Proteomic Signature of Host Response to SARS-CoV-2 Infection in the Nasopharynx

Abstract

Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 infection has become a global health pandemic. COVID-19 severity ranges from asymptomatic infection to severe multi-organ disease. Although the inflammatory response has been implicated in the pathogenesis of COVID-19, the exact nature of dysregulation in signaling pathways has not yet been elucidated underscoring the need for further molecular characterization of SARS-CoV-2 infection in humans. Here, we characterize the host response directly at the point of viral entry through analysis of nasopharyngeal swabs. Multiplexed high resolution mass spectrometry-based proteomic analysis of confirmed COVID-19 cases and negative controls identified 7,582 proteins and revealed significant upregulation of interferon-mediated antiviral signaling in addition to multiple other proteins that are not encoded by interferon-stimulated genes (ISGs) or well-characterized during viral infections. Downregulation of several proteasomal subunits, E3 ubiquitin ligases, and components of protein synthesis machinery was significant upon SARS-CoV-2 infection. Targeted proteomics to measure abundance levels of MX1, ISG15, Stat1, RIG-I and CXCL10, detected proteomic signatures of interferon-mediated anti-viral signaling that differentiated COVID-19 positive from negative cases. Phosphoproteomic analysis revealed increased phosphorylation of several proteins with known antiviral properties as well as several proteins involved in ciliary function (CEP131 and CFAP57) that have not previously been implicated in the context of coronavirus infections. Additionally, decreased phosphorylation levels of AKT and PKC, which have been shown to play varying roles in different viral infections, were observed in infected individuals relative to controls. These data provide novel insights that add depth to our understanding of SARS-CoV-2 infection in the upper airway and establish a proteomic signature for this viral infection.

Development of a multiomics model for identification of predictive biomarkers for COVID-19 severity: a retrospective cohort study

“…Elevated CXCL9, CXCL10, and CXCL11, which are secreted by chemotactically activated immune cells, are indicative of strong interferon-mediated responses. 17 LAG3 and LGALS9, involved in lymphocyte function, were elevated in the severe and critical groups; ICOSLG, however, was reduced. Although proinflammatory enzyme LTA4H was high in patients with severe and critical disease, VSIG4, a phagocytic receptor with anti-inflammatory effects, also showed a positive association with severity; this is a novel association that we report.…”

Proteomic deconvolution reveals distinct immune cell fractions in different body sites in SARS-Cov-2 positive individuals

“…This study analyzed publicly available data downloaded from the Protein Identification Database, PRIDE (https://www.ebi.ac.uk/pride/ ) repository. The data used in this analysis had the following identifiers: PXD019423 (gargle solution, n=3) (13), PXD018970 (Urine, n=15) ( 14), PXD022085 (BALF, n=5) (15), and PXD022889 (nasopharynx, n=18) (16). We acknowledge that the samples used in this study were processed in different laboratories worldwide, and the sample preparation protocols have been reported elsewhere in the respective publications (13,(15)(16)(17).…”

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

“…In Module 5 one of the most signi cantly enriched pathways is Cilium Assembly (FDR= 2.64e −04 ), which entails CEP131 affected by the variant rs2659015, which is enriched in asymptomatic patients (lor=-1.92; pval=0.001517767) and which received 100% model support. Intriguingly CEP131 has been recently found to be signi cantly regulated by phosphorylation during viral infection (Vanderboom et al, 2021).…”