing and even quarantine, have been put into place. Despite this, the possibility of a subsequent human pandemic exists due to the emergence of AIV during COVID-19 [9]. The introduction of AIVs into the naïve population may lead to devastating consequences. However, the virus must circumvent the person-to-person transmission hurdle to become a pandemic after trouncing the barrier between animals and humans. Over the last hundred years, only three AIV subtypes, A/H1, A/H2 and A/H3, gained the potential for transmission between humans. This transmission ensued in the Spanish pandemic (A/H1N1) in 1918, the Asian pandemic (A/H2N2) in 1957, the China pandemic (A/H3N2) in 1968, and the A/H1N1pandemic in 2009 [10]. The expanding emergence of zoonotic AIVs, and the mortality associated with influenza A viruses emphasizes the critical need for the world to be prepared for these pandemics. Initially, it was thought that AIVs could only spread in humans. However, after the initial human cases of the avian H5N1, an increase in the cases of zoonotic incidents appearing from chickens has been reported. Since then, the AIVs’ subtypes A/H5, A/H6, A/H7, A/H9 and A/H10 have also been identified as causing infections in chickens [10]. There is variability in the intensity of the illness caused by different viruses, which is distinguished by symptoms such as encephalitis, conjunctivitis, symptoms such as influenza, and pneumonia linked with the acute respiratory distress syndrome (ARDS). Among all the AIVs, H5N1 and H7N9 are of great concern, as they stand out because of their rate and number of fatalities. The avian influenza A (H5N1) strain can induce inflammatory and cytokine responses in both humans and birds with high mortality rates [11]. H7N9 is a potential influenza pandemic virus as: (i) It is widespread in the poultry market and overcomes host barriers, (ii) it has a reassortment with the local H9N2 and easily becomes adapted to a human host and (iii) at the population level, preexisting neutralizing antibodies are absent.
Genetic reassortment of AIVs has resulted in the occurrence of three pandemic IVs: H2N2, H3N2, and H1N1, which are known to impact the viral infectivity and ability of transmittance to mammals [12,13,14][12][13][14]. The antigenic drift and antigenic shift are two processes by which IVs undergo antigenic modification. Antigenic drift occurs when small mutations in the HA or NA glycoproteins arises due to the host immunity’s selection influence [15]. Antigenic shift occurs when the eight gene segments undergo genetic reassortment to create new HA/NA subtypes, which the general populace of humans has significantly less to no immunological defense against [16]. Understanding how IVs interact with their hosts and how environmental and societal variables affect these interactions is vital in order to respond to the newly developing and reemerging influenza illnesses [17]. Studies on the interactions between hosts and pathogens can assist in understanding the molecular pathogenesis of the disease and in developing the effective preventative and treatment measures against influenza [18,19][18][19].
When an infection is present, the host’s innate immunity acts as the first line of defense and produces pro-inflammatory reactions [20]. Adaptive immunity also plays an essential role in removing viral pathogens during the later stages of infection. Furthermore, during IAV infection, the respiratory mucosal immunity is generated in the associated mucosal tissues and is engaged in an antiviral defense. IAVs have evolved a variety of ways to escape the host defense and can establish an effective infection, despite the presence of several immunological systems to destroy the invading pathogens or to limit viral replication [21]. Therefore, it is crucial to comprehend how the human immune system reacts to AIVs to effectively manage severe H5N1 or H7N9 influenza illness and logically develop novel immunotherapies and vaccines. Understanding the pathogenesis and immunity of AIVs in humans is very important, especially for those strains that overcome the host barrier to infect people [2].

2. Epidemiology of Avian Influenza Viruses

IVs are a significant menace to public health and can cause mild to severe respiratory infections in humans. According to the World Health Organization (WHO), seasonal IVs, including H1N1 and H3N2 IAVs and influenza B viruses, cause around 3–5 million severe cases and 290,000–650,000 fatalities globally each year [22]. Additionally, AIVs such as H5N1, H7N9, and others can lead to many zoonotic infections. Pandemics are triggered when viruses from the animal pool transcend the species hurdle, generally because of an antigenic change during a reassortment stage between an AIV and a human IV. These pandemics can kill millions of people and cause more complications and mortalities than seasonal IV outbreaks [23]. Four hundred and forty years have passed since the “Spanish Influenza” pandemic. During this severe pandemic of 1918, about 500 million (about one-third of the world population) contracted the virus, and between fifty to hundred million people were reported to be killed [24]. Avian H1N1 viruses entered the swine population of Eurasia and were reported to be co-circulating with classical swine flu viruses in 1979 [25]. An H1N1 strain that swept through India in 2015 resulted in around 10,000 incidents and 774 mortalities [24]. Most of the time, pandemics are brought on by viruses with surface glycoproteins such as HA and NA, which, in dealing with, the human immune defense system is not very efficient. This was true in 1918, when most people appeared to be unaware of both the H1 HA and the N1 NA, and in 1957, when people were essentially resistant to both the H2 and N2 viruses. Only the H3 HA was transmitted to people for the first time in 1968, although the N2 of the H3N2 pandemic virus was obtained from the formerly perpetuating H2N2 virus. In 2009, a seasonal strain of the H1N1 virus infected people, but the pandemic strain contained antigenically different H1 and N1 surface glycoproteins [26]. The H3N2 virus became widespread among humans during the 1968 pandemic, and it has been the cause of numerous influenza pandemics ever since. H3N2 viruses have arisen from various sources, including domestic poultry, pigs and wild birds. Dogs have developed severe respiratory illnesses because of some H3N2 viruses that originated in birds. If different lineages of the H3N2 virus were passed on to humans, there would be a possibility of a human influenza pandemic [27]. The first infection due to the highly pathogenic H5N1 subtype was described in China in 1997, and the virus was found out to be of the A/goose/Guangdong/1/1996 lineage (GsGd), which caused 6 fatalities and 18 human infections. Viruses from this lineage caused a human infection again in 2003 [28]. For H5N1 virus infections, there is a human incubation period of 2 to 5 days, and varies up to 17 days [29]. A combined 907 human H5N1 cases were described worldwide between May 1, 1997 and April 30, 2015, of which 94.8% were established cases and 5.2% were possible cases. A total of 16 countries reported human instances between 1997 and 2015. As the illness migrated from East Asia to Southeast Asia, then West Asia, North Africa and other regions, more countries became afflicted between 2003 and 2008. The first human infection attributed to the novel H5N6 virus was identified in China, in April 2014. The outbreak of H5N8 viruses occurred in 2014 among wild birds and several poultries across the globe. In early 2014, many outbreaks amongst domestic ducks and migratory birds were reported in South Korea. As a result of these outbreaks, two subtypes of H5N8 were identified: Buran 2-like and Cochang 1-like. Since then, several episodes of these viruses have been reported in numerous domestic poultries across different continents [33][30]. In December 2020, cases of human infection by the H5N8 influenza virus were reported. Seven poultry workers contracted the virus; they were between 29 and 60 years of age, and included two males and five females [34][31]. The H6 subtype of AIV was first isolated in US in 1965 from a turkey. H6 AIVs were able to infect ducks and chickens, and they circulated in the US’s live poultry market. The H6N1 virus was found in dogs in China in 2014. Its molecular analysis revealed that it is closely related to the H6N1 virus in humans [35][32]. Viruses belonging to the H7 subtype can infect a broad range of species, including wild birds, mammals, seals, pigs, horses and humans. H7 is an LPAIV, which circulates asymptomatically in poultry but evolves as HPAIV, and can cause systemic diseases or even mortality. Humans have been reported to get infected sporadically from poultry. One death during the outbreak of HPAIV H7N7 was reported in the Netherlands in 2003. Three instances of mild H7N7 infections in humans were discovered in 2013 in Italy while observing the employees from the latest H7N7 epidemic at a poultry holding. H7N9 is an LPAIV that emerged in humans and poultry in China in February 2013. This virus also contributed to seasonal waves of zoonotic infections in China. [36][33]. Majority of human infections originated due to contact with poultry and not because of person-to-person transmission [37][34]. Human illnesses caused by H7N9 have been more severe since 2013 than all the prior H7 outbreaks in humans [38][35]. Since March 2013, the A/H7N9 virus has infected 657 individuals with a 38% fatality rate after crossing the host barrier from birds to humans [39][36]. This is unexpected, especially when considering the 1918 Spanish influenza pandemic, which was thought to be exceedingly severe and had a mortality rate of more than 2.5% [40,41,42][37][38][39]. More than 20 million birds were killed in Mexico in 2013 as a consequence of an HPAIV H7N3 virus pandemic and two verified minor human infections. H7N3 viruses have been found in poultry in some countries, including Chile and Canada [43,44,45][40][41][42]. In 1966, the first H9N2 viruses were isolated from turkeys in Wisconsin. This virus has been isolated from domestic ducks and wild birds throughout Eurasia and occasionally from poultry during sporadic outbreaks in the northern United States [46][43]. With the quick differentiation of H9N2 AIVs, more than 102 genotypic variations have been identified using the nomenclature scheme [47][44]. The ubiquity and elevated frequency of the mutation of H9N2 IVs, along with their capability to transmit internal genes to other AIVs and adjustment to the human host, may be key early indicators of the occurrence of new reassortants with pandemic capabilities. H10 AIVs have been isolated from a variety of mammalian and avian species. There have been sporadic reports of influenza infections due to this subtype, although person-to-person transmittance has not been proven. Two infants in Egypt in 2004 and two abattoir workers in Australia in 2010 were found to be infected with the H10 virus during an outbreak of avian influenza among chickens in Australia. It evolved from the internal genes of enzootic H9N2 viruses in chickens and H10 and N8 viruses’ surface genes from household ducks. This resulted in three deadly diseases and two fatalities in people [48,49,50,51,52,53,54,55,56,57,58,59,60][45][46][47][48][49][50][51][52][53][54][55][56][57]. H10 AIVs have also been detected in mink, seals, mammals and pigs [61,62,63,64,65,66,67,68][58][59][60][61][62][63][64][65].

