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Principal Investigator: Declan McCole
Organization: UNIVERSITY OF CALIFORNIA RIVERSIDE
Fiscal Year: 2021
Award: $378,939
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
SUMMARY/ABSTRACT
The global coronavirus disease 2019 (COVID-19) pandemic has affected over 70 million individuals in 220
countries (www.who.int). A major clinical confounder of COVID-19 is the lack of knowledge of host factors that
promote susceptibility to SARS-CoV-2 infection and more severe gastrointestinal symptoms in some patients.
Moreover, there is also a lack of interventions to mitigate these risks. Our preliminary studies identified that a
genetic marker of susceptibility to several intestinal diseases, the rs1893217 loss-of-function PTPN2 variant,
increased levels of the SARS-CoV-2 receptor, ACE2, in intestinal biopsies from inflammatory bowel disease
(IBD) patients. We hypothesize that individuals harboring PTPN2 loss-of-function variants may be more
susceptible to SARS-CoV-2 infection. We have already functionally validated our initial findings in IBD
patients that loss of activity of the PTPN2 gene results in increased ACE2 expression and SARS-Cov-2
spike protein cellular entry, using in vitro and/or in vivo models. Our overall objective will be to
mechanistically determine how PTPN2 loss-of-activity promotes SARS-CoV-2 cellular entry through upregulation
of ACE2 expression, and if this susceptibility can be mitigated by the clinically approved JAK inhibitor, tofacitinib.
Aim 1 will address how PTPN2 restricts expression of ACE2, and other host virus entry co-factors, to functionally
restrict virus entry in human intestinal epithelial cell (IEC) lines with reduced PTPN2 or expressing the IBD risk
PTPN2 variant rs1893217, as well as enteroids from Ptpn2-deficient mice. Aim 2 will o determine how PTPN2
deficiency in IECs alters the severity of infection with a mouse-adapted SARS-CoV-2, as well as intestinal
outcomes relevant to diarrheal symptoms in COVID-19 patients. Aim 3 will mechanistically determine if the JAK
inhibitor, tofacitinib can normalize ACE2 levels in vitro, in vivo, to reduce virus entry in IEC, human and mouse
enteroids, Ptpn2-deficient mice, and cells from PTPN2-genotyped IBD patients. We will also identify if tofacitinib
can modify ACE2 levels in IBD patients. We have established novel mouse lines and in vitro model systems for
this study. We will use these model systems in a series of innovative and established approaches, to allow us to
mechanistically define PTPN2 regulation of the fundamental interactions between SARS-CoV-2 and epithelial
cells that are required for virus entry and subsequently cause COVID-19. These experiments represent an
exciting new direction that synergizes the expertise of the investigative team. The results from these studies are
poised to generate significant advances in identifying 1) how a genetic risk variant of high relevance to several
NIDDK diseases can increase susceptibility to SARS-CoV-2 infection; 2) how SARS-CoV-2 can disrupt epithelial
integrity and homeostasis to promote diarrhea; 3) how an approved IBD therapeutic can be repurposed to
mitigate these risks. Therefore, the clinical implications of this study include identifying a novel mechanism that
can be targeted by existing JAK inhibitors for prophylactic or therapeutic administration, and genetic screening
of individuals for SARS-CoV-2 vaccine trials.
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Diseases><Non-tropical Sprue><Nontropical Sprue><Oral><Outcome><PTP Family Gene><PTPase><Patients><Phenotype><Phosphotyrosine Phosphatase><Phosphotyrosyl Protein Phosphatase><Physiological Homeostasis><Play><Predisposed to COVID-19><Predisposed to SARS-CoV-2><Predisposed to Severe acute respiratory syndrome coronavirus 2><Predisposition><Predisposition gene><Property><Protein Tyrosine Phosphatase><Protein Tyrosine Phosphatase Gene><Proteins><Pulmonary Body System><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Organ System><RNA Viruses><Receptor Protein><Receptor Type PTP Gene><Regulation><Reporting><Respiratory Disease><Respiratory Signs and Symptoms><Respiratory System><Respiratory System Disease><Respiratory System Disorder><Respiratory Tracts><Respiratory tract structure><Risk><Risk-associated variant><Role><Route><SARS corona virus 2><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 disease severity><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global 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multiplication><viral replication><virus infection><virus multiplication><virus-induced disease>