Impact of Herbal Therapies on COVID-19 and Influenza: Comparison
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Synthetic antivirals and corticosteroids have been used to treat both influenza and the SARS-CoV-2 disease named COVID-19. However, these medications are not always effective, produce several adverse effects, and are associated with high costs. Medicinal plants and their constituents act on several different targets and signaling pathways involved in the pathophysiology of influenza and COVID-19. Medicinal plants, in different formulations, can help to decrease viral spread and the time until full recovery. Plants reduced the incidence of acute respiratory syndromes and the symptom scores of the illnesses. Moreover, plants are related to few adverse effects and have low costs. In addition to their significance as natural antiviral agents, medicinal plants and their bioactive compounds may exhibit low bioavailability. 

  • medicinal plants
  • antiviral
  • SARS-CoV-2
  • COVID-19
  • i

1. COVID-19

Severe acute respiratory syndrome (SARS) and coronavirus-caused Middle East respiratory syndrome (MERS) are coronaviruses that could spread globally in the next few years. Coronaviridae is the family of viruses that comprises SARS-CoV-2, the third coronavirus strain that caused a pandemic. Although the SARS-CoV-2 origin is unknown, it is notorious that this virus comprises a single-stranded positive-sense RNA genome. Furthermore, this virus is giant and enveloped, scaling from 60 nm to 140 nm in diameter and having spikes of 9 to 12 nm. The spikes of SARS-CoV-2 are responsible for giving the virions the aspect of a solar corona. The genome of this coronavirus includes four different structural proteins that are important for its infectiousness: nucleocapsid (N protein), membrane (M protein), envelope (E protein), and spike (S protein). Transmission occurs principally via face-to-face contact or contaminated surfaces. Respiratory droplets are the main ones responsible for the spread of the virus, but aerosol spread can also be present. Face-to-face contact with contaminated respiratory droplets is the leading cause of transmission, mainly because asymptomatic people also spread the virus. Respiratory-contaminated droplets can transfer the virus from one infected human to another, even when face-to-face contact with ocular surfaces occurs. The infection causes common symptoms and signals through the infected people, such as fever, dry cough, shortness of breath, nausea, fatigue, myalgia, vomiting, diarrhea, headache, weakness, rhinorrhea, and anosmia or ageusia [52,53,54,55][1][2][3][4].
The pathophysiology of a SARS-CoV-2 infection is triggered when the virus first enters the nasal respiratory tract’s epithelial cells. In these nasal cells, the virus multiplies and starts to infect the lower respiratory areas using the angiotensin-converting enzyme receptor 2 (ACE2). In summary, the nasal epithelial cells serve for the virions to replicate using the RNA genome. Before large replications, these virions are released to infect even lower areas of the respiratory tract, reaching the alveolar zone of the lungs. COVID-19 is considered a multi-organ disease due to the presence of ACE2 receptors in many organs beyond the respiratory epithelium: the brain, kidney, pancreas, cardiovascular endothelium, liver, and bowel are all sites of the human body that exhibit ACE2 receptors. Pulmonary involvement is the center of coronavirus disease. The virus enters the pulmonary alveolar cells via endocytosis by binding the S protein to the ACE2 receptor, which includes the activation of the S protein by the type 2 transmembrane serine protease (TMPRSS2) and the cleavage of the ACE2 receptor. In the interior of the pulmonary cells, the virions release the RNA genome and start replicating. This multiplication is responsible for forming many new virions, which are liberated and infect new cells. In the meantime, immune cells start an inflammatory response against the presence of SARS-CoV-2 in the lungs. Lymphocytes, monocytes, macrophages, and neutrophils enhance cytokine release, which causes acute injuries to the pulmonary organs.
In summary, the vasculature of the lungs becomes very porous. Combined with the inflammatory response, the vasculature changes lead to pulmonary edema, pulmonary ischemia, activation of intravascular coagulation, respiratory failure (hypoxia), and progressive lung damage. Hyaline membrane formation is observed, and the pulmonary findings can be characteristic of the early-phase acute respiratory distress syndrome. In inflammation, oxidative stress or redox imbalance can also be associated with the severe acute respiratory disease caused by SARS-CoV-2. Oxidative phenomena are highly associated with inflammatory ambiances. The presence of reactive oxygen species and the decreased activities of antioxidant mechanisms are essential for viral replications [52,53,54,56][1][2][3][5].
Figure 1 represents the main aspects of the SARS-CoV-2 infection and the pathophysiological routes of the disease.
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Figure 1. Aspects of the SARS-CoV-2 infection and possible routes of the disease. M: membrane, N: nucleocapsid, E: envelope, S: spike, ACE2: angiotensin-converting enzyme receptor 2, TMPRSS2: type 2 transmembrane serine protease, IL-6: interleukin 6, IL-10: interleukin 10, IL-1: interleukin 1, IL-2: interleukin 2, TNF-α: factor tumor necrosis alfa, IFN-γ: interferon-gamma, +: plus.