3. Pathogenesis and Clinical Features of Severe Disease

Because the human population is immunologically unprepared for the aggressive HA subtypes, there is a small but significant danger of human-to-human transmission of the AIVs, which might result in a devastating pandemic [69,70][66][67]. An efficient reaction to the H5N1 AI pandemic or any other appearing and re-appearing disease necessitates a thorough interdisciplinary strategy for preparedness [17]. Understanding the relationship between the host and the infection might be helpful in developing better influenza vaccines and antiviral medications. Such investigations will, from the perspective of comparative biology, demonstrate the comparative molecular pathophysiology of the influenza illness and how healthy cellular functions operate [71][68].

3.1. Pathogenesis of AIV Illness in Gallinaceous Birds

HA is a critical factor in avian virulence, but the best internal gene combinations are necessary for maximal virulence expression [72][69]. For an infection to begin in birds, HA must attach to -2,3-galactose linkage cell receptors and prompt receptor-regulated endocytosis. This influences host particularity and cell or tissue reaction. As receptor-binding alterations occur, the variety of hosts that IVs can infect may also vary [73,74,75,76][70][71][72][73]. The distribution of these viruses in the tissues is determined by this breakdown pattern [74,77][71][74]. However, after an intranasal infection, H7N1 LPAIV RNA was found in organs other than the respiratory and digestive systems, demonstrating that the virus travels systemically [78][75]. Within 16 h of intranasal contact, the HPAIVs multiply in nasal epithelial cells. Within 24 h, they reach visceral organs, and by 48 h, the virus titers may shoot up to the maximum, leading to severe lesions in several visceral organs [79][76]. The capacity of HPAIVs to reproduce in macrophages, heterophils, and endothelial cells is crucial for the virus’ ability to move to other organs via the lymphatic and circulatory systems, where it multiplies in parenchymal cells [79,80,81][76][77][78].

3.2. Pathogenesis of AIV Illness in Non-Gallinaceous Birds

The current Eurasian-origin HPAI H5N1 viruses connected to the Gs/Gd virus target many hosts [82][79]. Additionally, they can cause mild to severe illnesses in non-gallinaceous birds. Several aquatic and terrestrial wild bird species have been observed to perish since 2002 as a result of the Eurasian-African H5N1 HPAIV infection [83,84,85,86][80][81][82][83]. Ten separate genetic lineages (clades 0 to 9) and various sub-lineages (e.g., 2.1.1, 2.1.2, 2.3.4.4, and others) have emerged in the H5N1 HPAIVs of the Eurasian-African lineage. For a range of bird species, these various influenza viruses have demonstrated distinct clinical traits and enhanced pathogenicity [79][76]. For instance, the HPAI H5N8 virus (clade 2.3.4.6) kills a lot of Baikal teals, quails, and bean geese; however, it has no symptoms in mallard ducks [85,87,88][82][84][85]. Additionally, these H5 HPAI lineages reproduce in more significant titers, which help the virus spread to the vulnerable wild duck population [85,87,88][82][84][85]. A similar viral pathogenesis occurs in both ducks and chickens, except for ducks, which have neither viral replication in the endothelium nor any accompanying endothelium lesions [89][86].

3.3. Pathogenesis of AIV (H5N1) Infection in People

If the H5N1 virus mutagenically transforms into a form that transmits amidst people, a pandemic of the highly deadly infectious illness H5N1 avian influenza may ensue. The lungs of infected individuals usually experience diffuse alveolar destruction, bleeding, and infection, specifically in isolated lung epithelial cells. The virus might additionally affect other organs such as the trachea, intestines, and brain [90][87], in addition to have the ability to pass across the placental hurdle and affecting the fetus [91][88]. In addition to the viral replication in humans, the irregular modulation of cytokines and chemokines might have a significant function in the pathogenesis of the H5N1 influenza. Other factors, including elevated levels of the apoptosis-inducing ligand, TNF-related apoptosis-inducing ligand (TRAIL) and lower cytotoxicity of CD8+ cells, are also suspected to be engaged. However, it is still unclear how exactly they lead to the infectivity of the H5N1 influenza. Numerous studies suggest that the pathophysiology of the H5N1 influenza may be significantly influenced by the abnormal production of proinflammatory cytokines and chemokines. In H5N1 autopsy cases, pathological characteristics that are associated with cytokine and chemokine dysregulation, such as hemophagocytic activity, have been observed [92,93,94][89][90][91]. Proinflammatory cytokines and chemokines have been found in significant amounts in the serum of several H5N1 patients [92,95,96][89][92][93]. The results of in vitro tests also confirm that an exacerbated immune response plays a part in the infectivity of the H5N1 influenza. In comparison to human influenza viruses, H5N1 avian influenza viruses dramatically increase the production of several cytokines and chemokines in human macrophages and respiratory epithelial cells [97,98,99][94][95][96]. The increased cytokine and chemokine production in the supernatants from the infected cells indicates the increased expression in these tests. In addition to their potential to upregulate cytokines and chemokines, H5N1 viruses may also be able to resist the antiviral effects of interferons and TNF-α [100][97]. Stimulating a functional TRAIL in H5N1 influenza virus-affected macrophages may play a substantial role in the pathogenesis of this illness. TRAIL is one of the several death receptor ligands that bind to the receptors for death receptor ligands produced on target cells, inducing cell apoptosis [101][98]. In Zhou and colleagues’ study, the TNF and TRAIL expression was demonstrated to be much higher in macrophages affected with the H5N1 IV in vitro compared to macrophages affected with the human H1N1 IV [101][98]. Furthermore, it has also been demonstrated that virus-infected T cells are more sensitive to the ligand-induced apoptosis. Both TRAIL sensitization and up-regulation may partially explain the lymphopenia and lung damage typically observed in H5N1 patients. Additionally, compared to H1N1-infected macrophages, it has been described in vitro that H5N1-infected macrophages exhibit a delayed beginning of apoptosis [102][99]. The longer lifespan of the affected macrophages further stimulates the apoptosis of T cells. The extended duration of the cytokine and chemokine production by macrophages may contribute to an increase in the immune-mediated illness. Human autopsies have revealed that leukocytes and alveolar epithelial cells all experience apoptosis in the lungs, spleen and intestinal organs [103][100]. Therefore, apoptosis could be one of the pathogenic pathways causing damage to the lungs and other organs. Apoptosis may be brought on by direct viral multiplication and the stimulation of the production of cytokines and chemokines. In humans and mice, a severe infection with avian IAVs is characterized by significant lymphopenia [104,105][101][102]. In one of the studies, it was demonstrated that the mice infected with the lethal H5N1 strain had higher amounts of plasmacytoid DCs (pDCs) expressing the Fas ligand (FasL), which caused the death of CD8+ T cells specific for influenza via a Fas-FasL-mediated pathway; the mice inoculated with the non-lethal H5N1 strain did not exhibit this [106][103]. Furthermore, it was demonstrated that mice infected with the lethal H5N1 virus accumulated more pDCs than other DC subsets in the lymph nodes (LNs) that drain into the lungs, and that the rise in FasL expression on pDCs was accompanied by elevated levels of the IL-12p40 monomer/homodimer in these LNs. The findings implied that pDCs exhibited a negative function in one of the lymphopenia-related pathways of the deadly H5N1 virus infection. In vitro findings also demonstrate that the HAs of H5N1 viruses decrease perforin activity in cytotoxic T cells, in contrast to H1N1 and H3N2 viruses [107,108][104][105]. This may result in a diminished cytotoxic function preventing the clearance of cells, such as the antigen-presenting cells (APCs) that carry the H5N1 virus or the HA (H5) protein. The chronic antigenic stimulation of cytotoxic T cells that causes excessive IFN production may also stimulate macrophages to produce proinflammatory cytokines more aggressively, which might further amplify the immune response in influenza patients.

3.4. Clinical Findings of H5N1 Infection

H5N1, which causes a variety of ailments, including severe and deadly respiratory conditions, can be challenging to diagnose. Despite the prevalence of some less severe illnesses, the hospitalization of patients with severe diseases has also been reported, aggravated by ARDS and multi-organ failure [30][106]. High viral loads, lymphopenia, exceptionally elevated circulatory levels of the IFN-inducible protein-10 (IP-10) and elevated levels of inflammatory cytokines and chemokines have all been linked to fatal outcomes in H5N1-infected patients [109,110][107][108]. Hemophagocytosis has also been observed in patients with a severe H5N1 infection [111][109]. Sputum production can occasionally be bloody, and it fluctuates in quantity. Radiographic changes include segmental or lobular consolidation with air bronchograms; diffuse, multifocal, or patchy infiltrates; and clinically apparent pneumonia in almost all instances [112][110]. Multi-organ failure has frequently been noted, together with symptoms of kidney malfunction and occasionally cardiac dilatation and supraventricular tachyarrhythmia [112,113,114][110][111][112]. In 1997, China had the foremost human epidemic of the avian influenza A (H5N1) virus. Six people who had the infection were proven dead. Without a middle host, infections were directly transferred from chickens to people. Asymptomatic illnesses to deadly pneumonitis and multiple organ failure are all within the clinical range of H5N1 infection. The most common pathologic finding was a reactive hemophagocytic syndrome, which may have led to lymphopenia, liver failure and aberrant clotting. The epidemic management benefited greatly from a quick diagnosis, which was made possible by a reverse-transcription polymerase chain reaction (RT-PCR) and a monoclonal antibody-based immunofluorescent test [113][111]. As per the examination of the case notes of 12 individuals with an H5N1 infection, confirmed by viral culture by an investigation in February 1998, seven individuals had a pneumonia-like disease with a clinical presentation resembling the flu [115][113]. Pancytopenia, elevated liver enzymes, and gastrointestinal symptoms were notably evident. Furthermore, for the quick identification of viruses in respiratory specimens, an H5-specific RT-PCR test proved effective. A widely available enzyme immunoassay for quick viral diagnosis proved more accurate than direct immunofluorescence. In addition, for the immediate exclusion of H5-subtype illness, direct immunofluorescence using a pool of monoclonal antibodies specific to H5 also proved effective.

