Peptidylarginine deiminases (PADs) are a family of
calcium-regulated
enzymes that are phylogenetically conserved and cause post-translational deimination/citrullination, contributing to
protein moonlighting in health and disease. PADs are implicated in a range of inflammatory and autoimmune conditions, in the regulation of extracellular vesicle (EV) release, and their roles in
infection and
immunomodulation are known to some extent, including in
viral infections. In the current study we describe putative roles for PADs in
COVID-19, based on in silico analysis of BioProject transcriptome data (PRJNA615032 BioProject), including lung biopsies from healthy volunteers and SARS-CoV-2-infected patients, as well as SARS-CoV-2-infected, and mock human bronchial epithelial NHBE and
adenocarcinoma alveolar basal epithelial A549 cell lines. In addition, BioProject Data PRJNA631753, analysing patients tissue biopsy data (n = 5), was utilised. We report a high individual variation observed for all PADI
isozymes in the patients' tissue biopsies, including lung, in response to
SARS-CoV-2 infection, while PADI2 and PADI4
mRNA showed most variability in lung tissue specifically. The other tissues assessed were heart, kidney, marrow, bowel, jejunum, skin and fat, which all varied with respect to
mRNA levels for the different PADI
isozymes. In vitro lung epithelial and
adenocarcinoma alveolar cell models revealed that PADI1, PADI2 and PADI4
mRNA levels were elevated, but PADI3 and PADI6
mRNA levels were reduced in SARS-CoV-2-infected NHBE cells. In A549 cells, PADI2
mRNA was elevated, PADI3 and PADI6
mRNA was downregulated, and no effect was observed on the PADI4 or PADI6
mRNA levels in infected cells, compared with control mock cells. Our findings indicate a link between PADI expression changes, including modulation of PADI2 and PADI4, particularly in lung tissue, in response to
SARS-CoV-2 infection. PADI
isozyme 1-6 expression in other organ biopsies also reveals putative links to
COVID-19 symptoms, including vascular, cardiac and cutaneous responses, kidney injury and
stroke. KEGG and GO pathway analysis furthermore identified links between PADs and inflammatory pathways, in particular between PAD4 and
viral infections, as well as identifying links for PADs with a range of comorbidities. The analysis presented here highlights roles for PADs in-host responses to SARS-CoV-2, and their potential as therapeutic targets in
COVID-19.