2. Influenza

Influenza viruses are responsible for causing acute respiratory disease in many mammals, including humans. These viruses affect the respiratory system causing infection, principally by direct viral infection and damage derived from the immunological response. The characteristics of the disease depend on the subtype of the influenza viruses. There are four different subtypes of influenza: influenza A, B, C, and D. Although only subtypes A and B cause seasonal flu, in the world, the influenza epidemic occurs all the time. These viruses are considered zoonotic, principally because the origins are related to reservoirs in bats and a variable of aquatic birds. Influenza viruses present an enormous variety due to the ability of the viruses to change very simply. The primary site of infections is the respiratory epithelium; however, often some immune cells can be infected and initiate viral replication. Influenza viruses present a negative-sense RNA genome that progressively accumulates mutations, principally due to this genomic lack of proofreading mechanisms. These alterations that happen continuously in the RNA of the viruses are the main factor responsible for influenza pandemics. The transmission is related to respiratory particles. Contaminated infectious respiratory particles are created when infected people sneeze or cough, and the particles contact healthy people via inhalation. Moreover, seasonal influenza correlates with an incubation period of 24 to 48 h; however, infected people transmit the viruses before (one to two days) and after (five to seven days) the onset of the symptoms. Common symptoms of the infection are cough, myalgia, chills, fever, and malaise. Although the symptoms correspond to an uncomplicated respiratory tract infection, influenza infection can bring other, worse outcomes. The complications are mainly cardiovascular, musculoskeletal, neurologic, and pulmonary [65,66,67,68][6][7][8][9].
The influenza infection’s pathophysiology derives from the viruses’ actions in infecting the upper and lower respiratory tracts. For these reasons, all cells in the respiratory system epithelium can be infected, including the nasal epithelium (the highest) and alveoli epithelium (the lowest). Inflammation is the primary pathophysiology mechanism of influenza infection. The immune responses can be related to worsening the commitment of the disease to the respiratory tract, principally due to inflammation. Influenza A is an influenza-like virus that mostly overburdens global health. Influenza A is mainly related to pandemic outbreaks when novel subtypes arrive, making this type of influenza virus the most significant preoccupation of the world’s public health experts. This happens principally because, with influenza A, new viruses can emerge from animals. Influenza B and C are only related to causing diseases related to epidemic proportions. Two influenza A viruses affect people nowadays (H1N1 and H3N2). Influenza A virus subtypes are associated with the glycoproteins that can appear on the virus’s surfaces. Hemagglutinin (16 to 18 subtypes) and neuraminidase (nine to 11) can interfere with infection rates and mortality. Hemagglutinin anchors the influenza virion to the human cell surface, and neuraminidase causes digestion of the host secretions, allowing the release of the viral particles from the infected cells of the host. When the alveolar epithelium of the lungs is affected, the host is at a high risk of developing severe disease, primarily due to the exposure of the viruses to the endothelial cells of the lungs. This phenomenon occurs when the influenza infection mediates the destruction of alveoli’s structures related to gas exchange in the respiratory epithelium [67,69,70,71][8][10][11][12]. Influenza is a health concern that presents a significant opportunity for technological advancements each year, primarily due to its seasonal nature. Recently, the importance of vaccination has been extensively demonstrated, proving to be the most effective defense against various infections, including SARS-CoV-2. Parenteral vaccination, which involves injecting vaccines into the body, is the most commonly used method for immunization against systemic and respiratory diseases and central nervous system disorders. It activates T and B cells, triggering a comprehensive immune response. However, mucosal vaccines, such as nasal vaccines, offer an additional advantage by stimulating immune cells in the mucosal tissues of the upper and lower respiratory tracts [72][13]. Strategies that imitate or hinder the function of neuraminidases present intriguing possibilities for treating viral and bacterial infections. Neuraminidases, also known as sialidases, are a class of enzymes that regulate the activity of sialic acids, which are known to have crucial roles in various biological processes and pathological conditions. These enzymes can be found in mammals, as well as in viruses and bacteria. This inherently multidisciplinary field encompasses structural biology, biochemistry, physiology, and the study of host-pathogen interactions. It offers exciting research opportunities that can enhance our understanding of the mechanisms involved in virus-bacteria co-infections and their impact on exacerbating respiratory diseases, particularly in the context of pre-existing pathological conditions [73][14]. Figure 2 represents the pathophysiological events of influenza infection and the potential medicinal plants’ inhibitory effects on pathological pathways.
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Figure 2.
Features of influenza infection pathogenesis and potential pathways of inhibition. ↓: decrease, Ф: inhibition.