3.5. Clinical Findings in H7N9 Infection

Rapidly progressing pneumonia brought on by H7N9 infection in humans is accompanied by leukopenia, lymphopenia and significantly elevated blood cytokine and chemokine concentrations [45][42]. In a case study of 111 patients, 97.3% of patients with avian H7N9 infections had pneumonia and 88.3% had lymphopenia, and in other cases in a series of 216 patients, it was reported that 61.3% of patients were taken to intensive care [5,116,117][5][114][115]. During the severe phase of infection, neutrophil-related immunity and the cell cycle was activated, while T cell processes were stimulated during the recovery period. In eight patients, the transcriptional profiling revealed the similar results, while mechanical ventilation or extracorporeal membrane oxidation was required for each of them [118][116]. During seasonal influenza epidemics, hospitalization rates for older adults were higher [48][45]. Children and young people spend more time in hospitals [2]. Males older than 60 demonstrated signs of a more severe illness during the initial wave of H7N9 infections [119][117]. Aging causes immunosenescence in the innate and adaptive immunological systems, which reduces the body’s ability to respond to the influenza infection and vaccination [120][118]. Some of the clinical and pathological characteristics of the severe A/H7N9 sickness brought on by the AIV infections included leukopenia, lymphopenia, viral spread in extra-pulmonary locations, extended viral discharge of H7N9 viral RNA in feces and urine, and multiple organ failure [121,122][119][120]. Indeed, in patients with H5N1 infection, large virus levels were also linked to death [123][121], while a reduced viral load during the latest H7N9 epidemic was linked to recuperation [2]. Pneumonia and ARDS are the frequent causes of AIV fatalities [123][121]. The hospitalized patients exhibit symptoms of viral pneumonia and bacterial co-infections [124][122]. However, patients in hospitals receive broad-spectrum antibiotic therapy [125][123], which makes detecting bacterial co-infection difficult. Type I/II diabetes and hypertension were prevalent among the hospitalized reports of illness due to the H7N9 influenza [126][124]. Interestingly, young infants with confirmed instances of H5N1 and H7N9 infections showed mild influenza symptoms [127][125]. Clinically, the children had a fever, but no ARS-related signs, such as pulmonary edema, were observed, which more specifically includes aging-related alterations to the immune system.

3.6. Clinical Findings in H5N6 Infection

The first severe avian influenza infection in humans with an H5N6 virus was found in China in 2014. The virological and clinical effects of a fatal H5N6 virus infection in a human patient were demonstrated in a 2015 investigation. The patient, who had a fever, acute pneumonia and lymphopenia at the beginning of the illness, went into septic shock and had ARDS, and succumbed on the 10th day of the disease [128][126]. The patient’s trachea or throat swab was used to isolate a unique reassortant H5N6 virus. Multiple basic amino acids were present at the cleavage location of the HA gene, demonstrating the high infectivity of the new H5N6 virus in chickens. Recently, an investigation also presented the first severe H5N6 virus-induced case of acute encephalitis with moderate pneumonia. A 6-year-old girl was taken to the hospital on January 25, 2022 with severe neurological symptoms, which quickly progressed to seizures and coma. Imaging of the brain revealed anomalies. Laboratory tests demonstrated that the serum’s transaminases, lactate dehydrogenase, and cytokines were unusually increased. From the patient’s blood, CSF, and tracheal aspirate samples, a unique reassortant H5N6 virus was found. According to a phylogenetic study, this virus, which belonged to the clade 2.3.4.4b, was a unique reassortant influenza A H5N6 virus of an avian origin. An epidemiological examination established that the direct source of the virus, in this instance, was wild ducks [129][127].

3.7. Clinical Findings in H7N2 Infection

An immunocompromised male with a fever and community-acquired pneumonia was found to be infected with a low pathogenic avian influenza A (H7N2) virus in New York, NY, USA, in 2003. The patient’s early complaints were related to ophthalmological symptoms. The fact that the examinations were carried out five months after the patient was admitted to the hospital, after which the influenza A isolate was recognized as an LPAI A H7N2 virus, was a study restriction. In addition, the patient’s medical history and clinical results were in accordant with an HIV infection and the community-acquired pneumonia, with a potential improvement from viral pneumonia or a clinical response to the antimicrobial medication therapy [130][128].

3.8. Clinical Findings in H7N7 Infection

A case of an HPAI H7N7 virus subtype first appeared in widespread poultry farms in the Netherlands around the end of February 2003. An epidemic investigation was initiated to determine the degree of the IAV subtype H7N7 transmission from chickens to people, even though the danger of transmission to humans was previously believed to be minimal. A total of 453 persons reported having health issues, including 90 cases of influenza-like sickness, 349 reports of conjunctivitis and 6 other complaints. The study found A/H7 in conjunctival samples from seventy-eight individuals who only had conjunctivitis, five individuals who also had influenza-like illness and conjunctivitis, two individuals who just had the influenza-like disease, and four individuals who reported additional symptoms. Out of eighty-three contacts screened, three had the A/H7 infection, and one became sick with the flu. Six people were infected with influenza A/H3N2. All employees who encountered the diseased persons were mandated to undergo the influenza virus vaccination and oseltamivir preventive therapy after 19 persons had been diagnosed with the infection. The A/H7 infections that were reported here made up more than half of the cases in the vaccination and treatment program [131][129]. The findings highlighted the significance of effective surveillance, outbreak readiness, and pandemic preparation.

3.9. Clinical Findings in H7N3 Infection

In 2004, poultry in British Columbia, Canada, experienced an epidemic of the highly virulent AI H7N3 virus. Even while the improved surveillance found 57 people who fit the criterion of a suspected case, only two were found to have an AI infection. Conjunctivitis and a mild influenza-like sickness were among the symptoms experienced by the two patients. There were no HA inhibition or serum-neutralizing antibody responses in either of the two verified cases. A highly localized infection without the production of systemic antibodies was projected to be one cause for such an observation. However, in suspected instances, respiratory symptoms were more common than conjunctival symptoms. The genomic sequences of the two avian viruses from the source farms of the human isolates were consistent with the HPAIV, while one of the human isolates’ genomic sequences was compatible with the LPAIV. The existence of an insertion sequence in the human LPAIV isolate suggested that the HPAIV in poultry underwent a mutation to become the LPAIV, both of which were undetected when circulating among the birds on the source farm in question. The possibility that the human who died underwent a mutation from HPAIV to LPAIV was a less plausible scenario [132][130].

3.10. Clinical Findings in H3N2 Infection

A sporadic person-to-person transmission of swine H3N2 viruses that caused a mild influenza-like disease was reported in children in 2011. The condition was found to be brought on by the triple reassortant influenza A (H3N2) virus that occurred from swine carrying the matrix (M) gene from the pandemic 2009 influenza A (H1N1) virus. These viruses were regarded as the reassortant between a pH1N1 virus and an influenza A H3N2 virus originating among North American swine. None of the H3N2 virus-infected children needed hospitalization, and they all fully recovered after a brief episode of febrile respiratory illness [133][131].

4. Diagnosis of Avian Influenza Virus

The diagnosis of AI involves the integration of traditional approaches with developing technologies that are quickly evolving. Selection of a diagnostic tool may be based on variety of factors, including its suitability for the motive, technical simplicity, speed, diagnostic sensitivity and expense. Tests for the precise detection of the AI virus fall into two categories: those that demonstrate the virus directly and those that demonstrate the virus exposure indirectly by detecting a particular antibody. Direct detection involves both traditional viral infection culture and the use of quicker, more efficient methods that may identify certain viral antigens or nucleic acids such as the PCR assay, or the isolation of the virus in a cell culture.

