COVID-19 News: PTPN2 Risk Variant rs1893217 Linked To Autoimmune Diseases Promotes SARS-CoV-2 Susceptibility And COVID-19 Severity
: A new research by scientists from the University of California Riverside, University of Zurich, McGill University-Montreal, University of California-San Diego and Beckman Research Institute of City of Hope has discovered that the autoimmune PTPN2 risk variant rs1893217 gene found in most individuals with autoimmune diseases including Inflammatory bowel disease IBD, rheumatoid arthritis, multiple sclerosis, psoriasis and even diabetes, enhances SARS-CoV-2 infection susceptibility and COVID-19 severity.
COVID-19, caused by SARS-CoV-2, has affected over 75.7 million individuals and killed over 1.68 million persons. While fatality rates are higher among the elderly and those with underlying comorbidities, host factors that promote susceptibility to SARS-CoV-2 infection and severe disease are poorly understood. Although individuals with certain autoimmune/inflammatory disorders show increased susceptibility to viral infections, there is incomplete knowledge of SARS-CoV-2 susceptibility in these diseases.
The study team report that the autoimmune PTPN2
risk variant rs1893217 promotes expression of the SARS-CoV-2 receptor, ACE2, and increases cellular entry mediated by SARS-CoV-2 spike protein. Elevated ACE2 expression and viral entry were mediated by increased JAK-STAT signaling, and were reversed by the JAK inhibitor, tofacitinib.
The study findings uncover a novel risk biomarker for increased expression of the SARS-CoV-2 receptor and viral entry, and identify a clinically approved therapeutic agent to mitigate this risk.
The study findings were published on a preprint server are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2020.12.09.416586v1
The human host entry of SARS-CoV-2 is mediated by the S glycoprotein (also known as the S protein). The S protein is sliced by the transmembrane protease serine protease 2 (TMPRSS2) and TMPRSS4 into S1 and S2 subunits in a process called ‘priming.’ S1 binds to angiotensin I converting enzyme 2 (ACE2) and S2 helps with the subsequent fusion of viral and host membranes. ACE2, TMPRSS2, and TMPRSS4 are all expressed abundantly on epithelial cells' surface, including lung type 2 pneumocytes and absorptive intestinal epithelial cells.
To date, the host factors that promote susceptibility to severe COVID-19 are poorly understood.
It is known that about 16-20% of humans carry a single nucleotide polymorphism (SNP) rs1893217 located in the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2). This SNP causes PTPN2 loss of function and is linked to increased risk for inflammatory and autoimmune diseases, including Type 1 diabetes, inflammatory bowel disease, and rheumatoid arthritis. https://pubmed.ncbi.nlm.nih.gov/17554260/
Though individuals with autoimmune / inflammatory disorders have increased susceptibility to viral infections, the mechanism by which SARS-CoV-2 susceptibility works in individual
s with these diseases is not clear.
Even with massive global efforts to understand COVID-19 pathogenesis, the host factors that promote susceptibility to infection and severe illness are not well understood. While a lot of attention has been focused on airway symptoms, studies show that 46% of all cases reported gastrointestinal (GI) symptoms and 33% of the cases presented with GI symptoms without respiratory symptoms.
It was also found that GI symptoms were associated with longer duration of disease and more severe illness with a high prevalence of acute renal insufficiency, which highlights the importance of early diagnosis and prognosis.
The study team reported that the autoimmune PTPN2 risk variant rs1893217 promotes the expression of the SARS-CoV-2 receptor, ACE2, and thus promotes cellular entry, which is mediated by SARS-CoV-2 spike S protein.
The study findings show that that SNP rs1893217 in PTPN2 is associated with elevated ACE2 expression and SARS-CoV-2 entry, which, according to the authors, is likely one of the first genetic susceptibility biomarkers identified for COVID-19.
The study findings consistently demonstrate that PTPN2 dysfunction promotes expression of ACE2 and uptake of SARS-CoV-2 spike protein, and this is further increased by inflammation.
The study also shows the elevated ACE2 expression and viral uptake in PTPN2 variant cells.
Furthermore since the study used samples collected before the outbreak of COVID-19, their identification of a genetic susceptibility marker avoids the possibility of ascertainment bias that happens in most COVID-19 genetic studies. This is because clinically significant COVID-19 patients are more likely to be recruited in research projects compared to asymptomatic cases.
Various other studies on genetic markers of COVID-19 susceptibility have hinted about the involvement of ABO blood groups, with group O linked to lower risk and group A associated with higher risk of contracting COVID-19 compared to non-A blood groups.
Moreover, a gene cluster on chromosome 3 has been linked with increased disease severity, though this link may have clear geographic distributions.
The study findings shows increased ACE2 expression and viral uptake in PTPN2 variant cells, which may not only suggest a potential novel genetic marker for increased severity, but also identifies an approved drug for arthritis and IBD, tofacitinib, and other JAK inhibitors like baricitinib, as potential therapeutic solutions to mitigate this risk.
The study team concluded,”Summarized, we demonstrate that SNP rs1893217 in PTPN2 is associated with increased expression of ACE2 and SARS-CoV-2 entry, and potentially represents one of the first identified COVID-19 genetic susceptibility biomarkers. By using samples collected well before the COVID19 outbreak, our identification of a genetic susceptibility marker avoids the potential for ascertainment bias in most genetic studies of COVID-19, as clinically significant COVID-19 patients are more likely to be included in research projects than asymptomatic cases. With respect to genetic markers of COVID-19 susceptibility, studies have proposed the involvement of ABO blood groups, with blood group O associated with lower risk, while blood group A was associated with higher risk of acquiring COVID-19 compared with non-A blood groups. However, this correlation did not culminate in therapeutic implications. Moreover, a cluster of genes on chromosome 3 has been linked with increased severity, although this may have distinct geographic distributions. In contrast, the study findings of increased ACE2 expression/viral particle uptake in PTPN2 variant cells might not only indicate a potentially novel genetic marker for increased disease, but also identifies tofacitinib-a drug already approved for treatment of arthritis and IBD and potentially other JAK inhibitors such as baricitinib, as a potential therapeutic strategy to specifically mitigate this risk."
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