IFN signaling and neutrophil degranulation transcriptional signatures are induced during SARS-CoV-2 infection

Abstract

The novel virus SARS-CoV-2 has infected more than 14 million people worldwide resulting in the Coronavirus disease 2019 (COVID-19). Limited information on the underlying immune mechanisms that drive disease or protection during COVID-19 severely hamper development of therapeutics and vaccines. Thus, the establishment of relevant animal models that mimic the pathobiology of the disease is urgent. Rhesus macaques infected with SARS-CoV-2 exhibit disease pathobiology similar to human COVID-19, thus serving as a relevant animal model. In the current study, we have characterized the transcriptional signatures induced in the lungs of juvenile and old rhesus macaques following SARS-CoV-2 infection. We show that genes associated with Interferon (IFN) signaling, neutrophil degranulation and innate immune pathways are significantly induced in macaque infected lungs, while pathways associated with collagen formation are downregulated. In COVID-19, increasing age is a significant risk factor for poor prognosis and increased mortality. We demonstrate that Type I IFN and Notch signaling pathways are significantly upregulated in lungs of juvenile infected macaques when compared with old infected macaques. These results are corroborated with increased peripheral neutrophil counts and neutrophil lymphocyte ratio in older individuals with COVID-19 disease. In contrast, pathways involving VEGF are downregulated in lungs of old infected macaques. Using samples from humans with SARS-CoV-2 infection and COVID-19, we validate a subset of our findings. Finally, neutrophil degranulation, innate immune system and IFN gamma signaling pathways are upregulated in both tuberculosis and COVID-19, two pulmonary diseases where neutrophils are associated with increased severity. Together, our transcriptomic studies have delineated disease pathways to improve our understanding of the immunopathogenesis of COVID-19 to facilitate the design of new therapeutics for COVID-19.

Responses to acute infection with SARS-CoV-2 in the lungs of rhesus macaques, baboons and marmosets

“…ACE2 protein levels were much lower in lung tissues derived from naive animals compared with SARS-CoV-2-infected animals ( Supplementary Fig. 2m,n), a finding that is consistent with a recent RNA-sequencing analysis showing that ACE2 is upregulated after infection, especially in young macaques 9 . The majority of S signal was detected in the epithelial layer with discrete distribution throughout the lung tissue ( Supplementary Fig.…”

“…Although there was viral clearance and improvement in radiological scores over the course of the study, the inflammation parameters studied and histology were more protracted resulting in a limited correlation between end-point histological and radiological scores. Furthermore, pathways related to angiogenesis and thrombosis are enriched in the lungs of infected macaques compared with healthy macaques 9 . Histopathology analysis was performed at 3 d.p.i.…”

Rationale for COVID-19 Treatment by Nebulized Interferon-β-1b–Literature Review and Personal Preliminary Experience

“…In contrast, the mild forms of COVID-19 seen in children are likely to be related to their ability to produce type I IFN more efficiently than elderly persons (Trouillet-Assant et al, 2020b). In accordance with these data, type I IFN signaling pathway has been shown to be significantly up-regulated in lungs of juvenile macaques infected with SARS-CoV2, as compared to old infected macaques (Rosa et al, 2020). In SARS-CoV-infected aged macaques, the severity of the disease is associated with an increase in the expression of genes associated with inflammation and reduced expression of IFN-β as compared to young adult animals, who display a mild form of the disease (Smits et al, 2010).…”

COVID‐19 case fatality rate and tuberculosis in a metropolitan setting

“…Tuberculosis may be a marker of individual comorbid or socioeconomic conditions known to increase the risk of progression to severe COVID‐19 14 . In addition, it is possible that tuberculosis could affect clinical outcomes of COVID‐19 patients through direct pathogenic effects, 15 as both infections share common disease pathways 16 . Although a meta‐analysis of Chinese studies did not find an association between tuberculosis and COVID‐19 severity, 6 it is important to note that these results may have been affected by the clinical heterogeneity of tuberculosis cases and sample size limitations.…”