5. Immune Response to Avian Influenza Viruses

The main goal of an immunological response is to identify and get rid of the infection. Vertebrates have an immune system composed of two functional components, the innate and the adaptive, which vary in terms of how quickly they respond to pathogens and how they recognize them [162,163][132][133]. Pattern recognition receptors (PRRs) are germline-encoded receptors that identify pathogen-associated molecular patterns (PAMPs) present on infectious microorganisms, which have evolved with conserved molecular markers. These receptors are utilized in the initial responses of the innate immune system [162,164,165][132][134][135]. On the other hand, highly specialized antigen receptors, created randomly by gene rearrangement on T cells and B lymphocytes, are used by the more sophisticated adaptive immune responses [164,166][134][136]. The innate immunological response activates the adaptive immunological response and also affects the type of response. The host’s immune response is imperative in understanding the pathogenesis of diseases caused by viruses and is the foundation for the creation of control measures [5]. The immune system’s response to illness with the AIVs and susceptibility to illness vary greatly among chicken species. The immunological mechanisms behind AIV resistance or susceptibility in avian species are unclear and likely rely on some variables, including but not limited to host genetics, isolate pathogenicity, infection dosage and bird immune state. Because the virus can harm the host so quickly and has evolved to modulate the host’s innate immune response, the virus is challenging for the immune system to combat. AIV also exhibits a high mutation frequency and the capacity to rearrange gene segments, which enable the virus to quickly change its antigenic makeup and escape the immune system’s adaptive response [167][137]. While a robust immune response is necessary for successful viral suppression, it must be finely controlled, since both in human and animal models an excessive and/or exaggerated inflammatory response has been linked to the worsening of tissue damage. The H5N1 virus such as H7N9 is of avian origin and generates a severe clinical presentation with a high death rate. The H5N1 virus is a good example of this double-edged effect. A “cytokine storm”, or the dysregulated rise of proinflammatory cytokines linked to H5N1 infections, is thought to be the primary factor contributing to the infection’s broad pulmonary tissue destruction [100,168][97][138]. The interleukin-6 (IL-6), interferon (IFN), tumor necrosis factor (TNF), and chemokines are examples of pro-inflammatory cytokines whose levels are markedly elevated during influenza virus infection [169][139]. The primary innate immune defense mechanism against viral infections depends on the degree of IFN production, and IFN is crucial in the early stages of the antiviral response [170,171][140][141]. When IFN production is dysregulated, it leads to inhibition of virus replication through the generation of antiviral mediators and exacerbation of the immunopathological destruction. Depending on the timing and intensity of the infection, there may be positive or negative outcomes due to these immune responses [172][142]. In addition, monocytes/macrophages and neutrophils are the primary innate immune cells engaged into the alveoli in the early phase of the infection following a viral infection [173][143]. In addition to being able to phagocytose the infected target cells, monocytes and macrophages can also differentiate into several subtypes that can release various cytokines. The most prevalent macrophage subtypes are classically activated macrophages (M1) and alternatively activated macrophages (M2) [174][144]. Depending on their quantities and maintenance times, pro-inflammatory cytokines secreted by polarized M1 cells early in an infection may have protective or immunopathological consequences [175][145]. M2 cells are involved in tissue healing and reducing inflammation. It has been observed that the ratio of M1 to M2 fluctuates continually until the pathogen is totally eradicated and the tissue healing approaches homoeostasis [176][146]. Four sources add to our current comprehension of the immunological response to AIVs, i.e., extrapolation from the knowledge of seasonal influenza viruses, information from in vitro investigations and animal models using AIVs, and analysis of the immunological reactions in patients infected with AIVs. By identifying PAMPs by PRRs, the innate immune system can identify viral illnesses. At least three different kinds of PRRs can detect influenza virus infection: TLRs, retinoic acid-induced gene I (RIG-I)-like receptors and nucleotide oligomerization domain (NOD)-like receptors [177][147].

6. Vaccine Development

It is evident that a continuous threat to world health is posed by illnesses that can spread from animal pools. IAVs have a variety of characteristics that make them a universal hazard. Because of the human population’s lack of immunological knowledge about these viruses, their subdivided genome and mistake-susceptible replication mechanism might result in the generation of new reassortant viruses [273,274,275,276,277][148][149][150][151][152]. Additionally, the fact that IAVs may spread to people, domestic animals and aquatic birds raises the possibility of reassortment and the eventual creation of new viruses. Vaccination is an effective methodology to circumvent the development of AIV infections. Seasonal flu vaccinations are safe and lessen the severity of yearly flu outbreaks. New influenza vaccinations are being developed to be prepared for potential pandemic IAV outbreaks in the future. It is possible to identify novel viral targets for vaccine development using the knowledge of the immune responses particular to influenza [278][153]. It may be useful to gain insights into the immune responses particular to influenza to identify new viral targets for vaccine development. Most of the vaccines used to date target the viral surface hemagglutinin (HA). The vaccines need to be updated, as the surface HA mutate easily via reassortments or antigenic drifts. Alternative approaches have been investigated due to the drawbacks of the traditional method of cultivating the virus in specific-pathogen-free embryonated hen eggs and a relatively new method of the cell culture of a virus to produce a vaccine. It has been demonstrated that recombinant HA-based vaccines can induce neutralizing antibodies against AIV. However, antibodies induced by a specific strain or subtype of the influenza virus are mostly ineffective in neutralizing other strains or subtypes. Due to the virus’s constant mutations, vaccines also needed to be updated after a certain period. Therefore, researchers are directing their efforts towards the development of universal influenza vaccines (UIVs) possessing a broad spectrum for neutralizing various influenza subtypes or strains [55][52].

