In the case of SARS-CoV-2, the virus is clearly unusually effective at evading the triggering of early innate immune responses, such as type 1 interferons (IFNs) (see below). It is plausible that much of the nature of COVID-19 as an illness is a consequence of this one big trick of SARS-CoV-2.
Transient lymphopenia is a common feature of many respiratory viral infections, such as with influenza A H3N2 virus, human rhinovirus or respiratory syncytial virus, but lymphopenia in these other infections typically occurs for only 2–4 days around symptom onset and rapidly recovers. By contrast, COVID-19-associated lymphopenia may be more severe or persistent than in these other infections and seems to be more selective for T cell lineages.[20]
Thus, although the mechanisms of lymphopenia in COVID-19 remain incompletely understood, the reduction in the number of T cells, in particular, in the periphery is a prominent feature of many individuals with severe disease.
Innate vs Adaptive Immune System
- Innate immune system
- This immune response can occur within a couple of hours of infection.
- The innate immune response serves multiple purposes:
- To slow down the viral replication and spread
- Restriction of viral replication within infected cells
- Creation of an antiviral state in the local tissue environment, including recruitment of effector cells of the innate immune system
- Priming the adaptive immune response
- Adaptive immune system
- This immune response can occur within ∼6–10 days after priming (see below)
Although the adaptive and innate immune systems are linked in important and powerful ways, they each consist of different cell types with different jobs.
In an idealized example of a generic viral infection, the following sequence of events happens (Figure 1A):[1]
An Idealized Immune Responses after a Viral Infection
- Innate immune system rapidly recognizes the infection and triggers the “alarm bells” of type I IFN expression and related molecules
- Children displayed higher basal expression of relevant pattern recognition receptors such as MDA5 & RIG-I in upper airway epithelial cells, macrophages & dendritic cells, resulting in stronger innate antiviral responses[21]
- The adaptive immune responses are triggered
- Adaptive immune responses are slow due to:
- The inherent time demands for extensive proliferation and differentiation of naive cells into effector cells.
- Once sufficient populations of effector T cells (helper T cells and cytotoxic T cells) and effector B cells (antibody secreting cells) have proliferated and differentiated, they often work together to rapidly and specifically clear infected cells and circulating virions.
Figure 1. An integrated working model of COVID-19 immunology and disease severity |
Specifics of SARS-CoV-2 infection
- In an average case of COVID-19, a simple temporal delay in innate immune responses is enough to result in
- Asymptomatic infection
- ∼40% of SARS-CoV-2 infections are asymptomatic[7]
- Clinically mild disease
- “Mild” is a COVID-19 clinical definition meaning not requiring hospitalization (Figure 1B).
- If the innate immune response delay is too long—because of particularly efficient evasion by the virus, defective innate immunity, or a combination of both—then it willresult in conditions that lead to severe enough lung disease for hospitalization (Figure 1C).
- Ineffective IFN innate immunity has been strongly associated with failure to control a primary SARS-CoV-2 infection and a high risk of fatal COVID-19
- Which was accompanied by innate cell immunopathology and a plasma cytokine signature of elevated CXCL10, interleukin (IL)-6, and IL-8 in many studies
- Impaired and delayed type I and type III IFN responses are associated with risk of severe COVID-19
- It is suggested that T cell responses may be important for control and resolution of a primary SARS-CoV-2 infection.[9-12]
- Most acute viral infections in humans induce the activation and proliferation of both CD4+ T cells and CD8+ T cells, so SARS-CoV-2 infection may not be unique in this regard.
- However, hyperactivation or hypoactivation of T cells, or skewing towards an ineffective differentiation state (for example, Th17 cells, exhausted T cells or terminally differentiated T cells), might not be optimal in some patients with COVID-19.
- It is plausible that the innate immune system tries to fill the vacuum left by the absence of a T cell response, attempting to control the virus with an ever-expanding innate immune response.
- That solution ends up untenable, as a massive innate response results in excessive lung immunopathology.
- This conclusion is consistent with many studies finding innate cytokine/chemokine signatures of immunopathology, and particularly observation of elevated frequencies of neutrophils (the most common cell type of the innate immune system) in blood,[14] and massive numbers of neutrophils in lungs, associated with severe, end-stage COVID-19 disease.[9,12,15,16]
- Elderly individuals have a smaller naive T cell pool
- Elderly are therefore more likely to struggle to make a T cell response quickly that can recognize this new virus, which also likely results in hampered neutralizing antibody responses, because neutralizing antibody responses are generally T cell-dependent.
References
- Adaptive immunity to SARS-CoV-2 and COVID-19
- Weaver C., Murphy K. Janeway’s Immunobiology. W.W. Norton, 2016
- Blanco-Melo D., Nilsson-Payant B.E., Liu W.-C., Uhl S., Hoagland D., Møller R., Jordan T.X., Oishi K., Panis M., Sachs D., et al. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. 2020; 181: 1036-1045.e9
- Arunachalam P.S., Wimmers F., Mok C.K.P.,Perera R.A.P.M., Scott M., Hagan T., Sigal N., Feng Y., Bristow L. Tak-Yin Tsang O. et al. Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans. Science. 2020; 369: 1210-1220.
- Bastard P., et al. HGID LabNIAID-USUHS Immune Response to COVID GroupCOVID CliniciansCOVID-STORM CliniciansImagine COVID GroupFrench COVID Cohort Study GroupMilieu Intérieur ConsortiumCoV-Contact CohortAmsterdam UMC Covid-19 BiobankCOVID Human Genetic Effort Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science. 2020; 370: eabd4585
- Laing A.G., et al. A dynamic COVID-19 immune signature includes associations with poor prognosis. Nat. Med. 2020; 26: 1623-1635
- Prevalence of asymptomatic SARS-CoV-2 infection: a narrative review. DP Oran, EJ Topol - Annals of internal medicine, 2020
- Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. A Grifoni, D Weiskopf, SI Ramirez, J Mateus, JM Dan… - Cell, 2020
- Liao, et al. Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19
- Rydyznski Moderbacher et al., 2020 Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity
- Sekine et al., 2020 Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study
- Zhou et al., 2020b Acute SARS-CoV-2 infection impairs dendritic cell and T cell responses
- Magleby et al., 2020 Impact of SARS-CoV-2 viral load on risk of intubation and mortality among hospitalized patients with coronavirus disease 2019
- Kuri-Cervantes et al., 2020 Comprehensive mapping of immune perturbations associated with severe COVID-19
- Radermecker et al., 2020 Neutrophil extracellular traps infiltrate the lung airway, interstitial, and vascular compartments in severe COVID-19
- Schurink et al., 2020 Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study
- Oja et al., 2020 Divergent SARS‐CoV‐2‐specific T‐and B‐cell responses in severe but not mild COVID‐19 patients
- Szabo et al., 2020 Analysis of respiratory and systemic immune responses in COVID-19 reveals mechanisms of disease pathogenesis
- Coronavirus Deranges the Immune System in Complex and Deadly Ways
- T cell responses in patients with COVID-19
- Pre-activated antiviral innate immunity in the upper airways controls early SARS-CoV-2 infection in children
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