COVID-19 is well understood to have a gender disparity, with males having both higher disease burden and poorer outcomes. The mechanism for this disparity is still largely not understood with men experiencing longer infection times, worsened symptoms and a higher mortality rate. In order to investigate this phenomenon, we performed a multiomics analysis on a differential dose model of SARS-CoV2 in both male and female mice. Mice were infected with increasing titers of viral PFU’s from 100-10000, with lungs collected at end point, formalin fixed, paraffin embedded, sectioned and subjected to shotgun mass spectrometry. Samples were extracted using a novel approach that removes formaldehyde with a high degree of efficiency, allowing for accurate quantification of >2000 protein groups.
Mass spectrometry data was searched in Peaks Studio V12 and outputs were then transformed with 0 values imputed to the lowest observed area value. Results revealed a significant decrease in proteins responsible for mRNA splicing and the SNARE complex responsible for transportation of RNA’s across the endoplasmic reticulum into the ribosome. Additionally, there was a significant decrease in ATPase and GTPase proteins responsible for fueling translational machinery and the mature ribosome; overall demonstrating a significant decrease in the major components of the spliceosome. This was further validated with single cell RNAseq, with preliminary data showing that there was an enrichment for transcripts related to cytoplasmic ribosomal proteins. Further investigation is warranted however there is compelling evidence that an inherent mechanism in protein translation and splicing in females is responsible for lower disease burden and increased survival during a COVID infection.