References

  1. Yoon, S.W.; Webby, R.J.; Webster, R.G. Evolution and ecology of influenza a viruses. Curr. Top. Microbiol. Immunol. 2014, 385, 359–375.
  2. Wang, Z.; Loh, L.; Kedzierski, L.; Kedzierska, K. Avian influenza viruses, inflammation, and CD8+ T cell immunity. Front. Immunol. 2016, 7, 60.
  3. Verhagen, J.H.; Fouchier, R.A.M.; Lewis, N. Highly pathogenic avian influenza viruses at the wild–domestic bird interface in europe: Future directions for research and surveillance. Viruses 2021, 13, 212.
  4. Bao, P.; Liu, Y.; Zhang, X.; Fan, H.; Zhao, J.; Mu, M.; Li, H.; Wang, Y.; Ge, H.; Li, S.; et al. Human infection with a reassortment avian influenza A H3N8 virus: An epidemiological investigation study. Nat. Commun. 2022, 13, 6817.
  5. Koutsakos, M.; Kedzierska, K.; Subbarao, K. Immune Responses to Avian Influenza Viruses. J. Immunol. 2019, 202, 382–391.
  6. Peiris, J.S.M.; De Jong, M.D.; Guan, Y. Avian influenza virus (H5N1): A threat to human health. Clin. Microbiol. Rev. 2007, 20, 243–267.
  7. Emergence of a Novel Swine-Origin Influenza A (H1N1) Virus in Humans. N. Engl. J. Med. 2009, 360, 2605–2615.
  8. Centers for Disease Control and Prevention (CDC) Serum cross-reactive antibody response to a novel influenza A (H1N1) virus after vaccination with seasonal influenza vaccine. Morb. Mortal. Wkly. Rep. 2009, 58, 521–524.
  9. Ye, Y.; Ye, Z.; Yang, L.; Xiang, B.; Zheng, C. Unignorable public health risk of avian influenza virus during COVID-19 pandemic. J. Med. Virol. 2022, 94, 4058–4060.
  10. de Vries, R.D.; Herfst, S.; Richard, M. Avian influenza A virus pandemic preparedness and vaccine development. Vaccines 2018, 6, 46.
  11. Goraya, M.U.; Ali, L.; Younis, I. Innate Immune Responses Against Avian Respiratory Viruses. Hosts Viruses 2017, 4, 78–87.
  12. Sun, Y.; Qin, K.; Wang, J.; Pu, J.; Tang, Q.; Hu, Y.; Bi, Y.; Zhao, X.; Yang, H.; Shu, Y.; et al. High genetic compatibility and increased pathogenicity of reassortants derived from avian H9N2 and pandemic H1N1/2009 influenza viruses. Proc. Natl. Acad. Sci. USA 2011, 108, 4164–4169.
  13. Zhang, Y.; Zhang, Q.; Kong, H.; Jiang, Y.; Gao, Y.; Deng, G.; Shi, J.; Tian, G.; Liu, L.; Liu, J.; et al. H5N1 hybrid viruses bearing 2009/H1N1 virus genes transmit in guinea pigs by respiratory droplet. Science 2013, 340, 1459–1463.
  14. Lowen, A.C. Constraints, Drivers, and Implications of Influenza A Virus Reassortment. Annu. Rev. Virol. 2017, 4, 105–121.
  15. Shoham, D. The Modes of Evolutionary Emergence of Primal and Late Pandemic Influenza Virus Strains from Viral Reservoir in Animals: An Interdisciplinary Analysis. Influenza Res. Treat. 2011, 2011, 861792.
  16. Taubenberger, J.K.; Morens, D.M. Influenza: The once and future pandemic. Public Health Rep. 2010, 125, 15–26.
  17. Fauci, A.S. Emerging and re-emerging infectious diseases: Influenza as a prototype of the host-pathogen balancing act. Cell 2006, 124, 665–670.
  18. Oldstone, M.B.A.; Teijaro, J.R.; Walsh, K.B.; Rosen, H. Dissecting influenza virus pathogenesis uncovers a novel chemical approach to combat the infection. Virology 2013, 435, 92–101.
  19. Herold, S.; Becker, C.; Ridge, K.M.; Budinger, G.R.S. Influenza virus-induced lung injury: Pathogenesis and implications for treatment. Eur. Respir. J. 2015, 45, 1463–1478.
  20. Wei, H.; Wang, S.; Chen, Q.; Chen, Y.; Chi, X.; Zhang, L.; Huang, S.; Gao, G.F.; Chen, J.L. Suppression of Interferon Lambda Signaling by SOCS-1 Results in Their Excessive Production during Influenza Virus Infection. PLoS Pathog. 2014, 10, e1003845.
  21. Chen, X.; Liu, S.; Goraya, M.U.; Maarouf, M.; Huang, S.; Chen, J.L. Host immune response to influenza A virus infection. Front. Immunol. 2018, 9, 320.
  22. Influenza. Available online: https://www.who.int/ (accessed on 25 November 2022).
  23. Bay, A.; Etlik, Ö.; Öner, A.F.; Ünal, Ö.; Arslan, H.; Bora, A.; Davran, R.; Yuca, S.A.; Dogan, M. Radiological and clinical course of pneumonia in patients with avian influenza H5N1. Eur. J. Radiol. 2007, 61, 245–250.
  24. Yang, R.; Sun, H.; Gao, F.; Luo, K.; Huang, Z.; Tong, Q.; Song, H.; Han, Q.; Liu, J.; Lan, Y.; et al. Human infection of avian influenza A virus and the viral origins: A descriptive study. Lancet Microbe 2022, 3, e824–e834.
  25. Trinh, T.T.T.; Duong, B.T.; Nguyen, A.T.V.; Tuong, H.T.; Hoang, V.T.; Than, D.D.; Nam, S.; Sung, H.W.; Yun, K.J.; Yeo, S.J.; et al. Emergence of novel reassortant h1n1 avian influenza viruses in Korean wild ducks in 2018 and 2019. Viruses 2021, 13, 30.
  26. Krammer, F.; Smith, G.J.D.; Fouchier, R.A.M.; Peiris, M.; Kedzierska, K.; Doherty, P.C.; Palese, P.; Shaw, M.L.; Treanor, J.; Webster, R.G.; et al. Influenza. Nat. Rev. Dis. Prim. 2018, 4, 4.
  27. Guan, L.; Shi, J.; Kong, X.; Ma, S.; Zhang, Y.; Yin, X.; He, X.; Liu, L.; Suzuki, Y.; Li, C.; et al. H3N2 avian influenza viruses detected in live poultry markets in China bind to human-type receptors and transmit in guinea pigs and ferrets. Emerg. Microbes Infect. 2019, 8, 1280–1290.
  28. Sutton, T.C. The pandemic threat of emerging H5 and H7 avian influenza viruses. Viruses 2018, 10, 461.
  29. WHO. Avian and Other Zoonotic Influenza. 2018. Available online: https://www.who.int/news-room/fact-sheets/detail/influenza-(avian-and-other-zoonotic) (accessed on 25 November 2022).
  30. Cui, P.; Zeng, X.; Li, X.; Li, Y.; Shi, J.; Zhao, C.; Qu, Z.; Wang, Y.; Guo, J.; Gu, W.; et al. Genetic and biological characteristics of the globally circulating H5N8 avian influenza viruses and the protective efficacy offered by the poultry vaccine currently used in China. Sci. China Life Sci. 2022, 65, 795–808.
  31. Pyankova, O.G.; Susloparov, I.M.; Moiseeva, A.A.; Kolosova, N.P.; Onkhonova, G.S.; Danilenko, A.V.; Vakalova, E.V.; Shendo, G.L.; Nekeshina, N.N.; Noskova, L.N.; et al. Isolation of clade 2.3.4.4b A(H5N8), a highly pathogenic avian influenza virus, from a worker during an outbreak on a poultry farm, Russia, December 2020. Eurosurveillance 2021, 26, 2100439.
  32. Wu, H.; Yang, F.; Liu, F.; Lu, R.; Peng, X.; Chen, B.; Yao, H.; Wu, N. Isolation and characterization of novel reassortant H6N1 avian influenza viruses from chickens in Eastern China. Virol. J. 2018, 15, 164.
  33. Wu, X.; Xiao, L.; Li, L. Research progress on human infection with avian influenza H7N9. Front. Med. 2020, 14, 8–20.
  34. Liu, W.J.; Tan, S.; Zhao, M.; Quan, C.; Bi, Y.; Wu, Y.; Zhang, S.; Zhang, H.; Xiao, H.; Qi, J.; et al. Cross-immunity against avian influenza a (H7N9) virus in the healthy population is affected by antigenicity-dependent substitutions. J. Infect. Dis. 2016, 214, 1937–1946.
  35. Naguib, M.M.; Verhagen, J.H.; Mostafa, A.; Wille, M.; Li, R.; Graaf, A.; Järhult, J.D.; Ellström, P.; Zohari, S.; Lundkvist, Å.; et al. Global patterns of avian influenza A (H7): Virus evolution and zoonotic threats. FEMS Microbiol. Rev. 2019, 43, 608–621.
  36. Li, Q.; Zhou, L.; Zhou, M.; Chen, Z.; Li, F.; Wu, H.; Xiang, N.; Chen, E.; Tang, F.; Wang, D.; et al. Epidemiology of Human Infections with Avian Influenza A(H7N9) Virus in China. N. Engl. J. Med. 2014, 370, 520–532.
  37. Taubenberger, J.K.; Morens, D.M. Influenza revisited. Emerg. Infect. Dis. 2006, 12, 1–2.
  38. Taubenberger, J.K.; Morens, D.M. 1918 Influenza: The mother of all pandemics. Emerg. Infect. Dis. 2006, 12, 15–22.
  39. Zhao, M.; Chen, J.; Tan, S.; Dong, T.; Jiang, H.; Zheng, J.; Quan, C.; Liao, Q.; Zhang, H.; Wang, X.; et al. Prolonged Evolution of Virus-Specific Memory T Cell Immunity after Severe Avian Influenza A (H7N9) Virus Infection. J. Virol. 2018, 92, e01024-18.
  40. Centers for Disease Control and Prevention (CDC) Notes from the field: Highly pathogenic avian influenza A (H7N3) virus infection in two poultry workers--Jalisco, Mexico, July 2012. Morb. Mortal. Wkly. Rep. 2012, 61, 726–727.
  41. Sekine, W.; Takenaka-Uema, A.; Kamiki, H.; Ishida, H.; Matsugo, H.; Murakami, S.; Horimoto, T. Adaptation of the H7N2 Feline Influenza Virus to Human Respiratory Cell Culture. Viruses 2022, 14, 1091.
  42. Terebuh, P.; Adija, A.; Edwards, L.; Rowe, T.; Jenkins, S.; Kleene, J.; Fukuda, K.; Katz, J.M.; Bridges, C.B. Human infection with avian influenza A(H7N2) virus—Virginia, 2002. Influenza Other Respi. Viruses 2018, 12, 529–532.
