Research Overview

Broadly speaking, the goals of the Sauer Lab are to understand host-pathogen interactions at a molecular level, with the goal of manipulating these interactions either for the treatment of infectious disease or the development of novel vaccines and immunotherapeutics.  The major workhorse of the lab is Listeria monocytogenes, an important foodborne pathogen that is also an ideal model organism for understanding many aspects of host pathogen interactions ranging from mechanisms of pathogenesis to host innate and adaptive immunity.  The lab is currently funded for four major focus areas:

1. How do intracellular pathogens parasitize their host cells? 

This project focuses on the mechanisms by which L. monocytogenes and other professional cytosolic pathogens survive and thrive in the host cell cytosol. Non-cytosol adapted bacteria are killed upon entry into the cytosol, however pathogens such as L. monocytogenes, Francisella tularensis, Shigella spp. and others are able to utilize this unique environment as a replication niche.  A bacterial genetic screen has revealed virulence factors required by L. monocytogenes to survive in the cytosol and ultimately to cause disease.  This project aims to complete the genetic screen and dissect the molecular mechanisms by which the virulence factors discovered in the screen contribute to cytosolic survival and ultimately disease progression. 

2. How can we take advantage of pathogen virulence strategies to develop novel antimicrobials?

Ultimately, the goal of identifying and characterizing virulence factors is to develop small molecule inhibitors of these critical proteins as a strategy for novel therapeutic intervention.  PASTA kinases are one example of essential virulence factors found in L. monocytogenes and many other important human pathogens including Staphylococcus aureus, Enterococcus spp. and Mycobacterium spp.  We have identified small molecule inhibitors of the PASTA kinases and together with our collaborators in Dr. Rob Striker's lab are interested in further developing these compounds as novel antibiotics.  In addition, we are utilizing combinations and genetic screens and phosphoproteomics to understand how PASTA kinases contribute to cell wall homeostasis and beta-lactam resistance in S. aureus.

3. How does the host recognize and respond to infection by intracellular pathogens?

Over the past 20 years it has become increasingly clear that host cells can detect pathogens in their cytosol and defend against these pathogens through the execution of cell autonomous defenses. However, the mechanisms by which these defenses are activated and targeted, as well as the molecule mechanisms of the defenses themselves are largely not understood.  In this project we are using CRISPR-Cas9 based forward genetic screens in macrophages to identify novel cell autonomous defenses against cytosolic bacteria and are dissecting the role that bacterial and host metabolism plays in activating and localizing those defenses.

4. How does recognition of intracellular pathogens by the innate immune system drive adaptive immune responses?

L. monocytogenes has been utilized as a tool to understand mechanisms of T-cell priming and cell mediated immunity for decades.  In addition, due to its ability to trigger robust CD8+ T-cell responses, L. monocytogenes is currently in clinical trials as an immunotherapeutic platform for the treatment of a variety of cancers.  Although it has been known for decades that L. monocytogenes that access the cytosol trigger robust CD8+ T-cell mediated immunity while those trapped in a phagosome cannot, the innate immune signaling pathways that mediate this response are unknown.  This project focuses on understanding how cytosol specific innate immune responses, notably the inflammasome and more recently eicosanoid signalling, control T-cell priming with the goal of developing more robust Listeria-based tumor immunotherapeutic platforms.  We study the role of these innate responses in T-cell priming not only in the context of model antigens but also in humanized mouse models of prostate cancer, in collaboration with Dr. Doug McNeel's lab.