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Principal Investigator: DIRK HOMANN
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2023
Award: $418,396
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
ABSTRACT
The possibility that infection with SARS-CoV-2 may trigger diabetes emerged as a concern in mid 2020. We have
addressed this issue by developing a research roadmap that identified complementary areas of investigation according
to several broad topics in the realm of relevant basic biomedical research. Based on our recent publication about the
expression of SARS-CoV-2 entry factors in the non-diabetic human pancreas, we have now developed a Research
Strategy that will assess the principal capacity of pancreatic SARS-CoV-2 infection and its primary consequences in a
series of in vitro, in vivo and ex vivo studies distributed across three Specific Aims:
In Aim 1 we will define expression patterns of ACE2 and other viral entry factors in dispersed human pancreatic cell
populations; will subject islets to in vitro SARS-CoV-2 infection and quantify infection patterns as well as alterations of
single-cell proteomes and transcriptomes by flow cytometry, high-dimensional mass cytometry, and scRNAseq; will
determine functional islet responses under conditions of viral infection by dynamic glucose-stimulated insulin secretion;
will conduct mechanistic studies with targeted ACE2 blockade and by generation of ACE2-deficient beta-like cells; and
will explore SARS-CoV-2 infection in the context of living pancreas slices that provide a more “physiological”
experimental platform for in vitro studies. In Aim 2, we will use the robust “minimal mass” model of human islet
transplantation into immunodeficient mice to delineate metabolic perturbations (blood glucose values, plasma insulin,
intraperitoneal glucose tolerance test) accrued in the wake of an in vivo SARS-CoV-2 challenge. To address the
considerable experimental and logistical challenges in these studies, we have developed a tiered approach that
progressively refines experimental designs (including use of a recently generated, sequenced and characterized
mouse-adapted [ma] SARS-CoV-2 strain) with the goal to imbue our models with escalating biological relevance. In
Aim 3, we will draw on our access to COVID-19 and control autopsy cases to reveal the ex vivo viral burden of natural
SARS-CoV-2 infection in the pancreas. These studies, which build on recently published pilot data as well as extensive
preparatory studies to adjust our staining protocols to the demands of at times suboptimal tissue quality, will define
SARS-CoV-2 protein and mRNA abundance, cellular association and distribution patterns across the COVID-19
pancreas. We will further leverage an established immunohistochemical multiplexing strategy to define the identity,
quantity and distribution of major immune cell subsets throughout COVID-19 and control pancreata. Thus, the proposed
work will generate an inclusive perspective on the cardinal viral and immunological components of the potentially
altered pancreatic histology in COVID-19.
Collectively, the proposed work addresses, and is expected to resolve at least in part, key aspects of the hypothesis
that SARS-CoV-2 infection may precipitate diabetes onset. Together with emerging epidemiological data, it may
therefore provide an important foundation for future risk assessment and the prioritization of prophylactic and/or
therapeutic intervention strategies.
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Publication><Series><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Severities><Slice><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Staining method><Stains><Sudden-Onset Diabetes Mellitus><Susceptibility><T1 DM><T1 diabetes><T1D><T1DM><T2 DM><T2D><T2DM><Therapeutic Intervention><Time><Tissues><Tropism><Type 1 Diabetes Mellitus><Type 1 diabetes><Type 2 Diabetes Mellitus><Type 2 diabetes><Type I Diabetes Mellitus><Type II Diabetes 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