  43. Peacock, T.P.; James, J.; Sealy, J.E.; Iqbal, M. A global perspective on h9n2 avian influenza virus. Viruses 2019, 11, 620.
  44. Bi, Y.; Lu, L.; Li, J.; Yin, Y.; Zhang, Y.; Gao, H.; Qin, Z.; Zeshan, B.; Liu, J.; Sun, L.; et al. Novel genetic reassortants in H9N2 influenza A viruses and their diverse pathogenicity to mice. Virol. J. 2011, 8, 505.
  45. Pu, J.; Wang, S.; Yin, Y.; Zhang, G.; Carter, R.A.; Wang, J.; Xu, G.; Sun, H.; Wang, M.; Wen, C.; et al. Evolution of the H9N2 influenza genotype that facilitated the genesis of the novel H7N9 virus. Proc. Natl. Acad. Sci. USA 2015, 112, 548–553.
  46. Liu, M.; Li, X.; Yuan, H.; Zhou, J.; Wu, J.; Bo, H.; Xia, W.; Xiong, Y.; Yang, L.; Gao, R.; et al. Genetic diversity of avian influenza A (H10N8) virus in live poultry markets and its association with human infections in China. Sci. Rep. 2015, 5, 7632.
  47. Ma, C.; Lam, T.T.-Y.; Chai, Y.; Wang, J.; Fan, X.; Hong, W.; Zhang, Y.; Li, L.; Liu, Y.; Smith, D.K.; et al. Emergence and Evolution of H10 Subtype Influenza Viruses in Poultry in China. J. Virol. 2015, 89, 3534–3541.
  48. Guan, M.; Hall, J.S.; Zhang, X.; Dusek, R.J.; Olivier, A.K.; Liu, L.; Li, L.; Krauss, S.; Danner, A.; Li, T.; et al. Aerosol Transmission of Gull-Origin Iceland Subtype H10N7 Influenza A Virus in Ferrets. J. Virol. 2019, 93, e00282-19.
  49. Horwood, P.F. Avian influenza H5N1: Still a pandemic threat? Microbiol. Aust. 2021, 42, 152–155.
  50. Hamid, S.; Arima, Y.; Dueger, E.; Konings, F.; Bell, L.; Lee, C.-K.; Luo, D.; Otsu, S.; Olowokure, B.; Li, A.; et al. From H5N1 to HxNy: An epidemiologic overview of human infections with avian influenza in the Western Pacific Region, 2003–2017. West. Pacific Surveill. Response J. 2018, 9, 53.
  51. Tosh, C.; Nagarajan, S.; Murugkar, H.V.; Jain, R.; Behera, P.; Katare, M.; Kulkarni, D.D.; Dubey, S.C. Phylogenetic evidence of multiple introduction of H5N1 virus in Malda district of West Bengal, India in 2008. Vet. Microbiol. 2011, 148, 132–139.
  52. Gomaa, M.R.; El Rifay, A.S.; Zeid, D.A.; Elabd, M.A.; Elabd, E.; Kandeil, A.; Shama, N.M.A.; Kamel, M.N.; Marouf, M.A.; Barakat, A.; et al. Incidence and seroprevalence of avian influenza in a cohort of backyard poultry growers, Egypt, August 2015-March 2019. Emerg. Infect. Dis. 2020, 26, 2129–2136.
  53. Spackman, E.; Pantin-Jackwood, M.J.; Kapczynski, D.R.; Swayne, D.E.; Suarez, D.L. H5N2 Highly Pathogenic Avian Influenza Viruses from the US 2014-2015 outbreak have an unusually long pre-clinical period in turkeys. BMC Vet. Res. 2016, 12, 260.
  54. Yang, L.; Zhao, X.; Li, X.; Bo, H.; Li, D.; Liu, J.; Wang, D. Case report for human infection with a highly pathogenic avian influenza A(H5N6) virus in Beijing, China 2019. Biosaf. Health 2020, 2, 49–52.
  55. Xiao, C.; Xu, J.; Lan, Y.; Huang, Z.; Zhou, L.; Guo, Y.; Li, X.; Yang, L.; Gao, G.F.; Wang, D.; et al. Five Independent Cases of Human Infection with Avian Influenza H5N6—Sichuan Province, China, 2021. China CDC Wkly. 2021, 3, 751–756.
  56. Shi, W.; Gao, G.F. Emerging H5N8 avian influenza viruses. Science 2021, 372, 784–786.
  57. European Centre for Disease Prevention and Control. Threat Assessment Brief: First Identification of Human Cases of Avian Influenza ) Infection; European Centre for Disease Prevention and Control: Stockholm, Sweden, 2021.
  58. Attaran, H.; Jin, W.; Luo, J.; Wang, C.; He, H.; He, H.; Attaran, H. Isolation and characterizations of a novel H6N1 avian influenza virus from Von Schrenck’s Bittern (Ixobrychus eurhythmus) in Jiangxi province, China. bioRxiv Mol. Biol. 2021, 2021-06.
  59. Poirot, E.; Levine, M.Z.; Russell, K.; Stewart, R.J.; Pompey, J.M.; Chiu, S.; Fry, A.M.; Gross, L.; Havers, F.P.; Li, Z.N.; et al. Detection of avian influenza A(H7N2) virus infection among animal shelter workers using a novel serological approach-New York City, 2016–2017. J. Infect. Dis. 2019, 219, 1688–1696.
  60. Uyeki, T.M.; Peiris, M. Novel Avian Influenza A Virus Infections of Humans. Infect. Dis. Clin. N. Am. 2019, 33, 907–932.
  61. Gu, M.; Xu, L.; Wang, X.; Liu, X. Current situation of H9N2 subtype avian influenza in China. Vet. Res. 2017, 48, 1–10.
  62. Pusch, E.A.; Suarez, D.L. The multifaceted zoonotic risk of H9N2 avian influenza. Vet. Sci. 2018, 5, 82.
  63. Schwartz, I.S.; Govender, N.P.; Sigler, L.; Jiang, Y.; Maphanga, T.G.; Toplis, B.; Botha, A.; Dukik, K.; Claire Hoving, J.; Muñoz, J.F.; et al. Emergomyces: The global rise of new dimorphic fungal pathogens. PLoS Pathog. 2019, 15, e1007977.
  64. Carnaccini, S.; Perez, D.R. H9 influenza viruses: An emerging challenge. Cold Spring Harb. Perspect. Med. 2020, 10, a038588.
  65. Herfst, S.; Zhang, J.; Richard, M.; McBride, R.; Lexmond, P.; Bestebroer, T.M.; Spronken, M.I.J.; de Meulder, D.; van den Brand, J.M.; Rosu, M.E.; et al. Hemagglutinin Traits Determine Transmission of Avian A/H10N7 Influenza Virus between Mammals. Cell Host Microbe 2020, 28, 602–613.
  66. Juno, J.; Fowke, K.R.; Keynan, Y. Immunogenetic factors associated with severe respiratory illness caused by zoonotic H1N1 and H5N1 influenza viruses. Clin. Dev. Immunol. 2012, 2012, 797180.
  67. Lin, T.Y.; Brass, A.L. Host genetic determinants of influenza pathogenicity. Curr. Opin. Virol. 2013, 3, 531–536.
  68. Hale, B.G.; Albrecht, R.A.; García-Sastre, A. Innate immune evasion strategies of influenza viruses. Future Microbiol. 2010, 5, 23–41.
  69. Bosch, F.X.; Orlich, M.; Klenk, H.D.; Rott, R. The structure of the hemagglutinin, a determinant for the pathogenicity of influenza viruses. Virology 1979, 95, 197–207.
  70. Nguyen, D.C.; Uyeki, T.M.; Jadhao, S.; Maines, T.; Shaw, M.; Matsuoka, Y.; Smith, C.; Rowe, T.; Lu, X.; Hall, H.; et al. Isolation and Characterization of Avian Influenza Viruses, Including Highly Pathogenic H5N1, from Poultry in Live Bird Markets in Hanoi, Vietnam, in 2001. J. Virol. 2005, 79, 4201–4212.
  71. Klenk, H.D.; Rott, R.; Orlich, M.; Blödorn, J. Activation of influenza A viruses by trypsin treatment. Virology 1975, 68, 426–439.
  72. Meseko, C.A.; Oluwayelu, D.O. Avian influenza. In Transboundary Animal Diseases in Sahelian Africa and Connected Regions; Springer: Cham, Switzerland, 2019; ISBN 9783030253851.
  73. Stieneke-Grober, A.; Vey, M.; Angliker, H.; Shaw, E.; Thomas, G.; Roberts, C.; Klenk, H.D.; Garten, W. Influenza virus hemagglutinin with multibasic cleavage site is activated by furin, a subtilisin-like endoprotease. EMBO J. 1992, 11, 2407–2414.
  74. Swayne, D.E.; Boulianne, M.; Logue, C.M.; McDougald, L.R.; Nair, V.; Suarez, D.L.; De Wit, S.; Grimes, T.; Johnson, D.; Kromm, M.; et al. Diseases of Poultry, 14th ed.; John and Wiley and Sons: Hoboken, NJ, USA, 2019; ISBN 9781119371199.
  75. Post, J.; Burt, D.W.; Cornelissen, J.B.W.J.; Broks, V.; Van Zoelen, D.; Peeters, B.; Rebel, J.M.J. Systemic virus distribution and host responses in brain and intestine of chickens infected with low pathogenic or high pathogenic avian influenza virus. Virol. J. 2012, 9, 61.
  76. Pantin-Jackwood, M.J.; Swayne, D.E. Pathogenesis and pathobiology of avian influenza virus infection in birds. OIE Rev. Sci. Tech. 2009, 28, 113–136.
  77. Swayne, D.E. Understanding the complex pathobiology of high pathogenicity avian influenza viruses in birds. Avian Dis. 2007, 51, 242–249.
  78. Kuiken, T.; van den Brand, J.; van Riel, D.; Pantin-Jackwood, M.; Swayne, D.E. Comparative pathology of select agent influenza a virus infections. Vet. Pathol. 2010, 47, 893–914.
  79. Taubenberger, J.K.; Kash, J.C. Influenza virus evolution, host adaptation, and pandemic formation. Cell Host Microbe 2010, 7, 440–451.
  80. Leigh Perkins, L.E.; Swayne, D.E. Pathogenicity of a Hong Kong-origin H5N1 highly pathogenic avian influenza virus for emus, geese, ducks, and pigeons. Avian Dis. 2002, 46, 53–63.
  81. Kim, H.R.; Kwon, Y.K.; Jang, I.; Lee, Y.J.; Kang, H.M.; Lee, E.K.; Song, B.M.; Lee, H.S.; Joo, Y.S.; Lee, K.H.; et al. Pathologic changes in wild birds infected with highly pathogenic avian influenza A(H5N8) viruses, South Korea, 2014. Emerg. Infect. Dis. 2015, 21, 775–780.
  82. Lee, D.H.; Kwon, J.H.; Noh, J.Y.; Park, J.K.; Yuk, S.S.; Erdene-Ochir, T.O.; Lee, J.B.; Park, S.Y.; Choi, I.S.; Lee, S.W.; et al. Pathogenicity of the Korean H5N8 highly pathogenic avian influenza virus in commercial domestic poultry species. Avian Pathol. 2016, 45, 208–211.
