Hormones Made by Viruses: A Novel Concept
By: Shin Jie Yong
Tags: Health, Future, Artificial Intelligence, Science, Technology

Hormones Made by Viruses: A Novel Concept

“Viruses continue to surprise.” This time with their own production of insulin and IGF.

Image by Julien Tromeur from Pixabay

The Idea

This novel research field explores how viruses can mimic the host endocrine system. “Mimicry is a common evolutionary phenomenon that occurs when an organism or cell imitates another to gain an advantage in competing for resources, protection, or survival,” explains Qian Huang, Ronald Kahn, and Emrah Altindis in Endocrinology a few months ago. “Until our recent discovery of viral insulin/IGF-1–like peptides (VILPs), knowledge on viral mimicry mechanisms was limited to mimics of growth factors and immunomodulatory proteins.”

Yes, they have made a novel discovery that viruses can produce hormones like insulin, insulin-like growth factors (IGFs), and potentially many others.

It started with the idea of Emrah Altindis, an assistant professor at Harvard Medical School, Massachusetts. His initial research field focuses on designing bacterial vaccines. As he attended a seminar that discussed the possible causes of type 1 diabetes, he began to wonder if microbes could also be involved.

The Test

Altindis collaborated with 10 other researchers — from Kumamoto University (Japan), Indiana University Bloomington (Indiana), Novo Nordisk A/S (Denmark), and within Harvard Medical School itself — to conceptualize and design experiments to test his hypothesis. This team of 11 scientists, with Altindis as the lead author, published their findings in 2018 in the Proceedings of the National Academy of Sciences of the United States of America (PNAS).

What did Altindis et al. do? First, they used bioinformatics techniques to screen all 7,455 complete viral genomes — in the National Center for Biotechnology Information (NCBI) database — for any DNA sequence similarity with any of the 62 known human hormones. They pinpointed 14 such viruses. Next, they used structural modelling techniques to predict the protein structure of these viral sequences. The aim is to see if both the sequence and structure matches that of the human’s; if they did, chances are that they share similar function at the protein level. Only a few viruses passed this second stage of analysis:

Insulin: Lymphocystis disease virus

Insulin-like growth factors (IGFs)-1 and -2: Lymphocystis disease virus and Singapore grouper iridovirus.

Endothelins 1 and 2: Deerpox virus.

They consequently synthesized the insulin and IGF viral hormones — they called them VILPs (viral insulin/IGF-1–like peptides). Why endothelins were left out was unexplained. They then tested the effects of these VILPs on mammalian cell cultures and mice.

As expected, these synthetic VILPs acted as the normal insulin or IGFs would. They bound to their respective receptors, activated similar signal cascades, and initiated glucose uptake by cells.

The next question is if these viruses — grouped as Iridoviruses that normally cause diseases in fish — are also found in humans? “It’s possible that humans get exposed to these viruses through just eating fish,” says the senior co-author Ronald Kahn, M.D.

To this end, Altindis et al. took another step further. They re-compiled and re-analyzed the sequencing data from three different human microbiome studies. Indeed, they detected the presence of these viruses in the human gut and blood microbiome. “These data support the hypothesis that humans are exposed to or can carry these Iridoviruses,” wrote the authors.

The Significance

In fishes, these Iridoviruses cause tumour-like growths on their skin, gills, and fins. Given the role of insulin and IGFs in a wide range of diseases, it hints at the “potential role of VILPs in hypoglycemia, insulin resistance, tumour formation, and production of/protection from type 1 diabetes,” Altindis et al. suggested.

This made sense from the evolutionary standpoint. Viruses that stop apoptosis and encourage cell growth — by expressing insulin or IGF — also enable these viruses to better survive, propagate, and replicate.

Besides cancer and tumorigenesis, “this research also opens up a new aspect to study in type 1 diabetes and autoimmunity,” Kahn adds. “It may be that these or similar microbial insulin-like molecules could be an environmental trigger to start the autoimmune reaction in type 1 diabetes. On the other hand, you could also imagine that this might desensitize the immune response and could be protective.”

Likewise for obesity and type 2 diabetes, “you could envision that these viral peptides could either protect from or contribute to insulin resistance,” explains Kahn.

Kahn is rather futuristic, suggesting that analyzing the viral insulin sequences could provide hints for pharmaceutical companies to design more advanced and cost-effective insulin. For instance, the insulin that is stable long-term and/or doesn’t need refrigeration, or more bio-available and fast-acting insulin. This is not entirely far-fetched as there have been successful cases to employ hormones from ‘unexpected species’ for drug development.

For instance, exendin-4 from the lizard venom, Gila monster (Heloderma suspectum) venom mimics human GLP-1 in stimulating insulin production. But, unlike human GLP-1, the lizard’s one has a longer half-life (~2.4 hours vs. 2 mins) and can, thus, last for 8 hours. The lizard’s exendin-4, hence, became an antidiabetic drug.

The Known Unknown

Altindis et al. emphasized that the current NCBI database contains the complete genomes of only 2–3% out of the estimated total number of mammalian viruses. This means that ~97% of the field of viral endocrinology remains uncharted. The authors further noted that their study might be an underestimate of the number of viral hormones detected due to the limitations of current bioinformatics techniques that may have missed out on smaller peptides.

“We are only beginning to appreciate the value and importance of the bacterial microbiome in health and disease, and our understanding of the role of viruses, including their role in endocrinology, is also just beginning,” writes David Irwin, PhD at the University of Toronto, Canada in response to Atindis et al.’s research. “Viruses continue to surprise.”