The Role of Innate Immunity and Bioactive Lipid Mediators in COVID-19 and Influenza

Abstract

In this review, we discuss spatiotemporal kinetics and inflammatory signatures of innate immune cells specifically found in response to SARS-CoV-2 compared to influenza virus infection. Importantly, we cover the current understanding on the mechanisms by which SARS-CoV-2 may fail to engage a coordinated type I response and instead may lead to exaggerated inflammation and death. This knowledge is central for the understanding of available data on specialized pro-resolving lipid mediators in severe SARS-CoV-2 infection pointing toward inhibited E-series resolvin synthesis in severe cases. By investigating a publicly available RNA-seq database of bronchoalveolar lavage cells from patients affected by COVID-19, we moreover offer insights into the regulation of key enzymes involved in lipid mediator synthesis, critically complementing the current knowledge about the mediator lipidome in severely affected patients. This review finally discusses different potential approaches to sustain the synthesis of 3-PUFA-derived pro-resolving lipid mediators, including resolvins and lipoxins, which may critically aid in the prevention of acute lung injury and death from COVID-19.

Vascular Damage, Thromboinflammation, Plasmablast Activation, T-Cell Dysregulation and Pathological Histiocytic Response in Pulmonary Draining Lymph Nodes of COVID-19

“…Importantly, prior studies have shown that lysozyme can play a role in antiviral activity and suggest that low lysozyme levels (as found in COVID-19) may increase virulence ( 65 , 66 ). SIGLEC-1 , which negatively regulates viral infection-triggered type I IFN production ( 67 ) in macrophages, was downregulated in our dataset - this further underscores a macrophage-mediated dysregulated IFN-response as a hallmark of severe disease ( 68 ), as previously observed in lung tissue of the same autopsy cohort ( 17 ). In line with these findings, early clinical trials of otilimab, an anti-GM-CSF (granulocyte-macrophage colony stimulating factor) monoclonal antibody, showed a reduction of all-cause mortality in older patients with severe COVID-19 ( 69 ).…”

“…Notably, the downregulation/knock-out of PTGDS is known to increase vascular permeability, neutrophilic influx and lung damage, in line with the clinical presentation of severe COVID-19 ( 78 ), which might be counteracted by COX2 inhibition ( 79 ). Thus, the therapeutic significance of pharmaceutic agents interfering with arachidonic acid metabolism ( 68 ) requires further investigation in adequately powered, randomized controlled trials.…”

Plasma Oxylipins and Their Precursors Are Strongly Associated with COVID-19 Severity and with Immune Response Markers

“…A persistent and excessive innate immune response contributes to COVID-19 severity. Various lipids, some acting as immune modulators, are dysregulated along the course of the disease [ 1 , 2 , 3 , 4 , 5 , 6 ], yet obtaining an exact metabolic picture of small lipids involvement is still work in progress [ 5 , 7 , 8 , 9 , 10 ]. Low molecular weight lipids (<500 Da) play diverse biochemical roles, as they are embedded in cell membranes and take part in cell signalling, energy production and storage, among other endogenous processes.…”

Correlation between structural heart disease and cardiac SARS-CoV-2 manifestations

“…COVID-19 patients with cardiac involvement exhibit an aggravated clinical course with poor prognosis, including higher morbidity and mortality 10 . It remains unclear whether these symptoms occur due to (a) viral infection of the myocardium or (b) secondary myocardial injury due to a fierce cytokine storm induced by the innate immune system in response to the infection 11 . Despite increasing evidence regarding cardiac involvement in COVID-19, it remains unclear which patients are at high risk for cardiac involvement.…”