Issue 11: Inflammatory mediators in COVID-19 (MAY 15, 2020)
ROLE OF MACROPHAGES IN COVID-19
Macrophages are a population of innate immune cells that sense and respond to microbial threats by producing inflammatory molecules that eliminate pathogens and promote tissue repair1. However, a dysregulated macrophage response can be damaging to the host. The major immunological cell suspected to be associated with inflammation and lung damage in COVID-19 is the macrophage.
Observational data show overlapping clinical features in severe COVID-19 with macrophage activating syndrome (MAS) and secondary hemophagocytic lymphohistiocytosis (HLH) associated with innate immune migration to lung tissues2. For instance, a cytokine profile resembling MAS/sHLH has been reported in COVID-19 patients, with notably increased IL-1β, IL-2, IL-6, IL-17, IL-8, TNF-α, and CCL23,4.
In this context, the inhibition of this immunological pathway may help to control excessive cytokine production and prevent pulmonary damage (i.e., fibrosis)5.
The JAK-STAT pathway is also thought to be involved in facilitating immune responses in some COVID-19 patients. Monocytes differentiate into pro-inflammatory macrophages though activation of KAK-STAT. SARS-CoV-2 inhibits TYK 2 (via NSP1), further driving inflammation by causing downstream effects that overlap with immunomodulatory pathways6.
Therefore, anti-cytokine, JAK inhibitors, and antihypertensives may quell hyperinflammation by interacting and inhibiting these signaling cascades.
Notably though, most JAK inhibitors have been associated with increased risk for thrombosis, viral reactivation, and myelosuppression6. However, these adverse effects (except myelosuppression) are likely to be dependent on duration and dose. As with IL-1 inhibitors, JAK inhibitors generally have short half-lives and can have efficacy within days. NK and T cells further promote the recruitment and activation of macrophages through GM-CSF, TNF, and IFNγ.
ROLE OF T CELLS IN COVID-19
CD8+ T cells are important for directly attacking and killing virus-infected cells, whereas CD4+ T cells are crucial for priming both CD8+ T cells and B cells. CD4+ T cells are also responsible for cytokine production to drive immune cell recruitment.7 Increased T cell exhaustion and reduced functional diversity predicted severe disease.
A common feature in many patients with COVID-19 is the presence of a global T cell lymphopenia, which is more pronounced in the CD8+ T cell compartment and is particularly prominent in patients with severe disease7. This is thought to be due to direct killing of lymphocytes. CD8+ T cells with a tissue-resident memory T cell gene signature was observed in the BALF of patients with mild COVID-19, in which inflammatory monocyte infiltration was minimal. Authors speculate that these results could suggest that pre-existing populations of tissue-resident memory T cells with potential cross-reactivity against SARS-CoV-2 that could enable rapid control of the virus, and protect against disease progression by limiting epithelial damage, local inflammation and accumulation of pathological macrophage populations.
Some authors have also proposed immunomodulation of invariant natural Killer T (iNKT) cells for regulating cytokine responses in hyperinflammatory conditions such as COVID-19 and sepsis)8-10. Polarization of iNKT cells into a T helper type 2 (Th2*) phenotype using the synthetic glycolipid, OCH, significantly reduced mortality from in a mouse model of sepsis. This reduction in mortality was associated with the systemic elevation of the Th2 anti-inflammatory cytokine IL-13 and reduction in several proinflammatory cytokines such as IL-17.
Clearly, several mechanisms are at play in the COVID-19 pathogenesis, and controlling key inflammatory responses appears to be crucial for mitigating disease severity.
- Merad and Martin, Nat Revs Immunol 2020
- McGonagle et al. Autoimmun Rev 2020.
- Wan et al. https://www.medrxiv.org/content/10.1101/2020.02.10.20021832v1.
- Ye et al. J Infect . 2020 Apr 10.
- Ingraham et al. Lancet Respir Med 2020
- Seif et al. nt Arch Allergy Immunol. 2020 May .
- Tay et al. Nat. Rev. Immunol. 2020 Apr 28 : 1–12.
- Gu et al. J. Exp. Med. 202, 415–424 .
- Rojas et al. Autoimmunity Rev. April 2020.
- Anantha et al. 2014; Clin Exp Immun 178: 292–309.
- Blanco-Melo et al. Cell 2020.
*Th2 cytokines: IL-4, -5, -10, and -13, are associated with promotion of IgE and eosinophilic responses in atopy, and anti-inflammatory responses. In excess, Th2 responses will counteract the Th1-mediated proinflammatory responses.