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Using Basic Science to Solve Clinical Problems

May 29, 2019
Cryo-electron tomography was used to visualize the interaction of Salmonella with host cells at unprecedented resolution.
Salmonella-Host
Since 2003, asylum seekers requiring a medical evaluation have been referred to the Yale Center for Asylum Medicine by attorneys from Yale Law School and the University of Connecticut Law School, as well as advocacy groups.

Across the globe, such diseases as AIDS, tuberculosis, and malaria take a toll on millions of people. To help conquer these illnesses, the Department of Microbial Pathogenesis operates on the concept that unlocking the pathogenesis of these infectious diseases requires an understanding of how microorganisms—those that cause diseases and those that do not—affect the biology of the infected host and its cells.

This approach—which aligns with Yale’s strengths in cell biology—is unique. Since the department’s creation in 1998, which was supported in part by a seed grant from the Klingestein Fund, founding chair Jorge Galan, PhD, DVM and his colleagues have examined host-pathogen interactions using advanced technologies in imaging and other areas to make groundbreaking discoveries.

One example of this approach is the work of Ya-Chi Ho, MD, PhD, whose lab is using a molecular virology framework to examine the mechanisms of HIV persistence. She has shown that HIV hides in CD4 T lymphocytes, that the virus is most commonly present in a defective form that acts as a decoy to throw off the immune system, and that infectious HIV is rare, found in only about one in a million of these cells. Dr. Ho developed an innovative technique known as HIV SortSeq that isolates single cells containing HIV and uses RNA sequencing to study them. Working closely with HIV care providers and bioinformaticians at Yale University and the National Institutes of Health (NIH) BEAT-HIV Collaboratory, Dr. Ho is using cutting-edge single-cell technologies to study HIV-host interactions in HIV-1-infected individuals and to develop HIV cure strategies.

Imaging across all scales to understand how viruses replicate and spread, Walther Mothes, PhD, discovered a different molecular mechanism that HIV uses to evade the immune system. HIV is an enveloped virus with a small number of spike proteins on its surface. He found that the spike protein forms specific structures on its surface that attach to and infect cells. These structures can change shape over time into three different conformations. The immune system develops antibodies that recognize the State 1 conformation, but his work with the National Institutes of Health Vaccine Research Center suggests that current vaccines under development use State 2 immunogens and elicit State 2-specific antibodies. Working with Jun Liu, PhD, at the West Campus, Dr. Mothes used parallel single-molecule imaging and cryo-electron tomography (cryo-ET) to visualize the structure of the State 1 conformation. The pair have used sophisticated imaging techniques to elicit the structure of the HIV spike protein that allows the virus to enter the cell.

In collaborating with other colleagues in the Department of Microbial Pathogenesis, Dr. Liu uses cryo-ET and cryo-electron microscopy (cryo-EM) to image bacterial nanomachines that have the remarkable ability to inject bacterial proteins into host cells for the pathogen’s benefit. These imaging studies, along with other studies in his collaborators’ laboratories, will provide the foundation for the development of much-needed next generation antimicrobials.

While many in the department use the imaging resources available at YSM, Hesper Rego, PhD, used her training in optical physics to build a unique structured illumination microscope that she is using to follow host-pathogen interactions over time. Concentrating on tuberculosis, she studies the non-genetic mechanisms that create diversity in microbial populations, focusing on phenotypic differences that help explain why only some of the millions of bacteria in an infection can survive antibiotic treatment. Her lab discovered a genetic toggle switch controlling the amount of heterogeneity in a bacterial population that helps illuminate how microorganisms behave at the single-cell level.

Erol Fikrig, MD, is taking a different approach, studying pathogen-host-vector interaction at the infection site in Zika and malaria. He used mass spectrometry and immunologic assays to identify proteins in mosquito saliva that contribute to protection against malaria and Zika infection. The possibility that these proteins are common to other mosquito-born viruses is leading him to search for new proteins that might work against other viruses. He is also hunting for the molecule in tick saliva that when secreted into the host elicits “tick rejection,” the phenomenon in which ticks either detach from or die when feeding from a person who’s already been bitten.

Pathogenic microbes can wreak havoc on the human body, but microbes don’t necessarily have to be pathogenic to play a role in health and disease. In his lab at the West Campus, Andrew Goodman, PhD, is working to understand how our resident commensal bacteria respond to pathogen invasion. He discovered how these commensal bacteria withstand inflammation—a key step in the battle between commensals and pathogens. His lab takes a broad view of the role of microbes in health; for example, the team is working to understand how our resident gut bacteria transform certain medical drugs into toxic compounds.

Driven by scientific curiosity, the unparalleled work taking place in the department reflects a commitment to outstanding science. A decade or two ago, the discoveries taking place today—and the technologies used to make them—would have been unthinkable.