Investigating the link between pericyte dysfunction and loss of glucose homeostasis in COVID-19

ABSTRACT
The coronavirus disease 2019 (COVID-19) is a global healthcare crisis that in the USA kills about 1 person every
minute. It is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). While respiratory
failure is still the most common cause of mortality in COVID-19 patients, serious manifestations are seen across
multiple organs, including the pancreas. There is an intricate relationship between COVID-19 and pancreatic
diseases such as pancreatitis and diabetes. Understanding the pathophysiological mechanisms that lead to
pancreatic dysfunction and glucose intolerance in infected patients is of utmost importance. The pathogenesis
of diabetes is intimately associated with the dysfunction of the pancreatic islet. There are numerous studies
indicating that SARS-CoV-2 directly attacks the vascular system. However, the possibility that islet microvascular
dysfunction triggers loss of glucose homeostasis in COVID-19 patients has not been explored. This project
focuses on the vascular pericyte because our published and preliminary data show that (a) pericytes in human
islets are very responsive to angiotensin II and express the key host cellular receptor of SARS-CoV-2, ACE2;
(b) pericytes can be infected with SARS-CoV-2 pseudo-entry viruses; and (c) incubation with a SARS-CoV-2
Spike recombinant protein increases pericyte basal Ca2+ levels. We therefore hypothesize that SARS-CoV-2
infects pancreas pericytes, interfering with their contractile properties and impairing their function. Pericyte
dysfunction will decrease local blood flow, leading to tissue hypoxia and inflammation and compromising
endocrine cell activity. We will test this hypothesis using living pancreas slices from humans and hamsters which
are a suitable animal model for COVID-19 research given the high homology of their ACE2 protein sequences.
This hypothesis will be tested in two Aims: 1) determine if pericytes are cellular targets of SARS-CoV-2 in the
pancreas, and (2) examine the effects of SARS-CoV-2 on islet pericyte function and microvascular responses
ex vivo and in vivo. In Aim 1, we will search for SARS-CoV-2 viral particles, characterize microvascular lesions
and the pericyte phenotype in the pancreas of COVID-19 patients. We will infect living pancreas slices with
SARS-CoV-2 pseudo-entry and live viruses and determine if pericytes are permissive for infection. In Aim 2, we
will assess the functional consequences of manipulating ACE2 expression and activity through interactions with
SARS-CoV-2 spike protein on pericyte Ca2+ responses and vasomotion ex vivo in living pancreas slices, and in
vivo by intraductal injections of pseudo-entry viruses in the hamster pancreas. We will follow longitudinally the
effects on glucose metabolism, as well as changes in local hypoxia, inflammation, endocrine cell mass and
function. This research has the potential to identify a mechanism of dysfunction in the endocrine pancreas. If the
hypothesis is correct, pericytes are cellular targets of this coronavirus. Their functional impairment could explain
why COVID-19 is linked to a loss of glucose homeostasis and other pancreatic disorders. We anticipate our
study of COVID-19–related diabetes to uncover novel mechanisms of the natural history of this disease.

Grant Number: 5R01DK133483-04
NIH Institute/Center: NIH
Principal Investigator: Joana Almaca