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Similarities and differences in the acute-phase response to SARS-CoV-2 in rhesus macaques and African green monkeys

ABSTRACT: Understanding SARS-CoV-2 immune pathology is critical for the development of effective vaccines and treatments. Here, we employed unbiased serial whole-blood transcriptome profiling by weighted gene network correlation analysis (WGCNA) at pre-specified timepoints of infection to understand SARS-CoV-2-related immune alterations in a cohort of rhesus macaques (RMs) and African green monkeys (AGMs) presenting with varying degrees of pulmonary pathology. We found that the bulk of transcriptional changes occurred at day 3 post-infection and normalized to pre-infection levels by 3 weeks. There was evidence of coordination of transcriptional networks in blood (defined by WGCNA) and the nasopharyngeal SARS-CoV-2 burden as well as the absolute monocyte count. Pathway analysis of gene modules revealed prominent regulation of type I and type II interferon stimulated genes (ISGs) in both RMs and AGMs, with the latter species exhibiting a greater breadth of ISG upregulation. Notably, pathways relating to neutrophil degranulation were enriched in blood of SARS-CoV-2 infected AGMs, but not RMs. Our results elude to hallmark similarities as well as differences in the RM and AGM acute response to SARS-CoV-2 infection, and may help guide the selection of particular NHP species in modeling aspects of COVID-19 disease outcome.

ORGANISM(S): Chlorocebus sabaeus Macaca mulatta

PROVIDER: GSE184949 | GEO | 2021/09/30

REPOSITORIES: GEO

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Project description:Inflammation following SARS-CoV-2 infection is a hallmark of COVID-19 and predictive of morbidity and death. However, the inflammatory pathways contributing to host-defense vs immune-mediated pathology have not been fully elucidated. This duality is clearly seen with type-I interferons (IFN-I) which are critical mediators of innate control of viral infections, but also drive recruitment of inflammatory cells to site of infection, a key feature of severe COVID-19. Here, we modulated IFN-I signaling in rhesus macaques (Macaca mulatta) prior to and during acute SARS-CoV-2 infection (day -1 through day 2 post infection) using a mutated IFNα2 (IFN-modulator; IFNmod) which blocks binding to IFNAR2 and signaling of endogenous IFN-I. IFNmod treatment resulted in a highly significant and consistent reduction in SARS-CoV-2 viral load in BAL, lung, and hilar LN (>3-log difference) and upper airways (nasal swabs). IFNmod also potently reduced inflammatory cytokines and chemokines in BAL, expansion of inflammatory monocytes (CD14+CD16+), and lung pathogenesis. Furthermore, Siglec-1 expression, which has been shown to enhance SARS-CoV-2 infection, was rapidly downregulated in the lung and on monocytes of IFNmod-treated SARS-CoV-2 infected RMs. Notably, while RNAseq analysis showed that IFNmod induced a modest upregulation of antiviral IFN-stimulated genes (ISGs) in uninfected RMs, it resulted in a robust reduction in pathways associated with both antiviral and inflammatory ISGs in SARS-CoV-2-infected RMs. In conclusion, IFNmod treatment provides sufficient levels of type I IFN signaling that inhibit viral replication while also limiting hyperinflammation. IFN-I plays a vital role in regulating SARS-CoV-2 replication, but uncontrolled IFN signaling has a detrimental impact on inflammation and pathogenesis. A better understanding of the role of IFN-I pathways is essential for designing therapies targeting these pathways and aimed at limiting COVID-19 pathogenesis.

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).

Project description:The COVID-19 pandemic remains a global health crisis, yet, the immunopathological mechanisms driving the development of severe disease remain poorly defined. Here, we utilize a rhesus macaque (RM) model of SARS-CoV-2 infection to delineate perturbations in the innate immune system during acute infection using an integrated systems analysis. We found that SARS-CoV-2 initiated a rapid infiltration (two days post infection) of plasmacytoid dendritic cells into the lower airway, commensurate with IFNA production, natural killer cell activation, and induction of interferon-stimulated genes. At this early interval, we also observed a significant increase of blood CD14-CD16+ monocytes. To dissect the contribution of lung myeloid subsets to airway inflammation, we generated a novel compendium of RM-specific lung macrophage gene expression using a combination of sc-RNA-Seq data and bulk RNA-Seq of purified populations under steady state conditions. Using these tools, we generated a longitudinal sc-RNA-seq dataset of airway cells in SARS-CoV-2-infected RMs. We identified that SARS-CoV-2 infection elicited a rapid recruitment of two subsets of macrophages into the airway: a C206+MRC1- population resembling murine interstitial macrophages, and a TREM2+ population consistent with CCR2+ infiltrating monocytes, into the alveolar space. These subsets were the predominant source of inflammatory cytokines, accounting for ~75% of IL6 and TNF production, and >90% of IL10 production, whereas the contribution of CD206+MRC+ alveolar macrophages was significantly lower. Treatment of SARS-CoV-2 infected RMs with baricitinib (Olumiant®), a novel JAK1/2 inhibitor that recently received Emergency Use Authorization for the treatment of hospitalized COVID-19 patients, was remarkably effective in eliminating the influx of infiltrating, non-alveolar macrophages in the alveolar space, with a concomitant reduction of inflammatory cytokines. This study has delineated the major subsets of lung macrophages driving inflammatory and anti-inflammatory cytokine production within the alveolar space during SARS-CoV-2 infection.

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Similarities and differences in the acute-phase response to SARS-CoV-2 in rhesus macaques and African green monkeys

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