Researchers Discover Bacterial Protein that Causes Genomic Instability and Contributes to Reduced Fertility, Birth Defects
Study Underscores Significant Implications for Cancer and Obstetrics Medicine, as well as Diagnostics, and Preventative Therapy
A team of researchers from the University of Maryland School of Maryland’s (UMSOM) Institute of Human Virology (IHV), a Center of Excellence of the Global Virus Network (GVN), published new findings that emphasize the crucial role of the urinary and genital tract microbiota in adverse pregnancy outcomes and genomic instability that originate in the womb during fetal development.
The study, published this week in the Proceedings of the National Academy of Sciences of the United States of America (PNAS), established a new link between genomic instability, reduced fertility, and a protein from Mycoplasma fermentans, a kind of bacterium that commonly colonizes the urogenital tract in humans.
This research was spearheaded by Davide Zella, PhD, Assistant Professor of Biochemistry and Molecular Biology at UMSOM’s IHV and member of the GVN and Robert Gallo, MD, The Homer & Martha Gudelsky Distinguished Professor in Medicine, Co-Founder and Emeritus Director of UMSOM’s IHV, and Co-Founder and Chair of the Scientific Leadership Board of the Global Virus Network.
"Our results not only broaden our understanding of the interplay between the urogenital tract microbiota and human reproductive health, but also shed light on the previously unidentified contribution of the human microbiota to genetic abnormalities," said co-lead author on the study Francesca Benedetti, PhD, Research Associate of Biochemistry and Molecular Biology in UMSOM’s IHV and member of the GVN. “We aim to further explore the mechanisms underlying these findings and their potential implications for preventing and treating chromosomal abnormalities and genetic diseases.”
The human microbiota is known to affect metabolism, susceptibility to infectious diseases, immune system regulation, and more. One of these bacterial components, Mycoplasmas, have been linked to various cancers.
The research team has been studying one Mycoplasma protein, DnaK, which belongs to a family of proteins that safeguards other bacterial proteins against damage and aids in their folding when they are newly made, acting as a so-called ‘chaperone.’ However, while this protein is advantageous for bacteria, its effects on animal cells are less favorable. To this regard, the team had previously demonstrated that this DnaK is taken up by the body’s cells and it interferes with key proteins involved in preserving DNA integrity and in cancer prevention, such as the tumor suppressor protein p53.
For this latest study, researchers created mice that make the DnaK protein normally produced by the bacterium Mycoplasma fermentans. These mice with exposure to DnaK accrued genomic instability in which entire sections of the genome were duplicated or deleted, resulting in mice with varying numbers of copies of certain genes.
The team noticed that some of these mice from 3-5 weeks of age had problems with movement and coordination. They found that these mice have a deletion in the Grid2 gene, which in humans leads to the rare genetic disease known as spinocerebellar ataxia-18 (SCAR18) that causes delayed development of skilled movements and intellectual disabilities.
“Remarkably, this instance marks the first time a mouse model successfully recapitulated a human genetic disease de novo, showcasing this model's potential for further cancer biology research,” said Dr. Zella.
More than a third of the female mice that made the DnaK protein were unable to get pregnant. Additionally, more than 20 percent of the pups born from moms with the DnaK protein had some sort of birth defect/deformity.
“The occurrences of genomic instability, in the form of increased number of copy number variations, could explain the decreased fertility and the increased instances of abnormally developed fetuses we observed upon DnaK exposure,” said Dr. Gallo. “These data build upon our initial work which discovered the disruptive role of DnaK on key proteins involved in the proper repair of damaged DNA, which are also known to play a role in the onset of copy number variations. Our ongoing commitment is to better understand the potential implications of these findings in cellular transformation and cancer.”
UMSOM Dean Mark T. Gladwin, MD, who is also Vice President for Medical Affairs, University of Maryland, Baltimore and the John Z. and Akiko K. Bowers Distinguished Professor, commended the work. “The researchers raise a significant question regarding whether DnaK can interfere with fetal development in humans. An important next step would be to investigate whether neutralizing either the bacteria or this protein could preserve fertility and prevent certain birth defects,” he said.
About the Institute of Human Virology
Formed in 1996 as a partnership between the State of Maryland, the City of Baltimore, the University System of Maryland, and the University of Maryland Medical System, the IHV is an institute of the University of Maryland School of Medicine and is home to some of the most globally-recognized and world-renowned experts in all of virology. The IHV combines the disciplines of basic research, epidemiology, and clinical research in a concerted effort to speed the discovery of diagnostics and therapeutics for a wide variety of chronic and deadly viral and immune disorders, most notably HIV, the virus that causes AIDS. For more information, visit ihv.org and follow us on Twitter @IHVmaryland.
About the Global Virus Network (GVN)
The GVN is essential and critical in the preparedness, defense, and first research response to emerging, exiting, and unidentified viruses that pose a clear and present threat to public health. Working in close coordination with established national and international institutions, the GVN is a coalition comprised of eminent human and animal virologists from 71 Centers of Excellence and 9 Affiliates in 40 countries, working collaboratively to train the next generation, advance knowledge about how to identify and diagnose pandemic viruses, mitigate and control how such viruses spread and make us sick, as well as develop drugs, vaccines, and treatments to combat them. No single institution in the world has expertise in all viral areas other than the GVN, which brings together the finest medical virologists to leverage their individual expertise and coalesce global teams of specialists on the scientific challenges, issues, and problems posed by pandemic viruses. The GVN is a non-profit 501(c)(3) organization. For more information, please visit https://gvn.org/. Follow us on Twitter at @GlobalVirusNews.