Induction of a cytokine storm involves suppression of the Osteopontin‐dependent TH1 response.

Cytokine release syndromes represent a severe turn in certain disease states, which may be caused by several infections, including those with the virus SARS‐CoV‐2. This inefficient, even harmful, immune response has been associated with a broad release of chemokines. Although a cellular (type I) immune reaction is efficacious against viral infections, we noted a type I deficit in the cytokine patterns produced by cytokine storms of all reported etiologies. Agents including lipopolysaccharide (LPS, bacterial), anti‐CD3 (antibody) and a version of the prominent SARS‐CoV‐2 viral surface molecule, Spike Glycoprotein, were individually sufficient to induce IL‐6 and multiple chemokines in mice. They failed to upregulate the TH1 inducer cytokine Osteopontin, and the pathophysiologic triggers actually suppressed the PMA‐induced Osteopontin secretion from monocytic cells. Osteopontin administration partially reversed the chemokine elevation, more effectively so in a mouse strain with TH1 bias. Corroboration was obtained from the inverse correlation in the levels of IL‐6 and Osteopontin in plasma samples from acute COVID‐19 patients. We hypothesize that the inhibition of Osteopontin by SARS‐CoV‐2 Spike Glycoprotein or LPS represents an immune evasion mechanism employed by the pathogens of origin. The ensuing dysfunctional inflammatory response promotes a vicious cycle of amplification, resulting in a cytokine storm. [ABSTRACT FROM AUTHOR]