  83. Nagarajan, S.; Tosh, C.; Smith, D.K.; Peiris, J.S.M.; Murugkar, H.V.; Sridevi, R.; Kumar, M.; Katare, M.; Jain, R.; Syed, Z.; et al. Avian influenza (H5N1) virus of clade 2.3.2 in domestic poultry in India. PLoS ONE 2012, 7, e31844.
  84. Pantin-Jackwood, M.J.; Costa-Hurtado, M.; Shepherd, E.; DeJesus, E.; Smith, D.; Spackman, E.; Kapczynski, D.R.; Suarez, D.L.; Stallknecht, D.E.; Swayne, D.E. Pathogenicity and Transmission of H5 and H7 Highly Pathogenic Avian Influenza Viruses in Mallards. J. Virol. 2016, 90, 9967–9982.
  85. Fouchier, R.A.M.; Munster, V.J. Epidemiology of low pathogenic avian influenza viruses in wild birds. OIE Rev. Sci. Tech. 2009, 28, 49–58.
  86. Pantin-Jackwood, M.J.; Swayne, D.E. Pathobiology of asian highly pathogenic avian influenza H5N1 virus infections in ducks. Avian Dis. 2007, 51, 250–259.
  87. Gobbo, F.; Zanardello, C.; Bottinelli, M.; Budai, J.; Bruno, F.; De Nardi, R.; Patregnani, T.; Catania, S.; Terregino, C. Silent Infection of Highly Pathogenic Avian Influenza Virus (H5N1) Clade 2.3.4.4b in a Commercial Chicken Broiler Flock in Italy. Viruses 2022, 14, 1600.
  88. Van Le, T.; Phan, L.T.; Ly, K.H.K.; Nguyen, L.T.; Nguyen, H.T.; Ho, N.T.T.; Trinh, T.X.; Tran Minh, N.N. Fatal avian influenza A(H5N1) infection in a 36-week pregnant woman survived by her newborn in Sóc Trăng Province, Vietnam, 2012. Influenza Other Respi. Viruses 2019, 13, 292–297.
  89. Peiris, J.S.M.; Yu, W.C.; Leung, C.W.; Cheung, C.Y.; Ng, W.F.; Nicholls, J.M.; Ng, T.K.; Chan, K.H.; Lai, S.T.; Lim, W.L.; et al. Re-emergence of fatal human influenza A subtype H5N1 disease. Lancet 2004, 363, 617–619.
  90. Ungchusak, K.; Auewarakul, P.; Dowell, S.F.; Kitphati, R.; Auwanit, W.; Puthavathana, P.; Uiprasertkul, M.; Boonnak, K.; Pittayawonganon, C.; Cox, N.J.; et al. Probable Person-to-Person Transmission of Avian Influenza A (H5N1). N. Engl. J. Med. 2005, 352, 333–340.
  91. Ku, A.S.W.; Chan, L.T.W. The first case of H5N1 avian influenza infection in a human with complications of adult respiratory distress syndrome and Reye’s syndrome. J. Paediatr. Child Health 1999, 35, 207–209.
  92. To, K.F.; Chan, P.K.S.; Chan, K.F.; Lee, W.K.; Lam, W.Y.; Wong, K.F.; Tang, N.L.S.; Tsang, D.N.C.; Sung, R.Y.T.; Buckley, T.A.; et al. Pathology of fatal human infection associated with avian influenza A H5N1 virus. J. Med. Virol. 2001, 63, 242–246.
  93. De Jong, M.D.; Simmons, C.P.; Thanh, T.T.; Hien, V.M.; Smith, G.J.D.; Chau, T.N.B.; Hoang, D.M.; Chau, N.V.V.; Khanh, T.H.; Dong, V.C.; et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat. Med. 2006, 12, 1203–1207.
  94. Zhou, J.; Law, H.K.W.; Cheung, C.Y.; Ng, I.H.Y.; Peiris, J.S.M.; Lau, Y.L. Differential expression of chemokines and their receptors in adult and neonatal macrophages infected with human or avian influenza viruses. J. Infect. Dis. 2006, 194, 61–70.
  95. Cheung, C.Y.; Poon, L.L.M.; Lau, A.S.; Luk, W.; Lau, Y.L.; Shortridge, K.F.; Gordon, S.; Guan, Y.; Peiris, J.S.M. Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: A mechanism for the unusual severity of human disease? Lancet 2002, 360, 1831–1837.
  96. Chan, M.C.W.; Cheung, C.Y.; Chui, W.H.; Tsao, G.S.W.; Nicholls, J.M.; Chan, Y.O.; Chan, R.W.Y.; Long, H.T.; Poon, L.L.M.; Guan, Y.; et al. Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells. Respir. Res. 2005, 6, 135.
  97. Kash, J.C.; Tumpey, T.M.; Proll, S.C.; Carter, V.; Perwitasari, O.; Thomas, M.J.; Basler, C.F.; Palese, P.; Taubenberger, J.K.; García-Sastre, A.; et al. Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus. Nature 2006, 443, 578–581.
  98. Zhou, J.; Law, H.K.W.; Cheung, C.Y.; Ng, I.H.Y.; Peiris, J.S.M.; Lau, Y.L. Functional tumor necrosis factor-related apoptosis-inducing ligand production by avian influenza virus-infected macrophages. J. Infect. Dis. 2006, 193, 945–953.
  99. Mok, C.K.P.; Lee, D.C.W.; Cheung, C.Y.; Peiris, M.; Lau, A.S.Y. Differential onset of apoptosis in influenza A virus H5N1- and H1N1-infected human blood macrophages. J. Gen. Virol. 2007, 88, 1275–1280.
  100. Uiprasertkul, M.; Kitphati, R.; Puthavathana, P.; Kriwong, R.; Kongchanagul, A.; Ungchusak, K.; Angkasekwinai, S.; Chokephaibulkit, K.; Srisook, K.; Vanprapar, N.; et al. Apoptosis and pathogenesis of avian influenza A (H5N1) virus in humans. Emerg. Infect. Dis. 2007, 13, 708–712.
  101. Fornek, J.L.; Gillim-Ross, L.; Santos, C.; Carter, V.; Ward, J.M.; Cheng, L.I.; Proll, S.; Katze, M.G.; Subbarao, K. A Single-Amino-Acid Substitution in a Polymerase Protein of an H5N1 Influenza Virus Is Associated with Systemic Infection and Impaired T-Cell Activation in Mice. J. Virol. 2009, 83, 11102–11115.
  102. Tumpey, T.M.; Lu, X.; Morken, T.; Zaki, S.R.; Katz, J.M. Depletion of Lymphocytes and Diminished Cytokine Production in Mice Infected with a Highly Virulent Influenza A (H5N1) Virus Isolated from Humans. J. Virol. 2000, 74, 6105–6116.
  103. Boonnak, K.; Vogel, L.; Feldmann, F.; Feldmann, H.; Legge, K.L.; Subbarao, K. Lymphopenia Associated with Highly Virulent H5N1 Virus Infection Due to Plasmacytoid Dendritic Cell–Mediated Apoptosis of T Cells. J. Immunol. 2014, 192, 5906–5912.
  104. Hsieh, S.-M.; Chang, S.-C. Cutting Edge: Insufficient Perforin Expression in CD8 + T Cells in Response to Hemagglutinin from Avian Influenza (H5N1) Virus. J. Immunol. 2006, 176, 4530–4533.
  105. Guilliams, M.; Lambrecht, B.N.; Hammad, H. Division of labor between lung dendritic cells and macrophages in the defense against pulmonary infections. Mucosal Immunol. 2013, 6, 464–473.
  106. Lai, S.; Qin, Y.; Cowling, B.J.; Ren, X.; Wardrop, N.A.; Gilbert, M.; Tsang, T.K.; Wu, P.; Feng, L.; Jiang, H.; et al. Global epidemiology of avian influenza A H5N1 virus infection in humans, 1997-2015: A systematic review of individual case data. Lancet Infect. Dis. 2016, 16, e108–e118.
  107. Gradil, G. Lethal Case of Viral-Bacterial Pneumonia with Relative Lymphopenia. Retrospective Evaluation. Inter Collegas 2019, 6, 106–111.
  108. Pawestri, H.A.; Eggink, D.; Isfandari, S.; Thanh, T.T.; Rogier Van Doorn, H.; Setiawaty, V.; De Jong, M.D. Viral Factors Associated with the High Mortality Related to Human Infections with Clade 2.1 Influenza A/H5N1 Virus in Indonesia. Clin. Infect. Dis. 2020, 70, 1139–1146.
  109. Perricone, C.; Bartoloni, E.; Bursi, R.; Cafaro, G.; Guidelli, G.M.; Shoenfeld, Y.; Gerli, R. COVID-19 as part of the hyperferritinemic syndromes: The role of iron depletion therapy. Immunol. Res. 2020, 68, 213–224.
  110. Chotpitayasunondh, T.; Ungchusak, K.; Hanshaoworakul, W.; Chunsuthiwat, S.; Sawanpanyalert, P.; Kijphati, R.; Lochindarat, S.; Srisan, P.; Suwan, P.; Osotthanakorn, Y.; et al. Human disease from influenza A (H5N1), Thailand, 2004. Emerg. Infect. Dis. 2005, 11, 201–209.
  111. Chan, P.K.S. Outbreak of avian influenza A(H5N1) virus infection in Hong Kong in 1997. Clin. Infect. Dis. 2002, 34, S58–S64.
  112. Tam, J.S. Influenza A (H5N1) in Hong Kong: An overview. Vaccine 2002, 20, S77–S81.
  113. Yuen, K.Y.; Chan, P.K.S.; Peiris, M.; Tsang, D.N.C.; Que, T.L.; Shortridge, K.; Cheung, P.T.; To, W.K.; Ho, E.T.F.; Sung, R.; et al. Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus. Lancet 1998, 351, 467–471.
  114. Hien, T.T.; Liem, N.T.; Dung, N.T.; San, L.T.; Mai, P.P.; Chau, N.; van, V.; Suu, P.T.; Dong, V.C.; Mai, L.T.Q.; et al. Avian Influenza A (H5N1) in 10 Patients in Vietnam. N. Engl. J. Med. 2004, 350, 1179–1188.
  115. Yang, Y.; Zhong, H.; Song, T.; He, J.; Guo, L.; Tan, X.; Huang, G.; Kang, M. Epidemiological and clinical characteristics of humans with avian influenza A (H7N9) infection in Guangdong, China, 2013–2017. Int. J. Infect. Dis. 2017, 65, 148–155.
  116. Guan, W.; Yang, Z.; Wu, N.C.; Lee, H.H.Y.; Li, Y.; Jiang, W.; Shen, L.; Wu, D.C.; Chen, R.; Zhong, N.; et al. Clinical correlations of transcriptional profile in patients infected with avian influenza H7N9 virus. J. Infect. Dis. 2018, 218, 1238–1248.
  117. Philippon, D.A.M.; Wu, P.; Cowling, B.J.; Lau, E.H.Y. Avian influenza human infections at the human-animal interface. J. Infect. Dis. 2020, 222, 528–537.
  118. Frasca, D.; DIaz, A.; Romero, M.; Garcia, D.; Blomberg, B.B. B Cell Immunosenescence. Annu. Rev. Cell Dev. Biol. 2020, 36, 551–574.
