The COVID-19 pandemic has hit the world with tremendous impact, with almost 300 million documented total cases worldwide. Due to its novelty, it is paramount that studies are done to gain a full understanding of the lasting effects that the novel coronaviruses can have.
In this SelectScience® interview, we speak with Dirk Homann, Professor in the Institutes of Diabetes, Obesity & Metabolism as well as Precision Immunology at the Icahn School of Medicine at Mount Sinai in New York. Prof. Homann runs a research program at the interface of infectious disease and autoimmune disease, with particular emphasis on Type 1 diabetes (T1D), and is currently at the helm of an important research project which links the coronavirus to diabetes.
DH: Over the past 40 years, almost every human pathogenic virus, or so it seems, has been considered as a potential trigger for T1D. But more often than not, tantalizing initial speculations have not stood the test of time (a notable exception are enteroviruses which continue to be an area of active investigation elucidating potential infectious causes for T1D).
So, adding SARS-CoV-2 to this list fits into a long tradition of diabetes research, and an article prominently communicated in the New England Journal of Medicine in 2020 did just that. Specifically, the authors proposed a “bi-directional dynamic” between COVID-19 and diabetes: for one, diabetes constitutes a risk factor for aggravated COVID-19 course, something that has since been confirmed in multiple studies. On the other hand, SARS-CoV-2 infection may also precipitate new diabetes onset for which the evidence to this day, however, remains much more limited. Nevertheless, the concept of a “bidirectional dynamic” has inspired the public imagination and with that the notion of SARS-CoV-2 infection as a potential diabetes trigger has gained traction.
We felt, however, that this concern was somewhat premature and together with our collaborators at the Universities of Florida and Indiana mapped out an experimental road map to better assess the risk for new onset diabetes as a consequence of acute SARS-CoV-2 infection.
DH: We first investigated the expression of viral entry factors – structures that permit cellular infection with SARS-CoV-2 – across the normal human pancreas. Drawing on the resources of the network for Pancreatic Organ Donors with Diabetes (nPOD) biorepository, we found that expression of these entry factors is limited to certain cell subsets including endothelial and ductal cells. In contrast, insulin-producing beta cells, which are compromised and destroyed in T1D, largely lacked the molecular machinery for virus entry. Accordingly, we concluded that direct SARS-CoV-2 infection and killing of beta cells constitutes an unlikely event. This work was published in late 2020 in Cell Metabolism together with a report from another investigator team that essentially made the same observations.
Our second line of investigation pertains to the deliberate in vitro infection of human islets, pancreatic mini-organs that contain the beta cells, with SARS-CoV-2. While certainly somewhat artificial, this type of work permits an elucidation of the principal extent and consequences of pancreatic SARS-Cov-2 infection under conditions of high virus exposure. Using state-of-the art single-cell technologies, we found the infection remained highly circumscribed, targeted a minority of beta cells in the absence of enhanced cell death, and promoted only modest cellular perturbations and inflammatory responses. Our manuscript detailing these findings is currently under peer review.
A third area of investigation is focused on analyses of COVID-19 autopsy pancreata where our ongoing work seeks to visualize and quantify expression of SARS-CoV-2 proteins and nucleic acids. Other groups have already published on this topic and by all accounts it appears that the viral burden in the pancreas is quite limited. This type of work is also complicated by the fact that the pancreas is prone to self-digestion, so the tissue integrity of COVID-19 autopsy pancreata is often compromised adding further difficulties to these investigations. We are trying to address these challenges by collecting larger numbers of COVID-19 donor pancreata which we think is necessary to arrive at robust experimental outcomes.
And lastly, in a fourth line of research, we are developing novel rodent models to study the consequences of human islet infection with SARS-CoV-2 in vivo.
DH: In our view, the notion that direct SARS-CoV-2 infection of beta cells can precipitate new-onset diabetes is confounded by the fact that several key stages of presumed disease development are relatively rare conditions or events: limited expression of viral entry factors by beta cells, limited extent and consequences of in vitro beta cell infection, and limited viral burden of SARS-CoV-2 in the COVID-19 pancreas. However, more subtle damage to the pancreatic microenvironment in the wake of SARS-CoV-2 infection, including microvascular thrombosis, may compound to enhance future diabetes incidence in at-risk individuals. I am partial to the “fertile-field hypothesis”, which stipulates that there's no one specific virus that directly causes diabetes, but rather, it's pancreatic damage caused by repeated viral infections. Meaning that down the road, if these individuals suffer a series of different viral infections including SARS-CoV-2, they may develop diabetes. If this is indeed the case will only emerge in observational studies to be conducted over the next few years. In general, however, I think it is of utmost importance that basic biomedical research is carefully informed and guided by corresponding epidemiological studies. And the fact that we are not in the throws of an acute new-onset diabetes crisis despite several hundred million COVID-19 cases to date is a compelling argument that the risk of developing actual new-onset diabetes, rather than the temporary disturbances of glucose metabolism associated with severe disease in general, is at best very limited.
DH: To comprehensively interrogate human islet cells, we employ a technology platform called mass cytometry to provide a higher dimensional single-cell readout (~45 distinct parameters). Here, highly specific antibodies for visualization of practically all pancreatic cell subsets and their broad phenotypic properties are conjugated to rare-earth metals and subsequently used for our mass cytometry-based single-cell investigations. We've found, perhaps somewhat surprisingly, that islet cells express quite a few markers typically expressed by immune cells. So, we therefore utilized BioLegend’s large portfolio of well-vetted immunology antibodies, specific for various human immune cell antigens, and leveraged these reagents for our human islet cell work.
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