Mehdi Benkahla, Ph.D.

Role of human herpesvirus-6 infection in the pathogenesis of type 1 diabetes

FUNDED: JANUARY 2019

FUNDED BY: The generosity of Robert and Rachel Perlmutter and various 2018 SPARK donors.

What was the goal of your SPARK project?

Type 1 diabetes is an autoimmune disease where T cells destroy insulin-producing beta cells in the pancreatic islets. Scientists still don’t understand the process that drives the immune system to target these cells. There are lines of evidence suggesting that both environmental factors such as viruses and genetic susceptibility play an important role in triggering the disease. Several viruses, mainly from the enterovirus family, have been considered as potential causal agents for type 1 diabetes. However, little is known about the involvement of other viruses, such as herpesviruses. My project was focused on looking specifically at whether human herpesvirus-6 (HHV-6) could play a role in the development of type 1 diabetes.

SPARK project results:

I used high-resolution confocal microscopy to detect HHV-6 in pancreas samples from diabetic and non-diabetic organ donors. I specifically focused on the HHV-6 gB protein, a protein that plays a critical role during membrane fusion and viral entry, as a marker for the presence or absence of HHV-6 in individual pancreatic islets. Our data showed that patients with type 1 diabetes have a significantly higher level of viral gB protein in the pancreas, compared to donors without diabetes. We detected the gB protein in the islets of six out of seven type 1 diabetes donors, compared with only one out of four non-diabetic donors, and two out of five donors with auto-antibodies. We published the results of the study titled “Human herpesvirus-6 is present at higher levels in the pancreatic tissues of donors with type 1 diabetes” in the Journal of Autoimmunity in November 2019. In summary, this novel research has shown that donors with type 1 diabetes are more likely to have been infected by a virus like HHV-6. This suggests a viral infection may be a

potential cause of the disease through an indirect mechanism. For example, maybe pancreata of type 1 patients are in general more susceptible to infections, possibly due to alterations in cellular pathways that could make them more vulnerable to harmful viruses.

What’s next for this project?

When studying the pancreatic sections and viral infections we faced many challenges since the organ was fixed. Upon completing my project, I submitted an application to the Network for Pancreatic Organ Donors with Diabetes (nPOD) with the hope of getting access to precious samples from patients. Our application was successful and in 2020 we were granted live human pancreatic slices to study viral infections. My next step is to secure additional grant dollars to continue this study using these rare samples. In that vein, I re-applied to the Tullie and Rickey Families SPARK Awards program this fall with the hopes of securing supplemental funding for this project. I’m honored to have been selected as a 2021 finalist, and to be the first Tullie and Rickey Families SPARK Awards alumnus to pitch for follow-on funding for my project. My hope is that if I’m successful in winning this award I will be able to tackle new research areas using this newly developed model of human pancreatic slices. I anticipate that with this additional preliminary data, we’ll be able to apply for NIH funding to take this project further and help unravel the mystery of beta cell death in type 1 diabetes.

What’s next for Mehdi?

In addition to competing for another Tullie and Rickey SPARK Award, I plan to apply for a postdoctoral fellowship to support my research while at LJI. This will help further my career and fund my current research projects with the hope of ultimately publishing my findings and advancing the type 1 diabetes field. Long term, I’d like to stay in the U.S. to continue studying type 1 diabetes whether in academia or industry.