Battles for gut resources and niches: how Salmonella induces superspreader hosts

Distinguished Lectures in Life Science

Denise Monack, Stanford University

November 14, 2023 @ 04:00 pm to 05:00 pm

Foster Auditorium, Paterno Library
University Park

Abstract:
The molecular understanding of host-pathogen interactions in the GI tract of hosts that shed high numbers of microbes and readily transmit disease, aka superspreaders, is incomplete. We use a mouse model of chronic, asymptomatic Salmonella enterica serovar Typhimurium (S.Tm) infection in which 20% of the mice are superspreaders. The Monack Lab studies the interactions between S.Tm and the host microbiome as well as the immune system in chronically infected hosts. Two overarching questions guide our research projects: 1) What immune cells and pathways are important in the distal gut? 2) What niches and nutrients does S.Tm exploit in the distal gut? To address the first question, we are studying the role of regulatory T cells in the colons of superspreader mice. In ongoing studies, we have found that gut regulatory T cells mediate immunological tolerance in S.Tm -infected superspreader hosts by suppressing cytotoxic activity of T cells. To address the second question, we recently performed untargeted metabolomics on the feces of mice and found superspreader hosts possess distinct metabolic signatures compared to non-superspreaders, including differential levels of L-arabinose. RNA-seq on S. Tm in superspreader fecal samples showed increased expression of the L-arabinose catabolism pathway in vivo. By combining bacterial genetics and diet manipulation, we demonstrate that diet-derived L-arabinose provides S. Tm a competitive advantage in the GI tract. We show that expansion of S. Tm in the GI tract requires a previously uncharacterized alpha-N-arabinofuranosidase that can liberate L-arabinose from dietary polysaccharides. Ultimately, we demonstrate that pathogen-liberated L-arabinose from the diet provides a competitive advantage to S. Tm in vivo. These findings propose L-arabinose as a critical driver of S. Tm expansion in the GI tracts of superspreader hosts.

About the Speaker:
Dr. Monack has a broad training in bacterial pathogenesis, with greater than 30 years of experience working in the field of host-pathogen interactions. She has published many basic research articles on bacterial pathogens and immune responses to infection and is particularly intrigued by the connections between immunity and metabolism. The primary focus of her research is to understand the genetic and molecular mechanisms of bacterial pathogenesis. She has developed a mouse model to study mechanisms of asymptomatic persistent Salmonella infections and transmission. Dr. Monack and her research team use this model to study various aspects of systemic and gut colonization. They recently identified a Salmonella-driven mechanism of granuloma macrophage polarization that involves injection of a Type 3 secreted effector, SteE. This allows the pathogen to antagonize TNF-mediated pathogen restriction during persistent infection. In addition, they use this model to study the immune responses during chronic infection and have defined a unique immune state in hosts that readily transmit pathogen which are referred to as superspreader hosts. They are currently characterizing granulomas in the mesenteric lymph nodes and spleen from persistently infected mice. Recent single-cell profiling of persistently infected mice to identify determinants of macrophage heterogeneity has led to the identification of macrophage populations with distinct phenotypes, functional programming, and spatial localization. Dr. Monack and her team are continuing to characterize immune responses within granulomas and aim to understand the roles of eosinophils during persistent bacterial infections using Salmonella Typhimurium as a model infection.

More recently, Dr. Monack and her team have begun to compare the interactions of typhoidal Salmonella strains (S. Typhi and S. Paratyphi A) with non-typhoidal Salmonella strains (S. Typhimurium) during infections of human macrophages. They have identified typhoidal-specific phenotypes in infection-related environments and in human macrophages. They have also identified a typhoidal-specific type 3 secreted effector that is crucial for replication of S. Typhi in human macrophages. In this proposal, which leverages my expertise in infectious diseases and pathogenesis, they will interrogate the functional significance of genomic variation across clinically relevant typhoidal Salmonella isolates.

In addition to scientific excellence, Dr. Monack is committed to training the next generation of scientists. She has mentored 15 previous graduate students and is currently mentoring 2 graduate students. She has mentored 17 previous postdoctoral fellows and is currently mentoring 3 postdoctoral fellows. The majority of trainees in her laboratory have received fellowships (e.g., NIH F32, Giannini, NSF, etc.). As part of her commitment to enriching trainee experiences, she organizes international conferences that are both stimulating and inclusive of trainees. For example, she has co-organized the Cold Spring Harbor Lab Microbial Pathogenesis & Host Response Conference four times and has ensured that trainees and newer assistant professors are invited to give oral presentations. She is also committed to mentoring trainees in Responsible Conduct of Research (RCR) and Rigor & Reproducibility (R&R) and participated in instructing trainees in our T32 Program refresher course (June 2022) and will offer this in 2023. Dr. Monack took a mentorship training course entitled “Providing Effective Feedback” at Stanford University in September 2022, and will attend another session in 2023. She is also a member of the Teaching and Mentoring Academy in the School of Medicine. She is equally committed to continuous learning about effective leadership and training, and increasing diversity, equity and inclusion of all trainees and scientists. Over the past five years, she has taken the Creating Inclusive Spaces of Belonging Workshop once in person and three times online.

Contact

Erika Ganda
ganda@psu.edu