Introduction

In this twenty-first century, the resurgence of novel, lethal, and highly contagious zoonotic viruses to which there is no pre-existing immunity pose a great threat to the survival of mankind as described in Table 1[1,2,3]. The evolutionary “arms race” between the host and the pathogen surges on and reaches its crescendo when the infectious agent mutates so quickly to successfully evade the host’s immune system [4]. This leads to a disease outbreak which could later develop into a pandemic as massive deaths soon ensue. This is followed by the global incapacitation of social, health, economic, and government systems [5,6,7]. If measures are not put in place to curtail spread of infection, these new emerging biological threats could serve as a catalyst for the total extinction of the human species [8]. Case in point in 1918, a new strain of H1N1 influenza viruses termed the “Spanish flu” led to the deadliest pandemic in human history [9]. This virus infected roughly one-third of the world’s population and caused an estimated 50 million deaths worldwide [10].

Table 1 List of zoonotic contagious viruses that cause lethal infections in humans (Source: cdc.gov and ncbi.nlm.nih.gov).
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More recently, novel strains of the usually benign coronaviruses, that routinely cause harmless common colds and have low virulence [11], mutated from their natural reservoir hosts and transitioned towards causing excess infectivity and mortality in humans. Notably, in 2002, Severe Acute Respiratory Syndrome Coronavirus 1 (SARS-CoV-1) originated from the Guangdong province in Southern China and was rapidly spread to greater than 8,000 people in over 25 different countries [119]. As a result, this hyperactivated state dampens host-specific T cell responses and further impairs T cell functionality [120,121,122]. In addition, CD4+ T cells from individuals who develop severe symptoms of COVID-19 have been reported to have defective IFNγ secretion and as such poorly orchestrate help to other cell subsets [122].

Lastly, the N protein of SARS-CoV-2 binds to mannose-binding lectin (MBL) leading to the activation of the alternative complement pathway [123]. This leads to the deposition of anaphylatoxins such as C5a that serve as chemo attractants for other inflammatory cells such as monocytes, neutrophils, and eosinophils through the secretion of diverse inflammatory cytokines and chemokines [123, 124]. This partly contributes to the ongoing cytokine storm as the excessive unchecked production of cytokines such as IL-6, IL-10, GMCSF, IL-1β, and TNF-α ensues [125, 126]. This uncontrolled release of inflammatory cytokines results in both local and systemic pathology. Within the lungs, injury occurs to the lung endothelium, epithelial cells, and bronchoalveolar capillaries leading to elevated vascular permeability, disseminated intravascular coagulation, focal demarcation of hemorrhages, and proteinaceous exudates within alveolar spaces [127,128,129]. Shortness of breath arises from poor oxygen supply/diffusion and low efficiency of gaseous exchange that gives the lungs an appearance of bi-lateral ground-glass opacity during computed tomography (CT) scans [130]. Systemic effects of COVID-19 also include damage to the central nervous system, which presents with acute hemorrhagic necrotizing encephalopathy [131], altered mental status, and seizures [132]. As a result of the cytokine storm, multiple organ failure that is characterized by clotting and elevated d-dimer levels within the cardiovascular system occurs. Acute kidney injury also takes place alongside necrotic destruction of the lymph nodes and spleen [133,134,135], (Fig. 4).

Fig 4
figure 4

Immunological events that lead to severe COVID-19. SARS-CoV-2 evades detection by neutralizing antibodies (nabs). Present non-nabs could contribute to the severity of pathogenesis by causing antibody-dependent enhancement (ADE). Following macrophage detection of the virus, delays in secretion of type 1 interferons avoid antiviral state hence favoring increased viral replication. In addition, macrophage function is dysregulated as evidenced by the failure to resolve inflammation within the lungs, inadequate repairs of the alveolar barrier, damage to the alveolar capillary networks, and increased buildup of debris leads to poor oxygen saturation as demonstrated by bi-lateral ground-glass opacity. In addition, the depletion of alveolar macrophages followed by subsequent enrichment of inflammatory Ficolin-1+ (FCN1+) macrophages, infiltration of polymorphonuclear neutrophils (PMNs) followed by activation of complement pathways lead to exaggerated production of inflammatory cytokines that later sustains a cytokine storm, and fuels systemic pathology.

