In December 2019, a novel coronavirus disease (COVID-19) emerged in Wuhan, Hubei province, China ^[1][2][3][1,2,3]. A cluster of patients with severe respiratory illnesses, such as viral pneumonia and lung failure, were observed around that time. The causal agent, unidentified at that time, has since been named the “Severe Acute Respiratory Syndrome Coronavirus” (SARS-CoV-2) virus. While initially there were few reports that person-to-person transmission was possible, it soon became evident that transmission from asymptomatic individuals or individuals having mild infection to others was observed to be possible ^[4][5][6][4,5,6]. This clearly was a factor in allowing SARS-CoV-2 to be disseminated across the borders of many nations in less than six months from discovery and resulted in the global spread of the COVID-19 pandemic in 2020 ^{[7][8][9][10]}[7,8,9,10]. Due to the high transmissivity of the coronavirus, COVID-19 was declared a global pandemic by the World Health Organization (WHO) on 11 March 2020 [11]. The causative agent, SARS-CoV-2, was confirmed via genome analysis to be a close relative of zoonotic coronaviruses and to be of a prior outbreak strain, SARS-CoV, which caused an epidemic in 2003. Clinical observations of SARS-CoV-2 infections normally manifest themselves as respiratory syndromes, although there is a degree of intestinal involvement, and the most severe symptoms are interstitial pneumonia and acute respiratory distress syndrome (ARDS) ^[11][12][13][11,12,13]. ARDS is considered a major driver in mortality and morbidity. The International Committee on Taxonomy of Viruses has established standardized rules for classifying viruses. Under these rules, a newly emerged virus is normally assigned to a species based on phylogeny and taxonomy.

SARS-CoV-2 uses the same receptor as SARS-CoV, ACE2, which primarily infects the respiratory tract. Bats are adapted to coronaviruses (CoVs) because of their high level of reactive oxygen species (ROS) and continual expression of interferon-stimulated genes, which have an advantage in suppressing CoV replication. They also have an attenuated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and NOD- and an LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome response, which leads to decreased viral virulence ^[14][112]. Hence, infected bats generally have no symptoms or show moderate symptoms. The high levels of ROS in bats are mutagenic, affecting the proofreading capability of CoV polymerase, and this effect is compounded during the long lifespan of bats (over 25 years) ^[14][112].

Toll-like receptors (TLR)-3, -7, -8, and -9 recognize viral RNA and DNA in the endosome, which is present in the cytoplasm. The viral RNA receptor retinoic-acid inducible gene I (RIG-I), the cytosolic receptor melanoma differentiation-associated gene 5 (MDA5), and nucleotidyl transferase cyclic GMP-AMP synthase (cGAS) recognize both viral RNA and DNA in the cytoplasm ^[15][113]. Activation of these receptor pathways activates the transcription factors NF-κB and Interferon regulatory factor 3 (IRF3), the secretion of type I Interferons (IFN-α/β), and a gamut of pro-inflammatory cytokines ^[15][113]. In a study conducted on ARDS that included mouse models induced by multiple noxae, including SARS-CoV, inhibition of the TLR-4 gene was observed, but no inhibition of TLR-3 or -9 genes was seen, resulting in alleviated acute lung injury. TLR-4 responds to bacteria; one hypothesis is that oxidized phospholipids due to SARS-CoV-2 can activate TLR-4 and result in the onset of ARDS. TLR-7 agonists may inhibit severe COVID-19 and reveal synergic activity with active anti-viral therapy ^[16][114]. Interleukin-6 (IL-6) and Tissue Necrosis Factor-alpha (TNF-α) are important cytokines in SARS-CoV-2 infection and secretion after TLR-4 activation. A remarkable binding has been reported between the viral S protein and TLR-1, TLR-4, and TLR-6, and TLR-4 has the highest binding energy ^[17][115].

It has been reported that after viral infection, host pattern recognition receptors (PRRs), including TLRs, RIG-I, and NOD-like receptors (NLR), detect the viral nucleic acid and induce the synthesis of type I interferons (IFNs) ^[18][116]. The N-protein of SARS-CoV plays as an immune escape protein and even escapes interferon response ^[18][116]. IFN-I levels associated with the severity of disease and COVID-19 can block the activation of IFN pathways, i.e., CoV proteins inhibit several steps of the signal transduction pathway that bridge the IFN receptor subunits (IFNAR1 and IFNAR2) to the STAT proteins that activate transcription ^[19][117]. Subsequently, neutrophils and monocytes/macrophages are triggered, come to the site of infection, and induce the hyperproduction of pro-inflammatory cytokines ^[20][118]. Specific Th1 and Th17 cells are also initiated, and these further contribute to the exaggerated inflammatory response ^[20][118].

