Our lab is interested in how intracellular pathogens parasitize host cells and how the host, in turn, recognizes these pathogens and defends against them. We use the bacterium Listeria monocytogenes, a Gram positive foodborne pathogen, as a model organism to address these questions. L. monocytogenes is capable of infecting a wide variety of cell types, including professional phagocytes such as macrophages and dendritic cells. Survival from infection with L. monocytogenes results in the development of robust and long term protective cell mediated immunity. To understand the complex game of tug and war between the bacteria and the host, we utilize genetics, both in the pathogen and in the host, to determine the factors necessary to promote disease (pathogen) and immunity (host).
Random mutagenesis of L. monocytogenes, utilizing transposons, allows us to screen for bacterial factors that the pathogen utilizes to parasitize normally bactericidal macrophages. These screens have highlighted the importance of specific central metabolism and cell wall biosynthesis pathways in the pathogenesis of L. monocytogenes. Similarly, transposon mutagenesis has allowed us to identify bacterial factors that impact innate immune recognition by the host. In particular we have identified bacterial mutants that both hyper- and hypo-induce various innate immune signaling pathways, specifically the inflammasome and a cytosolic type I IFN induction pathway. We use these bacterial mutants both to understand the downstream host signaling pathways and the ligands that trigger them.
Finally, we use the well defined ex vivo and in vivo murine Listeriosis models to understand the role of specific innate immune signaling pathways during infection by intracellular pathogens. Specifically, we utilize cells/mice lacking innate immune signaling molecules, in combination with L. monocytogenes mutants, to determine the role of inflammasome activation and type I interferon induction during acute infections and the development of long term immunity.
Our long term goals are to understand the mechanisms by which intracellular pathogens parasitize host cells and how the host defends against these pathogens. In addition, we are interested in continuing to develop L. monocytogenes as an immunotherapeutic platform.
- Felley LE, Sharma A, Theisen E, Romero-Masters JC, Sauer JD, Gumperz JE (2016) Human Invariant NKT Cells Induce IL-1β Secretion by Peripheral Blood Monocytes via a P2X7-Independent Pathway. J. Immunol. 197(6):2455-64 (PMC5011004) View Abstract · Pubmed Record
- Theisen E, Sauer JD (2016) Listeria monocytogenes and the Inflammasome: From Cytosolic Bacteriolysis to Tumor Immunotherapy. Curr. Top. Microbiol. Immunol. 397:133-60 (PMC5027901) View Abstract · Pubmed Record
- Vincent WJ, Freisinger CM, Lam PY, Huttenlocher A, Sauer JD (2016) Macrophages mediate flagellin induced inflammasome activation and host defense in zebrafish. Cell. Microbiol. 18(4):591-604 (PMC5027955) View Abstract · Pubmed Record
- Berti AD, Theisen E, Sauer JD, Nonejuie P, Olson J, Pogliano J, Sakoulas G, Nizet V, Proctor RA, Rose WE (2015) Penicillin Binding Protein 1 Is Important in the Compensatory Response of Staphylococcus aureus to Daptomycin-Induced Membrane Damage and Is a Potential Target for β-Lactam-Daptomycin Synergy. Antimicrob. Agents Chemother. 60(1):451-8 (PMC4704217) View Abstract · Pubmed Record