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Conclusions and future perspectives

This review has focused on both virus evolution and transmission patterns, changes in virus structure that enhance pathogenesis, and the immune evasion strategies that are used by the virus to evade immune detection. Except for the brief sidenote on targeting macrophages as reserviors/carriers for SARS-CoV-2 , we chose not to delve into therapeutic options that could be utilized to eradicate the pathogen as these approaches have been elaborately discussed in separate reviews [71, 109]. Indeed, comprehensive analysis of several tissues revealed that macrophages play a crucial role in redirecting inflammation and driving the pathogenesis of SARS-CoV-2 [136]. It has recently been shown that CD169+ tissue resident macrophages in the lymph nodes and spleens could serve as viral carriers of SARS-CoV-2 [137]. Similar to what is currently being done to develop long-acting HIV therapy [138,139,140], repurposing drugs to directly target diverse myeloid carriers such as macrophages may not only lower viral loads but also ensure the timely dissemination of pro-drugs into diverse tissues as these cells could act as drug carriers.

In addition, the intricate role of the stimulation of interferons (IFN) such as IFNα and IFNβ in delaying or exacerbating SARS-CoV-2 is yet to be fully delineated. The five transmembrane PRR referred to as the stimulator of interferon response genes (STING) is expressed in the endoplasmic reticulum of lung alveolar epithelial cells, endothelial cells, and splenocytes. STING senses PAMPs such as damaged DNA, viral nucleic acid sequences, or intermediate products resulting in the stimulation of type 1 IFN responses [141]. Early in infection, SARS-CoV-1 releases viral papain-like-proteases, found within the nsp3 and nsp16 proteins that inhibit STING’s downstream IFN secretion [142, 143]. There is no evidence of SARS-CoV-2 dysregulating STING function. However, Berthelot et al. suggest that extensive inflammatory damage associated with severe COVID-19 provides elevated amounts of damaged DNA leading to extensive hyperactivation of STING [141]. This could possibly lead to elevated expression of IFNs that could facilitate the continued infiltration of inflammatory cells such as neutrophils into the lungs and sustain the cytokine storm. Intriguingly, in bats, which are placental mammals that coexist with several coronaviruses and serve as natural reserviors [144], STING polymorphisims ensure lower IFN secretion that later contributes towards reduced immune pathogenesis [145]. Collectively, these observations highlight the need for further investigation of how STING polymorphisims could affect SARS-CoV-2 immune pathogenesis.

Tracing transmission patterns and evolutionary genomic changes in SARS-CoV-2 while factoring alterations in host immunity could accurately inform epidemiological models that offer reliable predictions on when the number of COVID-19 infections will decrease [146]. Additional studies are required to validate observations that the extent of pathogenicity could vary with different L and S SARS-CoV-2 lineages. Further investigations are also required to cross-validate the differences in pathogenesis observed in the predominant clades of the US west versus east coasts [41].

Recently, Korber et al. provided evidence that the predominant D614 mutation in the SARS-CoV-2 Spike protein is gradually being replaced by G614 mutations in diverse populations worldwide. This newly predominant mutant was shown to have acquired a fitness advantage highlighted by an increased replication capacity that was demonstrated by elevated viral loads. Infection with this variant was also demonstrated by reduced disease severity as measured by extended hospitalization. Lastly, it was also shown that G614 pseudo virions were more prone to neutralization antibodies [147]. Collectively, these results show that within an evolutionary context, SARS-CoV-2 is slowly transitioning into variants that favor suitable host-pathogen interactions [148]. By ensuring enhanced virus replication within a host while limiting host death, the predomianant G614 mutant guarantees better adaptation to the human host in comparisons to the original Wuhan D614 variant. Experiments are currently being conducted to evaluate whether these observed increases in infectivity have any visible effects on transmission dynamics within diverse populations [149]. In addition, an in-depth SARS-CoV-2 report by Kupferschmidt argues that although the G614 mutant easily infects a lab cell line, observations may not be reproducible within the diverse cell types found within a human host [149].

Though datasets such as that of GISAID may not reflect the true dynamism of transmission in resource-limited regions such as Africa, routine evaluation of mutations that occur in these areas is needed to inform the scientific community about how SARS-CoV-2 adapts to regions with endemic tropical co-infections such as HIV, malaria, helminths, and TB [150,151,152]. There is a need to carry out further research focused on the dynamics of SARS-CoV-2 spread in African Americans as these individuals have been shown to have higher incidences of COVID-19 [153, 154]. Additional studies are warranted to dissect which MHC/HLA-DR polymorphisms across different populations are associated with protection or susceptibility across different populations.

Future studies will also be needed to evaluate whether immunity developed following exposure to SARS-CoV-2 is capable of protection from future encounters with the pathogen [155]. Testing whether repeated exposures boost immunity [156] and evaluating protection from future infection with different SARS-CoV-2 clades without development of deleterious immune responses such as ADE could also inform strategies to design future vaccines. Lastly, extensive research should also be carried out to understand changes that occur in asymptomatic individuals as these persons have been reported to enable the rapid spread of COVID-19 and sustain transmission patterns of the global epidemic [22].