This week we profile a recent publication in The Journal of Immunology from the laboratory of Dr. Javeed Shah at UW.
Can you provide a brief overview of your lab’s current research focus?
Our lab is interested in understanding why some people develop symptomatic tuberculosis, a lung disease that is the second-leading cause of death by an infection behind SARS-CoV-2, while the vast majority of exposed indivdiduals do not. We identify susceptibility genes of interest using human genetics, then create mouse models to understand the tissues that they act in, and how they influence cellular function.
What is the significance of the findings in this publication?
In our mose recent publication, we found that TOLLIP, a gene associated with TB susceptibility, influences dendritic cell maturation, cytokine responses to M. tuberculosis ligands, and T cell activation in human cohorts. Using mice lacking the TOLLIP gene, we found that lung-resident dendritic cells also develop deiminished maturation during M. tuberculosis infection irrespective of bacterial burden or lung microenvirontment. Further, these mice develop diminished M. tuberculosis-specific T cell responses after infection, which is a critical component of an effective immune response to TB. Moreover, mice lacking TOLLIP did not induce T cell responses to the current vaccine against TB, Bacille Calmette-Guerin. These data suggest that TOLLIP alters dendritic cell activity in ways that impaire adaptive immune responses to TB in both mice and humans, and that understanding how this protein works may provide insight into improved vaccines and treatments.
What are the next steps for this research?
Our next steps are to better understand the breadth of how TOLLIP and other proteins like it influence other critical aspects of the host immune response to tuberculosis. In particular, we are excited to understand how TOLLIP influences macrophage function. Macrophages are related to dendritic cells from a development perspective, and are the primary cell infected by M. tuberculosis. These studies will help us understand the critical role that TOLLIP plays in regulating host immune responses.
If you’d like us to mention your funding sources, please list them.
This work was supported by the NIH, the Department of Veterans Affairs and the VA Puget Sound Healthcare System, the University of Washington Tuberculosis Research and Training Center, and the Bill and Melinda Gates Foundation.