In severe disease conditions, or when the viral load is high, the host immune system attempts to kill the virus. This eventually results in the release of many inflammatory mediators and the production of cytokines ^[21][119]. In return, these cytokines induce organ damage and, subsequently, edema, ARDS, acute lung injury (ALI), acute cardiac injury, and secondary infection, leading to death ^[22][120]. ACE2 receptors are abundantly expressed in the cardiovascular system, liver, digestive organs, and kidneys. In addition, all endothelial cells and smooth muscle cells across organs also express ACE2, enabling viral circulation and spread ^[23][121]. In the early phase of CoV infection, dendritic cells and epithelial cells release pro-inflammatory cytokines and chemokines such as IL-1β, IL-2, IL-6, IL-8, both IFN-α/β, TNF, C-C motif chemokine 3 (CCL3), CCL5, CCL2 and IP-10 (CXCL 10), a chemokine of the CXC family ^[24][122]. There is systemic lymphopenia, especially of Natural Killer (NK) cells, and atrophy of the spleen and lymph nodes. Furthermore, infiltration of activated monocytes, macrophages, and lymphocytes into the lung tissues and vascular system induces lesions in these organs ^[9][22][24][9,120,122].

In COVID-19 infection, cytotoxic T-cells (CD8+), helper T-Cells (CD4+), and subsets of CD4+: CCR4+, CCR6+, and Th17 cells express a high level of Human Leukocyte Antigen-DR isotype (HLA-DR) ^[25][123]. In some severe cases, the number of natural killer (NK) cells was very low or even undetectable ^[26][95]. Memory helper T-cells, regulatory T-cells, and γδ T-cell numbers also decrease in severe cases ^[19][27][117,124]. In addition, the total number of lymphocytes, particularly CD4+ T-cells, CD8+ T-cells, and IFNγ-expressing CD4+ T-cells decreased considerably in severe conditions ^[28][125]. Vγ9Vδ2 T cells are the dominant γδ T-cell subset in adults and with age; the numbers may vary. Elderly people with decreased numbers of Vγ9Vδ2 T-cells are vulnerable to SARS-CoV-2 infections ^[29][126]. Overall, increased expression of cytokines (IL-6, IL-10, and TNF-α), systemic T-cell lymphopenia (CD4+ and CD8+ T-cells), and decreased IFN-γ expression in CD4+ T cells play an important role in pulmonary damage, disease severity, and outcomes ^[28][125].

Despite lower numbers of T-cells in severe COVID-19 patients, these T-cells are more activated and exhibit a tendency to exhaustion with the expression of PD-1 and TIM-3 markers. On the other hand, recovering patients showed an increase in follicular helper CD4 T-cells (TFH) and decreased levels of inhibitory markers such as IFN with increased levels of granzyme and perforin ^[19][117].

Most of the infiltrating cells in the lungs are monocytes and macrophages, with moderate numbers of multi-nucleated giant cells but few lymphocytes. Among the infiltrating lymphocytes, most of them are CD4+ T-cells ^[22][120]. Peripheral blood of severe COVID-19 patients showed high numbers of CCR6+ and TH17 cells ^[30][127]. TH17 cells produce IL-22, which upregulates the antimicrobial peptides mucin and fibrinogen. Hence, the secretion of IL-22 may drive the formation of edema with abundant mucins and fibrin, which is seen in SARS-CoV-2 and SARS-CoV patients ^[30][127].

An increased number of monocyte subsets was seen in COVID-19 patients bearing the CD14+ and CD16+ surface proteins, and macrophages bearing the CD68+, CD80+, CD163+, and CD206+ surface markers ^[31][128]. An analysis of autopsies of COVID-19 patients showed that monocytes from infected patients that bear ACE2 receptors were associated with a delayed type I INF response ^[22][120].

There is also an increase in the neutrophil-to-lymphocyte ratio (NLR) in severe COVID-19 patients when compared to mild cases ^[27][124]. NLR is an indicator of systemic inflammation and infection and serves as a key indicator of bacterial infection. Increased NLR in infected patients associated with disease severity addresses a possible role in hyper-inflammatory responses to COVID-19 ^[27][124]. The platelet-to-lymphocyte ratio (PLR) is another important response by the body to severe disease. Patients with increased platelets are hospitalized for a longer time ^[32][129] and should be monitored because of the intensity of the cytokines produced ^[32][129]. An increase in thymosin level could regulate immune responses to elevate lymphocytes and develop a situation that can prevent the development of a severe disease condition ^[32][129]. Hence, understanding the host immune response against SARS-CoV-2 in COVID-19 patients can shed light on the immunopathogenesis of this disease and can help understand the molecular pathways for providing any medical intervention, which may provide long-term immunity by having circulated immune memory cells in the immune system and may enable the designing of prophylactic and therapeutic measures to overcome future pandemics such as coronaviruses.