Fungal Infections Study Identifies Specific Genetic Vulnerability Among Hmongs

Ten years ago, in Marathon County, Wisconsin, 55 people were afflicted with a rare fungal infection called blastomycosis. Thirty patients were hospitalized. Two people died.

The mushroom, Blastomyces dermatitidis, occurring naturally in moist soil and decomposing wood in the Great Lakes region and the Mississippi Valley, can cause flu-like illness and, in severe cases, death. Wisconsin has among the highest incidence rates of the disease among the United States and outbreaks of up to 100 cases occur periodically in that state.

Given the magnitude of the Marathon County epidemic, the state has asked the US Centers for Disease Control and Prevention to help launch an investigation -; exceptionally, 20 patients infected with the fungus were of Hmong descent. Investigators found that Asians had a disproportionate risk of contracting blastomycosis compared to other groups in the United States and dismissed lifestyle explanations such as gardening practices and recreation.

Now, a new study led by University of Wisconsin-Madison researchers, Caitlin Pepperell and Bruce Klein, has identified a specific genetic vulnerability in Hmongs that makes them more vulnerable to the fungus that causes the disease.

We were struck by this because it had not been described before … the rates were 10 to 100 times higher than what could be expected based solely on the number of inhabitants. It's really a question of Holy Grail -; why are some people more vulnerable and what is its basis? "

Bruce Klein, Infectious Disease Physician and Professor of Pediatrics, Internal Medicine, Medical Microbiology and Immunology at the UW School of Medicine and Public Health (SMPH)

Pepperell, also an infectious disease physician and badociate professor of medicine, medical microbiology and immunology at SMPH, is particularly aware of the understanding of these vulnerabilities. higher risk.

"Unfortunately, a typical case of blastomycosis is a significant delay in diagnosis because it is a (relatively) rare disease and that people do not know well," says Pepperell. The more people are treated early, the better their results.

At the beginning of the study, recently published in the journal open access mbioPepperell hypothesized that the Wisconsin Hmongs, which have "experienced a long series of forced migrations and migrations," may be more genetically isolated than other groups and thus have fewer genetic variations to combat certain diseases. .

This is because every gene we inherit exists in pairs, called alleles -; we receive a copy of each parent. Having two different alleles creates variation, but as is often the case in genetically isolated groups, the alleles may also be identical or homozygous. A person who inherits a good copy of a gene and a bad one still has some protection against its effects, while a person who has two bad ones is more vulnerable.

"Many disease-causing variants are homozygous," says Pepperell.

With the help of his former graduate student, coauthor Donny Xiong, the research team obtained the consent of nine of the Hmong patients concerned to draw blood and examine their cells.

Pepperell and her graduate student, Mary O'Neill, co-author of the study, searched for long periods of homozygosity in the genomes of the Hmong participants. They found them in an area known to be important for immune responses to fungi.

In this region are the genes of an immune element called cytokine interleukin-6 (IL-6), which contributes to the development of another immune responder called interleukin-17 (IL-17), involved in teaching to the body of the fight against fungi. infections. The research team discovered that Hmong cells created less IL-6 than European donor cells.

The specialized cells that produce IL-17, called T helper cells of type 17 cytokine (TH17), "patrol the mucosal surfaces of the body and play an important role in the alarming first-line defenses (of the body) "says Klein. "They serve as cavalry and wipe the invaders."

Klein's research team has already discovered in mice that TH17 cells were particularly important for reacting to fungal invaders and that IL-6 was essential to their creation. The finding suggests to researchers that Hmongs producing less IL-6 might have fewer TH17 cells and therefore less IL-17.

Klein's team returned to the mouse model and found that mice lacking IL-6 had significantly fewer TH17 cells than normal mice and were extremely vulnerable to the disease. Blastomyces infection, had a progressive illness and died earlier.

The researchers also found that Hmong donor cells produced significantly less IL-17 than Europeans in response to infection with another more common fungus, Candida albicans. Both groups are more likely to have been exposed to this fungus before – it is responsible for thrush and common badl yeast infections.

Klein and Pepperell continue to study genetic vulnerability to Blastomyces, which is part of a family of seven particularly pathogenic fungi that are harmless unless their spores are inhaled and do not reside in the lungs. Pepperell is interested in "zooming out" to see if any other genes may be different in Hmongs, as this study is specifically interested in genes related to the immune system and could miss further the view of 39; together.

For Klein, the work was "extremely rewarding". He has been studying blastomycosis in Wisconsin since 1981, first as a trainee with the CDC's Epidemic Intelligence Service, and has worked for a long time alongside the late state epidemiologist Jeff Davis, who died 39, last year. Together, they helped make Wisconsin the first state to make it a legally-reported infectious disease.

"It's like: 'fight', 'with this mushroom," he explains. He understands the implications of the results not only for patients, but also for public health at large. It also helps lay the foundation for the future, especially UW-Madison plans to create the SMPH Center for Human Genomics and Precision Medicine.

"This is a great example of the idea of ​​Wisconsin," says Klein. "This is something we should do: the state and the university are working together for the sake of public health and the people of Wisconsin."