Elucidating host-microbe interactions to address vector-borne diseases

In a new study, Yale researchers identify the targets in the human body to which pathogens transmitted by mosquitoes, ticks, and other vectors bind. Their findings, they say, could help address the rising threat of vector-borne diseases, a leading cause of death worldwide.

The study was published in Cell.

“We wanted to better understand the precise mechanisms by which pathogens interact with humans to infect the host and cause disease,” said first author Thomas Hart, Ph.D., postdoctoral associate at Yale School of Medicine (YSM). “To do so, we tested for interactions between thousands of human proteins and dozens of microbial pathogens, then examined the importance of those identified,” he said.

Pathogens must interact with host molecules, namely host proteins, to infect a host, evade the immune system, and cause symptoms, Hart explained.

For their research, the team probed a curated yeast display library of human proteins with 82 diverse pathogen samples. The yeast display library, created at Yale by Aaron Ring, MD, Ph.D., contained 3,324 human extracellular and secreted proteins.

Leveraging this library of highly curated human proteins allowed the researchers to test these interactions rapidly and systematically at an exceptional scale, Hart said.

One surprising finding was that Borrelia burgdorferi, which causes Lyme disease, appears to interact with epidermal growth factor (EGF), said corresponding author Erol Fikrig, MD, Waldemar Von Zedtwitz Professor of Medicine (Infectious Diseases) and professor of microbial pathogenesis at YSM; and professor of epidemiology (microbial diseases) at the Yale School of Public Health.

“Why Borrelia interacts with EGF and what that does for Borrelia pathogenesis is not yet known, and that could have implications for Lyme disease,” he said.

The researchers also found that the protein disulfide isomerase facilitates the invasion of Rickettsial pathogens, which cause diseases such as spotted fever and scrub typhus.

The study highlights how new technologies that enable unbiased proteome-scale screening can expose the precise mechanisms through which microbial pathogens invade and manipulate their human hosts, sense host residence and immune status, and trigger unique and often pathogen-specific disease pathologies, said co-author Noah Palm, Ph.D., YSM professor of immunobiology.

“Conversely, it also reveals new ways that mammalian hosts can recognize and respond to diverse pathogens,” he said.

Many of the host-microbe interactions uncovered were unpredictable and unexpected, revealing a suite of novel host-pathogen interactions that can potentially be leveraged to create new classes of anti-infectives that target unique and previously unknown host-microbe interaction nodes, Palm added.

The researchers compiled a resource that can be utilized by many investigators of different targets that pathogens—such as Plasmodium, Leptospira, and Borrelia burgdorferi—bind to, providing insights into the development of malaria, Leptospirosis, and Lyme disease, among other vector-borne diseases.

Hart emphasized the importance of uncovering these interactions. “This work expands our understanding of infectious disease pathogenesis and highlights exciting new targets for vaccines and treatments to prevent and treat these diseases more effectively,” he said.