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IL-10 suppresses T cell expansion while promoting tissue-resident memory cell formation during SARS-CoV-2 infection in rhesus macaques

ABSTRACT: SARS-CoV-2 infection leads to vastly divergent and heterogeneous clinical outcomes ranging from asymptomatic to fatal disease. Co-morbidities, sex, age, and host genetics together with vaccine status are known to affect disease severity. However, how the inflammatory milieu of the lung at the time of SARS-CoV-2 infection impacts control of the virus remains less well understood. Here, we identify key innate immune pathways required to limit viral replication, including the pro-inflammatory cytokine TNFα. Moreover, we demonstrate here that recent immune events in the lung proximal to the time of SARS-CoV-2 exposure can drastically impact viral control. A diverse set of pulmonary inflammatory stimuli, ranging from prior resolved respiratory infections of S. aureus or influenza, ongoing M. tuberculosis infection, or ovalbumin/alum-induced asthma to administration of defined TLR ligands and recombinant cytokines, resulted in an antiviral state that potently limited SARS-CoV-2 replication. In addition to type I interferons, the broadly inducible inflammatory cytokines TNFα and IL-1 very effectively conditioned the lung for enhanced viral control. Collectively, our work reveals that SARS-CoV-2 may benefit from an immunologically quiescent lung microenvironment and indicates that the recent and momentary pulmonary inflammatory tone during SARS-CoV-2 exposure may contribute to the population-wide variability in COVID-19 disease outcomes.

ORGANISM(S): Macaca mulatta Macaca fascicularis

PROVIDER: GSE268196 | GEO | 2024/05/30

REPOSITORIES: GEO

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Project description:Background: Type I interferons (IFNs) are essential to the clearance of viral diseases, in part by initiating upregulation of IFN regulated genes (IRGs). A clear distinction between genes upregulated directly by virus and genes upregulated by secondary IFN production has not been made. Here we investigated the genes regulated by IFN-a2b compared to the genes regulated by SARS-CoV infection in ferrets. Methods: We characterized early host immune responses in peripheral blood and lung necropsies of ferrets injected with IFN-a2b or infected with SARS-CoV/Tor 2 strain, using microarray analysis on the Affymetrix platform. Results: We identified a common IRG signature that was upregulated in both SARS-CoV infected ferrets as well as in ferrets injected with IFN-a2b. We also identified unique patterns of gene expression for leukocyte activation, cell adhesion and complement pathways between IFN-a2b injection and SARS-CoV infection. Conclusions: Our results define the effects of IFN-a2b on the immune system of ferrets highlighting genes regulated by IFN during SARS-CoV infection. We have shown the similarities and differences of top funcional gene groups as well as pathways that play key roles in early immune responses in ferrets in response to IFN-a2b or SARS-CoV. Key words: ferret, gene expression, SARS, interferon. Keywords: time course In experiments with IFN-a2b, for peripheral blood, 15 ferrets were randomly allocated to 3 groups: Day 0, 5 ferrets (no IFN injection), day 1, 6 ferrets (injected), and day 2, 4 ferrets (injected). For lung necropsies of injected ferrets with IFN-a2b, we used 12 ferrets in 3 groups: 4 ferrets, day 0 (no IFN injection), 4 ferrets, day 1 (injected) and 4 ferrets, day 2 (injected). Experimental groups for SARS-CoV infection was as follows: For peripheral blood, 3 and 4 ferrets for day 0 (no infection) and day 2 (infection) respectively. For lung neceropsies, a total of 9 ferrets in 3 groups, each with 3 replicates for day 0 (no infection), day 1 (infection) and day 2 (infection).

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IL-10 suppresses T cell expansion while promoting tissue-resident memory cell formation during SARS-CoV-2 infection in rhesus macaques

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