Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of the coronavirus disease 2019 (COVID-19) pandemic, has infected over 73.4 million individuals and claimed the lives of more than 1.63 million people worldwide. While fatality rates are generally low, they are higher among the elderly population and those with comorbidities such as diabetes and heart disease.
The entry of SARS-CoV-2 into host cells 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.
The host factors that promote susceptibility to severe COVID-19 are poorly understood
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. Although individuals with autoimmune / inflammatory disorders have increased susceptibility to viral infections, the mechanism by which SARS-CoV-2 susceptibility works in individuals with these diseases is not clear.
Despite 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. Also, 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.
“Despite tremendous effort to understand COVID-19 pathogenesis, risk factors for severe disease are still poorly defined.”
Identifying genetic susceptibility biomarkers for COVID-19
Recently, a team of researchers from the University of California Riverside, USA; University of Zurich, Switzerland; McGill University, Montreal, Quebec, Canada; and Beckman Research Institute of City of Hope, USA, 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. Their work is published on the preprint server, bioRxiv*.
The 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.
“Our data consistently demonstrate that PTPN2 dysfunction promotes expression of ACE2 and uptake of SARS-CoV-2 spike protein, and this is further increased by inflammation.”
Findings show elevated ACE2 expression and viral uptake in PTPN2 variant cells
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.
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.
In contrast, the findings of this study 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.
“Collectively, our 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.”
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
- Marianne R. Spalinger, Rong Hai, Jiang Li, Alina N. Santos, Tara M. Nordgren, Michel L. Tremblay, Lars Eckmann, Elaine Hanson, Michael Scharl, Xiwei Wu, Brigid S. Boland, Declan F. McCole. Identification of a Novel Susceptibility Marker for SARS-CoV-2 Infection in Human Subjects and Risk Mitigation with a Clinically Approved JAK Inhibitor in Human/Mouse Cells. BioRxiv preprint server. doi: https://doi.org/10.1101/2020.12.09.416586,
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