Immune Responses Dictate COVID-19 outcome

It is clear from this^[4] and other studies that the immune response in hospitalized patients with severe COVID-19 is characterized by lymphopenia and the expression of molecules associated with ongoing inflammation,^[5] whereas these same molecules are expressed at a lower level in people with mild or moderate disease.

Figure 1.  Immune responses to COVID-19 infection (source: [4])

a) Higher IFN-α in in people with severe disease (cf. moderate disease)

b) Higher expression of IFN-λ only in people with severe disease

c) Level of TNF-α (a inflammation-promoting cytokine) correlated with viral load in the nasal passages

d) Viral load declined over time in people with moderate disease (cf. severe disease)

e) IL-5 upregulated as people developed severe disease (cf. moderate disease)

f) Levels of CD4 and CD8 T cells were lower in people with moderate or severe disease (cf. healthy controls)

Immune Responses to COVID-19 Infection

A dysregulated immune response, a cytokine storm and cytokine-release syndrome^[8,9] are some of the terms used to describe the overexuberant defense response that is thought to contribute to disease severity in certain people who become seriously ill with COVID-19.

Based on [4], people with severe disease have (see also Figure 1):^[4]

• Higher expression of IFN-α  (Interferon type I) & IFN-λ (Interferon type III) (cf. ppl. w/ moderate disease)
• IFN-α  (Interferon type I)
• Beyond antiviral control, type I IFNs are known to have anti-inflammatory functions, particularly through the negative regulation of IL-1 and IL-18 and of inflammatory TH17 cells
• IFN-λ (Interferon type III)
• Type III interferons (IFNs) (or IFN-λ) can be induced in response to viral infections, and lead to JAK and STAT activation. The JAK/STAT pathway induces antiviral responses and IFN-stimulated gene transcription. 
• Viral load NOT declined over time (cf. ppl. w/ moderate disease)
• Higher level of IL-5 (cf. ppl. w/ moderate disease)
• which aids defense against parasitic worms, not viruses
• Lower level of CD4 and CD8 T cells (cf. healthy controls)
• which are key immune cells involved in viral clearance
• Higher level of pro-inflammatory cytokines (cf. healthy controls)
• IL-1α, IL-1β, IFN-α, IL-17A and IL-12 p70
• Higher levels of other cytokines (cf. ppl. w/ moderate disease)
• IFN-λ, thrombopoietin (which is associated with abnormalities in blood clotting), IL-21, IL-23 and IL-33
• Higher levels of cytokines associated with activation of inflammasome (cf. ppl. w/ moderate disease)
• which is a component of the immune response that is a driver of inflammation
• Higher Th1 cells  (cf. ppl. w/ moderate disease)
• Elevated cytokines associated with immune responses to fungi  (cf. ppl. w/ moderate disease)
• which are cytokines released by Th17 cells
• Elevated cytokines associated with immune responses to parasites or with allergic reactions (cf. ppl. w/ moderate disease)
• which are cytokines released by Th2 cells

Figure 2.  Type I and type III interferons are among the most potent anti-viral cytokines
 produced by the immune system.  Are they friends or foes?  (Source: [13])

Internal Immunity (IgG) vs Mucosal Immunity (IgA)

Vaccination will dramatically reduce your likelihood of serious illness or death if you’re exposed to SARS-CoV-2.  This largely protects vaccinated people from being overwhelmed by the coronavirus, unless they have an immunodeficiency or are exposed to an unusually large amount of the virus.

There’s two kinds of immunity:^[14]

• Internal Immunity
• Vaccines injected into our muscles provide internal immunity
• They are highly effective at stimulating internal immunity, which protects the inside of the body, including the lungs
• This occurs by release of antibodies of the Immunoglobulin G type, or IgG, into the blood and production of T-cells
• Mucosal Immunity
• Mucosal immunity provides the first line of defense by protecting the nose and mouth, and by doing so also reduces spread to others
• The mucous membranes secrete a particular form of antibodies of the Immunoglobulin A type (IgA)
• Vaccines administered via nasal spray provide mucosal immunity
• They’re still under development for Covid-19
• Vaccines administered via nasal spray exist for other ailments, including polio
• They can supplement existing shots with mucosal immunity
• Note that:
• Vaccines injected into our muscles—including all the approved inoculations against Covid—are largely ineffective at stimulating the secretion of IgA into our noses that occurs after actual infection with a virus. 
• For the previously infected, who thanks to natural mucosal immunity are likely at less risk than never-infected vaccinated people of spreading the virus to others

References

1. T follicular helper cells (British Society for Immunology)
2. Regulatory T Cells (British Society for Immunology)
3. Th1 and Th2 Lymphocytes in Autoimmune Disease
4. COVID-19 poses a riddle for the immune system
5. Zhang, X. et al. Nature 583, 437–440 (2020)
6. Lymphopenia in severe coronavirus disease-2019 (COVID-19): systematic review and meta-analysis
7. Kinetics of antibody responses dictate COVID-19 outcome
8. Moore, J. B. & June, C. H. Science 368, 473–474 (2020)
9. Hirano, T. & Murakami, M. Immunity 52, 731–733 (2020)
10. Interferon (IFN)-λ Takes the Helm: Immunomodulatory Roles of Type III IFNs
11. Human autoinflammatory disease reveals ELF4 as a transcriptional regulator of inflammation
12. T cells in Human Disease 
13. Interfering with SARS-CoV-2: are interferons friends or foes in COVID-19?
14. Follow Your Nose to Herd Immunity
15. Live Imaging of SARS-CoV-2 Infection in Mice Reveals that Neutralizing Antibodies Require Fc Function for Optimal Efficacy
• FcγR engagement by NAbs reduces virus load and limits immunopathology
• Both Fab and Fc effector functions of NAbs are essential for optimal in vivo efficacy against SARS-CoV-2
16. Designing spatial and temporal control of vaccine responses (good)