3. The Role of Medicinal Plants on COVID-19

A genuinely potent antiviral agent against COVID-19 is lacking. Although much research has been done for effective vaccines and drug agents against SARS-CoV-2, effective therapies have not yet been found. For these reasons, preventive and supportive therapeutics are usually used to manage a patient infected by SARS-CoV-2, mainly to control complications or avoid organ damage. Plants and herbs were previously shown to be natural substances corresponding to antiviral activities and producing anti-inflammatory and antioxidant actions. Common antivirals are associated with limited efficacy rates and can promote serious side effects.
Medicinal plants present diverse bioactive compounds that strongly correlate with the treatment and prevention of COVID-19. Mostly in the form of mixtures, medicinal plants and plants metabolites are rich in antiviral compounds and can integrate plant-based therapies into the fight against SARS-CoV-2 infection [74,75,76,77,78,79][15][16][17][18][19][20]. Moreover, natural compounds are more tolerable than typical medications and inexpensive.
Antiviral phytocompounds act through several mechanisms against SARS-CoV-2, principally interfering in COVID-19 pathophysiology. Medicinal plants often present many different bioactive compounds that have antiviral effects and promote anti-inflammatory and immunomodulatory effects. This combination of activities can augment the efficacy of using a specific plant to treat a viral infection [74,80,81][15][21][22].
The first line of defense promoted by natural compounds against SARS-CoV-2 is related to the entrance into the cells, inhibiting the interaction between the viral spike protein and the receptor that interacts with this structural component of the virus. Spike proteins and ACE2 receptors interact via the spike glycoprotein receptor-binding domain. This domain recognizes the ACE2 receptor, leading to the viral particles’ internalization into the host cells. The internalization of the viral particles permits the genome of the SARS-CoV-2 to penetrate the host cells. Due to these facts, blockers of ACE2 receptors can be effective against the pathogenesis of COVID-19 disease. Furthermore, the virus-ACE2 interaction depends on a protease called TMPRSS2. This molecule corresponds to a transmembrane serine protease responsible for the cleavage of the protein spike and the ACE2 receptor, an essential phenomenon during viral internalization. Due to these reasons, TMPRSS2 inhibitors can also be necessary in combating SARS-CoV-2. Medicinal plants can exhibit several bioactive compounds associated with ACE2 receptors and TMPRSS2 protease inhibitions. Emodin and caffeic acid are molecules that promote activities that inhibit ACE2 receptors. Kaempferol, luteolin, sulforaphane, quercetin, and cryptotanshinone promote activities that inhibit TMPRSS2 proteases. The inhibitory actions of medicinal plants’ compounds on ACE2 and TMPRSS2 can correspond to a necessary adjuvant treatment against COVID-19. The effective blockage of the virus’ entry into the host cells can significantly inhibit infection [74,77,78,80][15][18][19][21]. Interfering in SARS-CoV-2 replication integrates with inhibitory effects against the pathogenic routes of COVID-19 infection. The causal virus of COVID-19 necessitates the replication of enzymes. The proteolytic activities of two enzymes are essential to replicating polyproteins during the viral maturation in the host cells. These two proteins are chymotrypsin-like protease [3CL(pro)] and papain-like proteinase [PL(pro)]. PL(pro) is a non-structural protein of SARS-CoV-2 that plays roles in the cleavage process of viral polyproteins into action-active proteins. In addition, PL(pro) corresponds to an antagonist of the innate immunological system, mainly targeting interferon production and the signaling pathways of nuclear factor-kappa B (NF-kB). In turn, 3CL(pro) is also a non-structural protein encoded by the SARS-CoV-2 genetic material that exerts effects on the viral replication processing polyproteins of the virus. Amentoflavone, herbacetin, pectolinarin, rhoifolin, dihydrotanshinone, and gallocatechin gallate are bioactive compounds of different medicinal plants that exert potential inhibitors of SARS-CoV-2 3CL(pro) protease. Dieckol, hirsutenone, tomentin E, and psoralidin can exert possible effects inhibiting SARS-CoV-2 PL(pro) protease [74,77,78,80,82,83,84,85,86][15][18][19][21][23][24][25][26][27]. Another phytotherapy against COVID-19 can correspond to helicase inhibitors. SARS-CoV-2 uses helicases known as NTPase to replicate the viral genome and the transcript and translate this genomic material. There are two bioactive compounds referred to that inhibit the activities of SARS-CoV-2 helicase: myricetin and scutellarein. These two compounds inhibit the helicase by inhibiting the ATPase activity associated with the correct function of the SARS-CoV-2 helicase non-structural proteins. Helicase is a protein related to synthesizing variable parts of the virus, from viral structural proteins to viral enzymes. The inhibition of helicase may discourage the assembly of the mature SARS-CoV-2 virions at the final stage of the replication process. Therefore, the inhibition of helicase protein might be considered in treating COVID-19 infection. SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibitors have also been evaluated as potent agents against COVID-19. This enzyme is essential, principally due to its synthesis of SARS-CoV-2 sense and antisense RNAs associated with viral replication. Figure 3 summarizes the potential pathways to inhibit COVID-19 infection using medicinal plants.
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Figure 3. Features of SARS-CoV-2 infectious process and potential pathways to inhibit COVID-19 infection. ACE2: angiotensin-converting enzyme 2 receptor, TMPRSS2: type 2 transmembrane serine protease, RdRp: SARS-CoV-2 RNA-dependent RNA polymerase, PL(pro): papain-like proteinase, 3CL(pro): chymotrypsin-like protease, S: SARS-CoV-2 spike protein, M: SARS-CoV-2 membrane protein, N: SARS-CoV-2 nucleocapsid protein, E: SARS-CoV-2 envelope protein, ↓: decrease.

