Covid-19 — The Mechanisms of Immune-Mediated Tissue Damage

Host antiviral responses against COVID-19 infection depend on the activation of both the immune systems and cellular self-defense mechanisms. The occurrence of immune over-response or immune deficiency is responsible for the condition of infected Covid-19 patients becoming critical or severe.^[1]

In this article, we will cover MIS-C (Multisystem inflammatory syndrome in children) immunopathology that help elucidate mechanisms of immune-mediated tissue damage for the infected Covid-19 children.  Note that, in adults, a similar condition has occasionally been reported, which has been called multisystem inflammatory syndrome in adults (MIS-A).

Figure 1. Schematic model of immunopathology drivers in MIS-C. 

What is MIS-C? 

MIS-C is a rare and potentially life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV2 infection in otherwise healthy children.  These kids often develop fever, abdominal pain, rash, and often shock. 

Figure 2. Features of Severe Disease (Source: [6])

Research Findings^[2]

Carrie L. Lucas et al. assessed 15 MIS-C patients and clinically defined severe (MIS-C-S) vs moderate (-M) based on the requirement for vasoactive medication and/or positive pressure ventilatory support. This stratification turned out to be key for their new insights.

Finding #1

MIS-C patients are + for anti-SARS-CoV-2 antibodies but not necessarily viral RNA. They also found that the anti-viral gene signature in COVID19 patients is not seen in MIS-C. Still unclear if MIS-C could be set off by another post-viral microbial trigger (gut?).

Figure 3.  C.HD: Child Healthy Donors;
MIS-C-R:  Recovered MISC-C patients;
A.HD: Adult Healthy Donors;
COVID19-A: COVID-19 patients from early timepoint
(median of 7 days after symptom onset)
COVID19-B:  COVID-19 patients from late timepoint
(median of 16 days after symptom onset)

Finding #2

Serum proteomics in MIS-C vs child healthy donor (C.HD) highlights cytokine storm, fluid shear stress, and coagulation pathways. How does innate immunity contribute?

Two potential clues: elevated myeloid S100A alarmins (inflammation amplifiers) and elevated NK/CD8 cytotoxicity genes. 

Figure 4. 

Left: Overall, there was a significant enrichment in myeloid-derived proteins 

among the differentially expressed proteins in serum

Right: Moreover, pathway analysis of differential proteins 

in the serum revealed enrichment of terms 

associated with ‘Cytokine-cytokine receptor interaction’, 

‘Fluid shear stress and atherosclerosis’, 

and ‘Complement and coagulation cascades’, 

which are consistent with the inflammatory phenotype in the patients 

Finding #3

Are there autoantibodies? Support for this possibility first came from serum antibody screens for reactivity to human proteins (see @BrodinPetter, @BogunovicLab work). They found elevated plasmablasts in MIS-C, and increased IgG1+ cells.

Figure 5. MIS-C patients have increased proliferating plasmablasts
harboring IgG1 and IgG3 and a coordinated CD4 T cell response

Next is where severe vs moderate comes in. They see more pronounced plasmablast phenotypes and elevated serum E-selectin (endothelial) in MIS-C-S. Importantly, they also detect binding of serum IgG from severe patients to cultured cardiac endothelial cells.

What about TCR reactivity? They don’t know yet. Intriguingly, they found a significant increase in Vb11-2 TCRs in severe MIS-C.^[3] So far, they don’t know if TCR skewing occurs before (from SARS-CoV-2?) or after MIS-C onset.

Finding #4

In [7], Swedish scientists sought to investigate the dynamics of, and relationship between, serum markers of brain injury (neurofilament light [NfL], Glial Fibrillary Acidic Protein [GFAP] and total Tau) and markers of dysregulated host response to SARS-CoV-2 including measures of autoinflammation (proinflammatory cytokines) and autoimmunity.

During hospitalization, patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, and there was evidence of ongoing active brain injury at follow-up 4 months later. 

Raised NfL and GFAP were associated with both elevations of pro-inflammatory cytokines and the presence of autoantibodies; autoantibodies were commonly seen against lung surfactant proteins as well as brain proteins such as myelin associated glycoprotein, but reactivity was seen to a large number of different antigens. Furthermore, a distinct process characterized by elevation of serum total Tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses in the same manner as NfL and GFAP.

 

References

1. L. Huang, Y. Shi, B. Gong, L. Jiang, X. Liu, J. Yang, J. Tang, C. You, Q. Jiang, B. Long, T. Zeng, M. Luo, F. Zeng, F. Zeng, S. Wang, X. Yang, Z. Yang, Blood single cell immune profiling reveals the interferon-MAPK pathway mediated adaptive immune response for COVID-19, medRxiv, (2020) 2020.2003.2015.20033472.
2. Post-infectious inflammatory disease in MIS-C features elevated cytotoxicity signatures and autoreactivity that correlates with severity 
3. Identification of a unique TCR repertoire, consistent with a superantigen selection process in Children with Multi-system Inflammatory Syndrome
4. Longitudinal analyses reveal immunological misfiring in severe COVID-19
5. Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children
6. The autoimmune signature of hyperinflammatory multisystem inflammatory syndrome in children
7. Brain Injury in COVID-19 is Associated with Autoinflammation and Autoimmunity