Gastrointestinal involvement attenuates COVID-19 severity and mortality (preprint)

Given that gastrointestinal (GI) symptoms are a prominent extrapulmonary manifestation of coronavirus disease 2019 (COVID-19), we investigated the impact of GI infection on disease pathogenesis in three large cohorts of patients in the United States and Europe. Unexpectedly, we observed that GI involvement was associated with a significant reduction in disease severity and mortality, with an accompanying reduction in key inflammatory proteins including IL-6, CXCL8, IL-17A and CCL28 in circulation. In a fourth cohort of COVID-19 patients in which GI biopsies were obtained, we identified severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) within small intestinal enterocytes for the first time in vivo but failed to obtain culturable virus. High dimensional analyses of GI tissues confirmed low levels of cellular inflammation in the GI lamina propria and an active downregulation of key inflammatory genes including IFNG, CXCL8, CXCL2 and IL1B among others. These data draw attention to organ-level heterogeneity in disease pathogenesis and highlight the role of the GI tract in attenuating SARS-CoV-2-associated inflammation with related mortality benefit.

Cytotoxic lymphocytes are dysregulated in multisystem inflammatory syndrome in children (preprint)

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and multiple organ involvement in individuals under 21 years following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To identify genes, pathways and cell types driving MIS-C, we sequenced the blood transcriptomes of MIS-C cases, pediatric cases of coronavirus disease 2019, and healthy controls. We define a MIS-C transcriptional signature partially shared with the transcriptional response to SARS-CoV-2 infection and with the signature of Kawasaki disease, a clinically similar condition. By projecting the MIS-C signature onto a co-expression network, we identified disease gene modules and found genes downregulated in MIS-C clustered in a module enriched for the transcriptional signatures of exhausted CD8+ T-cells and CD56dimCD57+ NK cells. Bayesian network analyses revealed nine key regulators of this module, including TBX21, a central coordinator of exhausted CD8+ T-cell differentiation. Together, these findings suggest dysregulated cytotoxic lymphocyte response to SARS-Cov-2 infection in MIS-C.

SARS-CoV-2 causes severe alveolar inflammation and barrier dysfunction (preprint)

Infections with SARS-CoV-2 lead to mild to severe coronavirus disease-19 (COVID-19) with systemic symptoms. Although the viral infection originates in the respiratory system, it is unclear how the virus can overcome the alveolar barrier, which is observed in severe COVID-19 disease courses. To elucidate the viral effects on the barrier integrity and immune reactions, we used mono-cell culture systems and a complex human alveolus-on-a-chip model composed of epithelial, endothelial, and mononuclear cells. Our data show that SARS-CoV-2 efficiently infected epithelial cells with high viral loads and inflammatory response, including the interferon expression. By contrast, the adjacent endothelial layer was no infected and did neither show productive virus replication or interferon release. With prolonged infection, both cell types are damaged, and the barrier function is deteriorated, allowing the viral particles to overbear. In our study, we demonstrate that although SARS-CoV-2 is dependent on the epithelium for efficient replication, the neighboring endothelial cells are affected, e.g., by the epithelial cytokine release, which results in the damage of the alveolar barrier function and viral dissemination.

Intestinal inflammation modulates the expression of ACE2 and TMPRSS2 and potentially overlaps with the pathogenesis of SARS-CoV-2 related disease (preprint)

Immune dysregulation and cytokine release syndrome have emerged as pathological hallmarks of severe Coronavirus Disease 2019 (COVID-19), leading to the evaluation of cytokine antagonists as therapeutic agents. A number of immune-directed therapies being considered for COVID-19 patients are already in clinical use in chronic inflammatory conditions like inflammatory bowel disease (IBD). These considerations led us to systematically examine the intersections between COVID-19 and the GI tract during health and intestinal inflammation. We have observed that IBD medications, both biologic and non-biologic, do not significantly impact ACE2 and TMPRSS2 expression in the uninflamed intestines. Additionally, by comparing SARS CoV2-induced epithelial gene signatures with IBD-associated genes, we have identified a shared molecular subnetwork between COVID-19 and IBD. These data generate a novel appreciation of the confluence of COVID-19- and IBD-associated inflammation and provide mechanistic insights supporting further investigation of specific IBD drugs in the treatment of COVID-19.