University of California, Davis

- SARS-CoV-2 viral infection was found to not significantly trigger IFN expression and only activated 5 of 13 pro-inflammatory mediators, which play important roles in the body's innate immune response. The virus possesses an gene identified as ORF3b that produces an IFN-antagonizing protein which inhibits synthesis and signaling and leads to unchecked viral replication.

- Virus entry triggers the generation of pro-inflammatory cytokines (IL-6, IP-10, macrophage inflammatory protein 1α (MIP1α), MIP1β and MCP1) which recruit monocytes, macrophages, and T-cells to the sites of infections. This promotes further inflammation and creation of a feedback loop leading to a cytokine storm.

Manipulation of Innate Immune and Pro-inflammatory Response

A review study presented on the pathophysiology of the COVID-19 virus and found that entry and replication by the virus into cells expressing ACE 2 receptors triggers host cell pyroptosis, generating pro-inflammatory cytokines and chemokines which recruit monocytes, macrophages, and T-cells. This results in further inflammation and creation of a pro-inflammatory feedback loop, leading to overproduction of cytokines that accumulate in the lungs, causing a cytokine storm.

Review Investigating the Immunopathogenesis of COVID-19

Tay, M. Z., Poh, C. M., Rénia, L., Macary, P. A., &amp; Ng, L. F. (2020). The trinity of COVID-19: Immunity, inflammation and intervention. Nature Reviews Immunology, 20(6), 363-374. doi:10.1038/s41577-020-0311-8
https://www.nature.com/articles/s41577-020-0311-8

The trinity of COVID-19: immunity, inflammation and intervention

Various genes have shown to be differentially expressed in COVID-19 patient bronchial alveolar lavage fluid (BALF) as compared to control data. The following list includes upregulated genes involved in known, clinical characterizations of COVID-19.
- cytokine storm ( CCL2/3/4/7/8, CXCL1/2/6/8/28, CCL3L3, CCL4L2)
- hypoxia (HIF1A, HLF)
- inflammasome /sepsis (IL1R1/2, IL5RA, IL33, IL31RA)

Immunity markers:
- alveolar cells (EHF, PAX9, ELF3, GHRL2) 
- immune cells (RFX3, SOX5, TP63, HOPX) 
- antiviral regulation (NR3C2)
- lymphocyte B cells (CD24 and CD38)
- lymphocyte T cells (CD4, CD8) (detected but not consistently upregulated)

Notable upregulated genes: 
- Cytokines 
- Epiregulin (EREG)
- Eph ligand genes (EFNA1, EFNA5)


Upregulation of Pulmonary Immune Cell-Derived Ligands from SARS-CoV-2 Infection.

- Response occurs ~1 week after onset of symptoms
- Some may not develop long-lasting antibodies to the virus
- Convalescent plasma treatment is a viable option
- The majority of antibodies to SARS-CoV-1 do not bind to the SARS-CoV-2 virus, likely due to differences in the receptor-binding-domain

B-Cell Immunity in COVID-19

- CD8+ T-cells: Directly attacks and kills virus-infected cells
- CD4+ T-cells: Primes CD8+ T cells and antibody-producing B cells, responsible for cytokine production
- T-cell exhaustion and reduced functional diversity lead to severe disease

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