4. The Role of Medicinal Plants on Influenza

As previously mentioned, influenza viruses are responsible for causing human respiratory infections. Moreover, it is known that infection augments the susceptibility of the infected individual to pneumonia. Therefore, an influenza infection can associate with acute respiratory distress syndrome. Nowadays, several synthetic drugs are used to treat influenza. The existing or in-development drugs Oseltamivir, Zanamivir, Peramivir, and Laninamivir are recommended, due to their inhibitory activity on influenza viruses’ neuraminidase. Oseltamivir and Zanamivir are antivirals that are extensively available and have been for decades. Amantadine and Rimantadine are considered influenza A inhibitor drugs. Interacting with viral replication is an effective way to block influenza infection. It is known that influenza only replicates in the interior of the host cells. Therefore, antiviral medications need to penetrate cells without causing cytotoxicity. Furthermore, there is a variable amount of antiviral agents against influenza. The effectiveness of these drugs is limited, principally due to their adverse effects and the presence of antiviral resistance. These limitations contribute to the need for natural antiviral bioactive compounds to treat influenza infections. Medicinal plants and herbs play a fundamental role in treating influenza in some countries around the globe. In most countries, these natural compounds are the leading choice to treat this disease [104,105,106,107,108,109,110][28][29][30][31][32][33][34].
Medicinal plants and herbs target specific actions or features of the influenza viruses to treat the infectious process. Anti-influenza bioactive compounds deactivate or restrain the viruses directly or inhibit influenza indirectly. Some of these actions correspond to regulations of the host immune system, which can amplify the function of the host’s immunological properties, leading the human organism to defeat the infection. These actions include inducing interferon production, boosting the activities of the immune cells, stimulating phagocytosis, enhancing macrophage activation, and stimulating the production of IL-1 [102,106][30][35].

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