Coronavirus induces diabetic macrophage-mediated inflammation via SETDB2

Abstract

COVID-19 induces a robust, extended inflammatory “cytokine storm” that contributes to an increased morbidity and mortality, particularly in patients with type 2 diabetes (T2D). Macrophages are a key innate immune cell population responsible for the cytokine storm that has been shown, in T2D, to promote excess inflammation in response to infection. Using peripheral monocytes and sera from human patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and a murine hepatitis coronavirus (MHV-A59) (an established murine model of SARS), we identified that coronavirus induces an increased Mφ-mediated inflammatory response due to a coronavirus-induced decrease in the histone methyltransferase, SETDB2. This decrease in SETDB2 upon coronavirus infection results in a decrease of the repressive trimethylation of histone 3 lysine 9 (H3K9me3) at NFkB binding sites on inflammatory gene promoters, effectively increasing inflammation. Mφs isolated from mice with a myeloid-specific deletion of SETDB2 displayed increased pathologic inflammation following coronavirus infection. Further, IFNβ directly regulates SETDB2 in Mφs via JaK1/STAT3 signaling, as blockade of this pathway altered SETDB2 and the inflammatory response to coronavirus infection. Importantly, we also found that loss of SETDB2 mediates an increased inflammatory response in diabetic Mϕs in response to coronavirus infection. Treatment of coronavirus-infected diabetic Mφs with IFNβ reversed the inflammatory cytokine production via up-regulation of SETDB2/H3K9me3 on inflammatory gene promoters. Together, these results describe a potential mechanism for the increased Mφ-mediated cytokine storm in patients with T2D in response to COVID-19 and suggest that therapeutic targeting of the IFNβ/SETDB2 axis in T2D patients may decrease pathologic inflammation associated with COVID-19.

An explainable model of host genetic interactions linked to COVID-19 severity

“…Some categories show a prevalence of associations with risk factors, such as "respiratory or thoracic disease", including speci c traits such as chronic bronchitis, emphysema or COPD (the latter also found in the "infectious disease" category). Other categories enriched for associations with variants enriched in severe patients are "immune system disorders", including traits such as immunode ciency with antibody defects, or "pancreas disease", including several instances mainly associated to Type 2 diabetes, which is a known risk factor for severe COVID-19 (Onder et al, 2020) and whose molecular connection to cytokine storm in ammatory response has now begun to emerge (Melvin et al, 2021). Taken together, these results further corroborate our analysis.…”

Preexisting comorbidities shape the immune response associated with severe COVID-19

“…Poorly controlled diabetes has been linked to an inhibited lymphocyte proliferative response and impaired monocyte, macrophage, and neutrophil functions. 37,38 Interestingly, although being related to obesity and hypertension through the metabolic syndrome, in our study focusing on severe COVID-19-associated immune signatures, it was characterized not only by unconventional T-cell dysregulation but also by reduced expression of the costimulatory receptor CD86 in conventional DCs type 2. One could hypothesize that patients with COVID-19 and several comorbidities that are part of the metabolic syndrome might display dysregulation of several immune branches, thus explaining these patients' highly increased need for mechanical ventilation, intensive care unit admissions, and COVID-19 mortality.…”

The (apparent) antibody paradox in COVID-19

“…Similarly, inappropriate macrophage activation has been noted in patients with type 2 diabetes [ 128 ]. This could contribute to the cytokine storm and multiple-organ dysfunction seen in the systemic phase of the infection.…”