Periods of extreme heat often result in an increase in deaths, mostly related to heart conditions. A UofL research study shows that heat also can impair the immune system and increase damaging inflammation, according to Daniel Riggs, assistant professor of environmental medicine and affiliated with .

Riggs and his colleagues recorded levels of immune cells and biomarkers in the blood of 624 participants in Louisville during summer months. They then compared those levels with the Universal Thermal Climate Index for that day, which factors in air temperature, relative humidity, wind speed and ultraviolet radiation levels as a measure of heat exposure.

They found that when it was hotter, the participants had higher levels of immune molecules in their blood, indicating a general immune response and inflammation, as well as lower levels of B-cells, which allow the body to fight specific infections. This means that with higher heat, people may be more susceptible to infection and more sensitive to environmental exposures, which in turn can contribute to worsened heart disease.

“We know that certain changes in the immune system and increased inflammation are a leading mechanism in many types of cardiovascular disease. Our findings suggest that heat exposure could be contributing to these processes that ultimately lead to greater risk of cardiovascular disease,” Riggs said.

Riggs presented at the American Heart Association Epidemiology, Prevention, Lifestyle and Cardiometabolic Health Conference in March.

The work, recently published in the journal , reveals an underappreciated connection between genetics and our antibodies. Antibodies are key players in our immune system, with important roles in human health and disease, including in infection, autoimmunity, cancer and even vaccine responsiveness.

“Our work demonstrates that not everyone has the same capacity to generate certain types of antibodies due to genetics,” said Oscar Rodriguez, a post-doctoral fellow at UofL, and the first author of the study. “This could have critical implications for how we assess outcomes related to treatments and vaccines that depend on the antibody response.”

Vaccines, for example, work by simulating a viral infection and triggering an immune response — a sort of drill that teaches the body what a virus looks like and how to fight it. While it’s commonly known that individual response to vaccines can vary from person to person, this work shows more clearly than ever that these variations may depend on the antibody genes a person has inherited.

“For a long time, we’ve assumed vaccines could be designed using a one-size-fits-all approach,” said Melissa Smith, director of the , and lead author of the study. “This research shows that genetics predisposes us to qualitatively and quantitatively different antibody responses. If this information could be used to understand when individuals will or won’t respond to a given vaccine or treatment, that could be hugely impactful.”

The research also revealed that differences in our antibody responses could be linked to broader patterns of genetic diversity across human populations. This stresses the need to better characterize diversity in the genes that encode antibodies, and specifically increase the sampling of understudied populations. This is one of the driving forces behind research being conducted by this team.

Critical for advancing this effort is the recent acquisition of a by the Sequencing Technology Center. UofL is one of only a handful of service providers in the country to offer access to this technology. Its use by this team could help improve our understanding of ancestry-specific immune gene-associated disease through the characterization of antibody genes in thousands of individuals worldwide, leading to improved and more equitable patient care. 

“We are currently building the most comprehensive catalogs of human antibody genetic variation from diverse genetic ancestries,” said Corey T. Watson, associate professor in the , and senior author of the study. “By studying a greater number of populations across the globe, we will be able to clarify the contribution genes make in positioning our immune systems to respond in a variety of disease contexts, and hopefully inform next-generation treatments.”

“Now we are hoping to determine which bacteria or metabolites are interacting to determine the severity or lack of severity of illness in the individual,” Schmidt said. “If we can identify the bacteria, it raises hope that we can target those mechanisms to prevent severity of the disease, thereby reducing illness and death from malaria in sub-Saharan Africa.”

Globally, afflicts more than 200 million people and causes more than 400,000 deaths each year, with 90 percent of cases occurring in sub-Saharan Africa. However, many more individuals are infected with the Plasmodium parasite but do not become seriously ill. Schmidt’s research aims to learn more about why some people become seriously ill while others do not.

In 2016, Schmidt published research in revealing that mice having one community of microbiota colonizing their gut were less susceptible to severe infection from Plasmodium than mice with a different community of microbiota. In this research, Schmidt showed that when the microbiota from the mice experiencing low or high levels of illness were transplanted to mice that previously had no microbiota (germ-free mice), the transplanted mice had similar levels of disease following infection as the low and high donor controls, respectively. These results demonstrate that it was the gut microbiota causing differences in disease severity.

In another series of experiments, he treated mice with antibiotics followed by doses of Lactobacillus and Bifidobacteria in lab-cultured yogurt. The parasite burden in the susceptible mice decreased dramatically and symptoms of illness were reduced in the mice treated with the yogurt.

Schmidt believes the antibiotic allowed the Lactobacillus and Bifidobacteria introduced in the yogurt to colonize the gut, thereby controlling the Plasmodium population.

“Enteric bacteria provide a competitive environment for other bacteria to grow and survive in. Treatment of mice with antibiotics provided an opportunity for the Lactobacillus and Bifidobacteria to grow and provide protection against severe malaria. Alternatively, it is possible the Lactobacillus prevented recovery of bacteria that cause severe malaria,” Schmidt said.

Schmidt hopes to further isolate which bacteria are responsible for protecting the host from illness and tease apart the mechanisms by which they influence Plasmodium populations and immune response. This should allow collaboration with other researchers to test those effects in humans.

“Nathan’s current findings and the proposed studies will enhance our understanding of how microbiota may modulate host immunity to malaria, which could explain why some individuals develop severe disease while others suffer milder symptoms. This is an understudied area with many opportunities,” said Nejat Egilmez, PhD, chair of the Department of Microbiology and Immunology.

Schmidt is one of a growing number of researchers investigating links between gut microbiota and disease across the UofL Health Sciences Center campus.

“The role of commensal microbiota in host physiology and health is a highly active, cutting-edge area of research amounting to a new paradigm in medicine,” Egilmez said. “In addition to Nathan, several of our faculty, including Drs. Michele Kosiewicz, Krishna Jala and Hari Bodduluri, have ongoing projects exploring the link between host microbiota and diseases such as autoimmune disorders, infectious disease and cancer. The new award will create opportunities for future collaborations not only amongst these individuals but also with others in the department who study the more basic processes underlying host immunity and microbial pathogenesis.”