Nav: Home

Investigation into fungal infection reveals genetic vulnerability in Hmong

July 15, 2019

MADISON - Ten years ago, in Marathon County, Wisconsin, 55 people were sickened by an uncommon fungal infection called blastomycosis. Thirty patients were hospitalized. Two people died.

The fungus, Blastomyces dermatitidis, found naturally in wet soil and in decomposing wood throughout 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 in the U.S. and outbreaks ranging up to 100 cases periodically occur in the state.

Given the size of the Marathon County outbreak, the state asked the U.S. Centers for Disease Control and Prevention for help launching an investigation -- unusually, 20 patients infected with the fungus were of Hmong descent. Investigators found that Asian people had a disproportionate risk of developing blastomycosis infections relative to other groups in the U.S. and they ruled out 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 among Hmong people that renders them more susceptible to the disease-causing fungus.

"We were struck by this because it hadn't been described before ... rates were 10-to-100 times greater than one might expect based on population numbers alone," says Klein, an infectious disease physician and professor of pediatrics, internal medicine, and medical microbiology and immunology at the UW School of Medicine and Public Health (SMPH). "It's really been a holy grail question -- why are some people more vulnerable and what is the basis for this?"

Understanding these vulnerabilities is really important for patients, says Pepperell, also an infectious disease physician and associate professor of medicine and medical microbiology and immunology at SMPH, because it can help physicians make better-informed and more timely decisions about treatment for people who are at higher risk.

"Unfortunately, a really typical story with blastomycosis is having a long delay to diagnosis because it's a (relatively) rare disease and people are not familiar with it," Pepperell says. The earlier people are treated, the better their outcomes.

At the start of the study, recently published in the open-access journal mBio, Pepperell surmised that Hmong people in Wisconsin, who have "experienced a long series of forced displacements and migrations," might be more genetically isolated than other groups and thus have less genetic variation powering their fight against some diseases.

That's because every gene we inherit exists in pairs called alleles -- we get one copy from each parent. Having two alleles that are different creates variation, but as is often the case in genetically isolated groups, the alleles can also be identical, or homozygous. A person who inherits one good copy of a gene and one bad still has some protection from its effects, while a person who gets two bad copies is more vulnerable.

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

With the help of her former graduate student, co-author Donny Xiong, the research team gained consent from nine of the affected Hmong patients to collect blood and examine their cells.

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

Within that region are genes for an immune element known as cytokine interleukin-6 (IL-6), which helps lead to the development of another immune responder known as interleukin-17 (IL-17), involved in teaching the body to fight fungal infections. The research team found that the cells of Hmong people created less IL-6 than the cells of European donors.

The specialized cells that produce IL-17, called Type 17 cytokine T helper cells (TH17), "patrol the mucosal surfaces of the body and are important in alarming (the body's) first-line defenses," Klein explains. "They serve as the cavalry and mop up invaders."

Klein's research team found previously in mice that TH17 cells are particularly important for responding to fungal invaders and that IL-6 is pivotal to their creation. The finding suggested to the researchers that Hmong people who produce less IL-6 may have fewer TH17 cells, and thus, less IL-17.

So, Klein's team went back to the mouse model and found that mice lacking IL-6 had significantly fewer TH17 cells than normal mice, were extremely vulnerable to Blastomyces infection, experienced progressive disease, and died sooner.

The researchers also found that Hmong donor cells produced significantly less IL-17 than those from 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's responsible for thrush and common vaginal 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 take up residence in the lungs. Pepperell is interested in "zooming out" to see if other genes may be different in Hmong people, since this study looked specifically at immune-related genes and could be missing more of the big picture.

For Klein, the work has been "extremely gratifying." He has studied blastomycosis in Wisconsin since 1981, first as a trainee with the CDC's Epidemic Intelligence Service, and long worked alongside the late state epidemiologist, Jeff Davis, who passed away just last year. Together, they helped establish Wisconsin as the first state to make it a legally reportable infectious disease.