- Huynh TN, Luo S, Pensinger D, Sauer JD, Tong L, Woodward JJ (2015) An HD-domain phosphodiesterase mediates cooperative hydrolysis of c-di-AMP to affect bacterial growth and virulence. Proc. Natl. Acad. Sci. U.S.A. 112(7):E747-56 (PMC4343097) View Abstract · Pubmed Record
- Sureka K, Choi PH, Precit M, Delince M, Pensinger DA, Huynh TN, Jurado AR, Goo YA, Sadilek M, Iavarone AT, Sauer JD, Tong L, Woodward JJ (2014) The cyclic dinucleotide c-di-AMP is an allosteric regulator of metabolic enzyme function. Cell 158(6):1389-401 (PMC4166403) View Abstract · Pubmed Record
- Pensinger DA, Aliota MT, Schaenzer AJ, Boldon KM, Ansari IU, Vincent WJ, Knight B, Reniere ML, Striker R, Sauer JD (2014) Selective pharmacologic inhibition of a PASTA kinase increases Listeria monocytogenes susceptibility to β-lactam antibiotics. Antimicrob. Agents Chemother. 58(8):4486-94 (PMC4135996) View Abstract · Pubmed Record
- Fonseca MV, Sauer JD, Crepin S, Byrne B, Swanson MS (2014) The phtC-phtD locus equips Legionella pneumophila for thymidine salvage and replication in macrophages. Infect. Immun. 82(2):720-30 (PMC3911408) View Abstract · Pubmed Record
- Williams CR, Dustin ML, Sauer JD (2013) Inflammasome-mediated inhibition of Listeria monocytogenes-stimulated immunity is independent of myelomonocytic function. PLoS ONE 8(12):e83191 (PMC3857309) View Abstract · Pubmed Record
- Witte CE, Whiteley AT, Burke TP, Sauer JD, Portnoy DA, Woodward JJ (2013) Cyclic di-AMP is critical for Listeria monocytogenes growth, cell wall homeostasis, and establishment of infection. MBio 4(3):e00282-13 (PMC3663569) View Abstract · Pubmed Record
- Witte CE, Archer KA, Rae CS, Sauer JD, Woodward JJ, Portnoy DA (2012) Innate immune pathways triggered by Listeria monocytogenes and their role in the induction of cell-mediated immunity. Adv. Immunol. 113:135-56 View Abstract · Pubmed Record
- Sauer JD, Pereyre S, Archer KA, Burke TP, Hanson B, Lauer P, Portnoy DA (2011) Listeria monocytogenes engineered to activate the Nlrc4 inflammasome are severely attenuated and are poor inducers of protective immunity. Proc. Natl. Acad. Sci. U.S.A. 108(30):12419-24 (PMC3145703) View Abstract · Pubmed Record
- Lightfield KL, Persson J, Trinidad NJ, Brubaker SW, Kofoed EM, Sauer JD, Dunipace EA, Warren SE, Miao EA, Vance RE (2011) Differential requirements for NAIP5 in activation of the NLRC4 inflammasome. Infect. Immun. 79(4):1606-14 (PMC3067536) View Abstract · Pubmed Record
- Sauer JD, Sotelo-Troha K, von Moltke J, Monroe KM, Rae CS, Brubaker SW, Hyodo M, Hayakawa Y, Woodward JJ, Portnoy DA, Vance RE (2011) The N-ethyl-N-nitrosourea-induced Goldenticket mouse mutant reveals an essential function of Sting in the in vivo interferon response to Listeria monocytogenes and cyclic dinucleotides. Infect. Immun. 79(2):688-94 (PMC3028833) View Abstract · Pubmed Record
- Sauer JD, Witte CE, Zemansky J, Hanson B, Lauer P, Portnoy DA (2010) Listeria monocytogenes triggers AIM2-mediated pyroptosis upon infrequent bacteriolysis in the macrophage cytosol. Cell Host Microbe 7(5):412-9 (PMC2947455) View Abstract · Pubmed Record
- Henry T, Kirimanjeswara GS, Ruby T, Jones JW, Peng K, Perret M, Ho L, Sauer JD, Iwakura Y, Metzger DW, Monack DM (2010) Type I IFN signaling constrains IL-17A/F secretion by gammadelta T cells during bacterial infections. J. Immunol. 184(7):3755-67 (PMC2879132) View Abstract · Pubmed Record
- Chen DE, Podell S, Sauer JD, Swanson MS, Saier MH (2008) The phagosomal nutrient transporter (Pht) family. Microbiology (Reading, Engl.) 154(Pt 1):42-53 View Abstract · Pubmed Record