  119. Yang, Y.; Wong, G.; Yang, L.; Tan, S.; Li, J.; Bai, B.; Xu, Z.; Li, H.; Xu, W.; Zhao, X.; et al. Comparison between human infections caused by highly and low pathogenic H7N9 avian influenza viruses in Wave Five: Clinical and virological findings. J. Infect. 2019, 78, 241–248.
  120. Wu, X.X.; Tang, S.J.; Yao, S.H.; Zhou, Y.Q.; Xiao, L.L.; Cheng, L.F.; Liu, F.M.; Wu, N.P.; Yao, H.P.; Li, L.J. The viral distribution and pathological characteristics of BALB/c mice infected with highly pathogenic Influenza H7N9 virus. Virol. J. 2021, 18, 1–11.
  121. Pronier, C.; Gacouin, A.; Lagathu, G.; Le Tulzo, Y.; Tadié, J.M.; Thibault, V. Respiratory Influenza viral load as a marker of poor prognosis in patients with severe symptoms. J. Clin. Virol. 2021, 136, 104761.
  122. Zheng, S.; Zou, Q.; Wang, X.; Bao, J.; Yu, F.; Guo, F.; Liu, P.; Shen, Y.; Wang, Y.; Yang, S.; et al. Factors associated with fatality due to avian influenza A(H7N9) infection in China. Clin. Infect. Dis. 2020, 71, 128–132.
  123. Morgan, D.J.; Casulli, J.; Chew, C.; Connolly, E.; Lui, S.; Brand, O.J.; Rahman, R.; Jagger, C.; Hussell, T. Innate Immune Cell Suppression and the Link With Secondary Lung Bacterial Pneumonia. Front. Immunol. 2018, 9, 2943.
  124. Deng, L.S.; Yuan, J.; Ding, L.; Chen, Y.L.; Zhao, C.H.; Chen, G.Q.; Li, X.H.; Li, X.H.; Luo, W.T.; Lan, J.F.; et al. Comparison of patients hospitalized with COVID-19, H7N9 and H1N1. Infect. Dis. Poverty 2020, 9, 163.
  125. Liu, R.; Zhao, B.; Li, Y.; Zhang, X.; Chen, S.; Chen, T. Clinical and epidemiological characteristics of a young child infected with avian influenza A (H9N2) virus in China. J. Int. Med. Res. 2018, 46, 3462–3467.
  126. Pan, M.; Gao, R.; Lv, Q.; Huang, S.; Zhou, Z.; Yang, L.; Li, X.; Zhao, X.; Zou, X.; Tong, W.; et al. Human infection with a novel, highly pathogenic avian influenza A (H5N6) virus: Virological and clinical findings. J. Infect. 2016, 72, 52–59.
  127. Zhang, L.; Liu, K.; Su, Q.; Chen, X.; Wang, X.; Li, Q.; Wang, W.; Mao, X.; Xu, J.; Zhou, X.; et al. Clinical features of the first critical case of acute encephalitis caused by the avian influenza A (H5N6) virus. Emerg. Microbes Infect. 2022, 11, 2437–2446.
  128. Ostrowsky, B.; Huang, A.; Terry, W.; Anton, D.; Brunagel, B.; Traynor, L.; Abid, S.; Johnson, G.; Kacica, M.; Katz, J.; et al. Low pathogenic avian influenza A (H7N2) virus infection in immunocompromised adult, New York, USA, 2003. Emerg. Infect. Dis. 2012, 18, 1128–1131.
  129. Koopmans, M.; Wilbrink, B.; Conyn, M.; Natrop, G.; Van Der Nat, H.; Vennema, H.; Meijer, A.; Van Steenbergen, J.; Fouchier, R.; Osterhaus, A.; et al. Transmission of H7N7 avian influenza A virus to human beings during a large outbreak in commercial poultry farms in the Netherlands. Lancet 2004, 363, 587–593.
  130. Tweed, S.A.; Skowronski, D.M.; David, S.T.; Larder, A.; Petric, M.; Lees, W.; Li, Y.; Katz, J.; Krajden, M.; Tellier, R.; et al. Human illness from avian influenza H7N3, British Columbia. Emerg. Infect. Dis. 2004, 10, 2196–2199.
  131. Prescott, K.; Kroona, S.; Quinlisk, P.; Gipple, D.; Garvey, A.; Desjardin, L.; Jirsa, S.; Benfer, J.; Gomez, T.; Finelli, L.; et al. Limited human-to-human transmission of Novel Influenza a (H3N2) virus—Iowa, November 2011. Morb. Mortal. Wkly. Rep. 2011, 60, 1615–1617.
  132. Medzhitov, R.; Janeway, C. Innate immune recognition: Mechanisms and pathways. Immunol. Rev. 2000, 173, 89–97.
  133. Medzhitov, R.; Janeway, C.A. An ancient system of host defense. Curr. Opin. Immunol. 1998, 10, 12–15.
  134. Fearon, D.T.; Locksley, R.M. The instructive role of innate immunity in the acquired immune response. Science 1996, 272, 50–54.
  135. Medzhitov, R.; Janeway, C.A. Innate immunity: Impact on the adaptive immune response. Curr. Opin. Immunol. 1997, 9, 4–9.
  136. Matis, L. Specificity and selection of gamma-delta receptor-expressing T cells. Immunol. Res. 1991, 10, 5–14.
  137. Vervelde, L.; Kapczynski, D.R. The innate and adaptive immune response to avian influenza virus. In Animal Influenza; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2016.
  138. Wu, X.X.; Zhao, L.Z.; Tang, S.J.; Weng, T.H.; Wu, W.G.; Yao, S.H.; Wu, H.B.; Cheng, L.F.; Wang, J.; Hu, F.Y.; et al. Novel pathogenic characteristics of highly pathogenic avian influenza virus H7N9: Viraemia and extrapulmonary infection. Emerg. Microbes Infect. 2020, 9, 962–975.
  139. Ichiyama, T.; Isumi, H.; Ozawa, H.; Matsubara, T.; Morishima, T.; Furukawa, S. Cerebrospinal fluid and serum levels of cytokines and soluble tumor necrosis factor receptor in influenza virus-associated encephalopathy. Scand. J. Infect. Dis. 2003, 35, 59–61.
  140. Channappanavar, R.; Fehr, A.R.; Zheng, J.; Wohlford-Lenane, C.; Abrahante, J.E.; Mack, M.; Sompallae, R.; McCray, P.B.; Meyerholz, D.K.; Perlman, S. IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes. J. Clin. Investig. 2019, 129, 3625–3639.
  141. Cilloniz, C.; Pantin-Jackwood, M.J.; Ni, C.; Goodman, A.G.; Peng, X.; Proll, S.C.; Carter, V.S.; Rosenzweig, E.R.; Szretter, K.J.; Katz, J.M.; et al. Lethal Dissemination of H5N1 Influenza Virus Is Associated with Dysregulation of Inflammation and Lipoxin Signaling in a Mouse Model of Infection. J. Virol. 2010, 84, 7613–7624.
  142. Karki, R.; Sharma, B.R.; Tuladhar, S.; Williams, E.P.; Zalduondo, L.; Samir, P.; Zheng, M.; Sundaram, B.; Banoth, B.; Malireddi, R.K.S.; et al. Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes. Cell 2021, 184, 149–168.
  143. La Gruta, N.L.; Kedzierska, K.; Stambas, J.; Doherty, P.C. A question of self-preservation: Immunopathology in influenza virus infection. Immunol. Cell Biol. 2007, 85, 85–92.
  144. Zhang, N.; Bao, Y.J.; Tong, A.H.Y.; Zuyderduyn, S.; Bader, G.D.; Malik Peiris, J.S.; Lok, S.; Lee, S.M.Y. Whole transcriptome analysis reveals differential gene expression profile reflecting macrophage polarization in response to influenza A H5N1 virus infection. BMC Med. Genomics 2018, 11, 1–14.
  145. Geng, P.; Zhu, H.; Zhou, W.; Su, C.; Chen, M.; Huang, C.; Xia, C.; Huang, H.; Cao, Y.; Shi, X. Baicalin Inhibits Influenza A Virus Infection via Promotion of M1 Macrophage Polarization. Front. Pharmacol. 2020, 11, 01298.
  146. Davis, M.J.; Tsang, T.M.; Qiu, Y.; Dayrit, J.K.; Freij, J.B.; Huffnagle, G.B.; Olszewski, M.A. Macrophage M1/M2 polarization dynamically adapts to changes in cytokine microenvironments in Cryptococcus neoformans infection. MBio 2013, 4, e00264-13.
  147. Neerukonda, S.N.; Katneni, U. Avian pattern recognition receptor sensing and signaling. Vet. Sci. 2020, 7, 14.
  148. Kumar, A.; Vijayakumar, P.; Gandhale, P.N.; Ranaware, P.B.; Kumar, H.; Kulkarni, D.D.; Raut, A.A.; Mishra, A. Genome-wide gene expression pattern underlying differential host response to high or low pathogenic H5N1 avian influenza virus in ducks. Acta Virol. 2017, 61, 66–76.
  149. Barber, M.R.W.; Aldridge, J.R.; Webster, R.G.; Magor, K.E. Association of RIG-I with innate immunity of ducks to influenza. Proc. Natl. Acad. Sci. USA 2010, 107, 5913–5918.
  150. Chen, Y.; Liang, W.; Yang, S.; Wu, N.; Gao, H.; Sheng, J.; Yao, H.; Wo, J.; Fang, Q.; Cui, D.; et al. Human infections with the emerging avian influenza A H7N9 virus from wet market poultry: Clinical analysis and characterisation of viral genome. Lancet 2013, 381, 1916–1925.
  151. Quiñones-Parra, S.; Grant, E.; Loh, L.; Nguyen, T.H.O.; Campbell, K.A.; Tong, S.Y.C.; Miller, A.; Doherty, P.C.; Vijaykrishna, D.; Rossjohn, J.; et al. Preexisting CD8+ T-cell immunity to the H7N9 influenza a virus varies across ethnicities. Proc. Natl. Acad. Sci. USA 2014, 111, 1049–1054.
  152. Kerstetter, L.J.; Buckley, S.; Bliss, C.M.; Coughlan, L. Adenoviral Vectors as Vaccines for Emerging Avian Influenza Viruses. Front. Immunol. 2021, 11, 607333.
  153. Kreijtz, J.H.C.M.; Bodewes, R.; van den Brand, J.M.A.; de Mutsert, G.; Baas, C.; van Amerongen, G.; Fouchier, R.A.M.; Osterhaus, A.D.M.E.; Rimmelzwaan, G.F. Infection of mice with a human influenza A/H3N2 virus induces protective immunity against lethal infection with influenza A/H5N1 virus. Vaccine 2009, 27, 4983–4989.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Academic Video Service
Feedback