"It's like: 'Battle on,'" with this fungus," Klein says. He appreciates the implications the findings have not just for individual patients, but also for public health more broadly. It also helps lay the groundwork for the future, particularly as plans are forged by UW-Madison to establish the SMPH Center for Human Genomics and Precision Medicine.

"This is a great example of the Wisconsin Idea," Klein says. "This is something we should be doing -- the state and the university working together for the benefit of public health and people in Wisconsin."
-end-
This study was supported by a pilot grant from the UW-Madison Department of Medicine, the Wisconsin Partnership Program, the National Institutes of Health (AI035681, AI093553), the National Science Foundation Graduate Research Fellowship Program (DGE-1255259), and the Ruth L. Kirschstein National Research Service Award through the National Institute for Minority Health and Health Disparities (F30 MD011547).

Kelly April Tyrrell, kelly.tyrrell@wisc.edu, 608-262-9772

University of Wisconsin-Madison

Related Public Health Articles:

Public health guidelines aim to lower health risks of cannabis use
Canada's Lower-Risk Cannabis Use Guidelines, released today with the endorsement of key medical and public health organizations, provide 10 science-based recommendations to enable cannabis users to reduce their health risks.
Study clusters health behavior groups to broaden public health interventions
A new study led by a University of Kansas researcher has used national health statistics and identified how to cluster seven health behavior groups based on smoking status, alcohol use, physical activity, physician visits and flu vaccination are associated with mortality.
Public health experts celebrate 30 years of CDC's prevention research solutions for communities with health disparities
It has been 30 years since CDC created the Prevention Research Centers (PRC) Program, currently a network of 26 academic institutions across the US dedicated to moving new discoveries into the communities that need them.
Public health experts support federally mandated smoke-free public housing
In response to a new federal rule mandating smoke-free policies in federally funded public housing authorities, three public health experts applaud the efforts of the US Department of Housing and Urban Development to protect nonsmoking residents from the harmful effects of tobacco exposure.
The Lancet Public Health: UK soft drinks industry levy estimated to have significant health benefits, especially among children
The UK soft drinks industry levy, due to be introduced in April 2018, is estimated to have significant health benefits, especially among children, according to the first study to estimate its health impact, published in The Lancet Public Health.
Social sciences & health innovations: Making health public
The international conference 'Social Sciences & Health Innovations: Making Health Public' is the third event organized as a collaborative endeavor between Maastricht University, the Netherlands, and Tomsk State University, the Russian Federation, with participation from Siberian State Medical University (the Russian Federation).
Columbia Mailman School Awards Public Health Prize to NYC Health Commissioner Dr. Mary T.
Dr. Mary T. Bassett, Commissioner of the New York City Department of Health and Mental Hygiene, was awarded the Frank A.
Poor health literacy a public health issue
America's poor record on health literacy is a public health issue, but one that can be fixed -- not by logging onto the internet but by increased interaction with your fellow human beings, a Michigan State University researcher argues.
Despite health law's bow to prevention, US public health funding is dropping: AJPH study
Although the language of the Affordable Care Act emphasizes disease prevention -- for example, mandating insurance coverage of clinical preventive services such as mammograms -- funding for public health programs to prevent disease have actually been declining in recent years.
'Chemsex' needs to become a public health priority
Chemsex -- sex under the influence of illegal drugs -- needs to become a public health priority, argue experts in The BMJ this week.

Related Public Health Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Anthropomorphic
Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#SB2 2019 Science Birthday Minisode: Mary Golda Ross
Our second annual Science Birthday is here, and this year we celebrate the wonderful Mary Golda Ross, born 9 August 1908. She died in 2008 at age 99, but left a lasting mark on the science of rocketry and space exploration as an early woman in engineering, and one of the first Native Americans in engineering. Join Rachelle and Bethany for this very special birthday minisode celebrating Mary and her achievements. Thanks to our Patreons who make this show possible! Read more about Mary G. Ross: Interview with Mary Ross on Lash Publications International, by Laurel Sheppard Meet Mary Golda...