Innate immune responses shape development of adaptive immunity and mediate resistance to infectious agents and tumors. Research in my lab focuses on better-understanding how innate immune responses are regulated and dysregulated in the context of health and disease. We strive to gain new mechanistic insight into the workings of the innate immune system. A long-term goal of our work is to identify strategies to therapeutically tune innate immunity in the context of infectious, cancerous, and inflammatory diseases.
Research in the lab leverages our expertise in immunology, bacterial pathogenesis, and bacterial infection model systems. Pathogenic bacteria subvert and exploit regulation of innate immune responses to establish infections and to disseminate. By better defining how pathogens thwart or manipulate immune responses, we can learn from the pathogens how to fine-tune host immune regulatory circuits.
Cytokines play a central role in regulation of immune responses. These small proteins direct the activity of diverse myeloid and lymphoid cell populations to shape developing immune responses. Previous research in our lab helped to identify and study host molecules regulating the production of type I interferons (IFNs), a class of cytokines produced very early after the onset of viral and bacterial infections. We have also identified and studied novel functional effects of these cytokines. Type I IFN production suppresses host resistance to many bacterial infections. We discovered that this suppressive effect is associated with impaired myeloid cell responsiveness to a different class of cytokine: IFN-gamma. This suppression correlates with the ability of type I IFNs to silence expression of ifngr1, a gene that encodes a critical component of the receptor for IFN-gamma. To investigate the functional significance of this suppression, we generated and utilized a novel transgenic mouse model. In the presence of type I IFNs, myeloid cells in these transgenic mice retain increased responsiveness to IFN-gamma and evidence heightened anti-microbial (M1) activation. They also more efficiently engulf and kill invading bacteria and resist systemic bacterial infection. These results support the hypothesis that suppression of myeloid cell IFNGR is an important mechanism contributing to increased susceptibility during infection by bacteria that elicit type I IFN production. Current work in the lab strives to better understand how IFNGR expression is regulated and how this affects host inflammatory and immune responses. Such information may reveal host-directed strategies to treat bacterial infections and other diseases where M1 activation mediates protection, like cancer. These studies may also identify approaches to dampen myeloid cell M1 activation in settings where a heightened inflammatory response contributes to disease, like inflammatory bowel diseases or multiple sclerosis.
Natural killer (NK) cells are an innate immune cell population that responds very rapidly to infection by viral, bacterial, and other pathogens. Activated NK cells also recognize and kill tumor cells. NK cells are a major source of early IFN-gamma production during bacterial infections but paradoxically can have a detrimental effect on host resistance. Work in my lab has led to an improved understanding of how NK cell activity is regulated during bacterial infection. We have identified a protein (p60) produced by the bacterium Listeria monocytogenes that can indirectly promote NK cell activation. We defined a region of this protein, L1S, that binds to dendritic cells (DC) and elicits cytokine production and other responses that regulate NK cell activation. Recently, we showed that L. monocytogenes infection or DC stimulation with L1S ultimately induces NK cells to secrete an anti-inflammatory cytokine called interleukin (IL)-10. Current work in the lab strives to better understand the mechanisms by which L1S stimulates DC and how this stimulation promotes various NK cell activities. We have also begun to investigate the effects of L1S in driving NK cell activation and anti-tumor responses in vivo.
Dr. Lenz completed a B.A. degree in Microbiology at Kansas State University (Manhattan), earned a Ph.D. in Immunology from the University of Washington (Seattle), and completed postdoctoral research at the University of California (Berkeley).
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