Bacterial Pathogenesis and Protein Targeting
Our laboratory studies mechanisms whereby pathogenic bacteria cause human diseases in an effort to develop vaccines and therapeutics to combat these infections. Currently, we are focusing on MRSA (Staphylococcus aureus soft tissue and bloodstream infections), anthrax (Bacillus anthracis), and plague (Yersinia pestis). This work is conducted at the University of Chicago’s Hyde Park campus and at the Howard Taylor Ricketts Laboratory (Argonne National Laboratory), a facility for experimental work in high containment.
Our work has uncovered the mechanisms whereby surface proteins of Gram-positive bacteria are secreted, anchored to the cell wall or assembled into fimbrial structures, and released from the bacterial envelope (1). In S. aureus, this has led to the characterization of key virulence factors - staphylococcal protein A (SpA) and adenosine synthase (AdsA) - that block innate and adaptive immune responses in infected hosts by capturing Fcγ of immunoglobulin (2), crosslink B cell receptors to promote superantigen activity (3), inhibit immune responses with adenosine signaling (4) and promote macrophage cell death via deoxyadenosine synthesis (5). These insights have led to the development of vaccines (6), antibodies and therapeutics that prevent disease (7), improve the outcome of S. aureus infections or induce immunity (2, 8). Our future work will unravel the molecular mechanisms of S. aureus immune evasion and protein traffic across the bacterial envelope to discover new therapeutics and vaccines (9).
Bacillus anthracis assembles its S-layer and poly-γ-D-glutamic acid (PDGA) capsule to control the chain length of its vegetative forms and to prevent phagocytic clearance of the pathogen in mammalian hosts (1). S-layers are constituted from two S-layer proteins - Sap and EA1 - that require specific secretion and assembly factors to form a two-dimensional crystalline array on the bacterial surface, tethered via SLH domains to the secondary cell wall polysaccharide (SCWP) of peptidoglycan (10, 11). Twenty-two S-layer associated proteins - BSLs - fulfill discrete biological roles during vegetative replication, whereas linear PDGA strands traverse the S-layer and block phagocyte uptake (12, 13). Our current work characterizes the genes and mechanisms involved in SCWP and PDGA synthesis and the biological functions of S-layer and BSLs in promoting vegetative growth (14, 15). These insights are translated into the development of therapeutics against B. anthracis and into the design of protective vaccines (16, 17).
Yersinia pestis colonizes the gastrointestinal tract of fleas to support transmission of bacteria into mammalian hosts and then uses a type III secretion system and its effector proteins to kill host immune cells (18, 19). We are studying Y. pestis genes and the molecular biology that supports this complex life-style to determine the causes of pandemic plague outbreaks and to develop vaccines that can prevent outbreaks and spread of this catastrophic disease (20, 21).
- Schneewind, O., and D. M. Missiakas. 2012. Protein secretion and surface display in Gram-positive bacteria. Philos. Trans. R. Soc. Lond. B Biol. Sci. 367:1123-1139.
- Falugi, F., H. K. Kim, D. M. Missiakas, and O. Schneewind. 2013. The role of protein A in the evasion of host adaptive immune responses by Staphylococcus aureus mBio 4:e00575-00513.
- Pauli, N. T., H. K. Kim, F. Falugi, M. Huang, J. Dulac, C. H. Dunand, N. Y. Zheng, K. Kaur, S. Andrews, Y. Huang, A. Dedent, K. Frank, A. Charnot-Katsikas, O. Schneewind, and P. C. Wilson. 2014. Staphylococcus aureus infection induces protein A-mediated immune evasion in humans. J. Exp. Med. EPub ahead of press.
- Thammavongsa, V., J. W. Kern, D. M. Missiakas, and O. Schneewind. 2009. Staphylococcus aureus synthesizes adenosine to escape host immune responses. J. Exp. Med. 206:2417-2427.
- Thammavongsa, V., D. M. Missiakas, and O. Schneewind. 2013. Staphylococcus aureus conversion of neutrophil extracellular traps into deoxyadenosine promotes immune cell death Science 342:863-866.
- Kim, H. K., A. G. Cheng, H.-Y. Kim, D. M. Missiakas, and O. Schneewind. 2010. Non-toxigenic protein A vaccine for methicillin-resistant Staphylococcus aureus infections. J. Exp. Med. 207:1863-1870.
- Zhang, J., H. Liu, K. Zhu, S. Gong, S. Dramsi, Y. T. Wang, J. Li, F. Chen, R. Zhang, L. Zhou, L. Lan, H. Jiang, O. Schneewind, C. Luo, and C. G. Yang. 2014. Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase. Proc. Natl. Acad. Sci. USA 111:13517-13522.
- Kim, H. K., C. Emolo, A. C. DeDent, F. Falugi, D. M. Missiakas, and O. Schneewind. 2012. Protein A-specific monoclonal antibodies and the prevention of Staphylococcus aureus disease in mice. Infect. Immun. 80:3460-3470.
- Thammavongsa, V., H. K. Kim, D. M. Missiakas, and O. Schneewind. 2015. Staphylococcal manipulation of host immune responses. Nat. Rev. Microbiol. in press.
- Kern, J. W., R. Wilton, R. Zhang, A. Binkowski, A. Joachimiak, and O. Schneewind. 2011. Structure of the SLH domains from Bacillus anthracis surface array protein. J. Biol. Chem. 286:26042-26049.
- Nguyen-Mau, S.-M., S. Y. Oh, V. Kern, D. Missiakas, and O. Schneewind. 2012. Secretion genes as determinants of Bacillus anthracis chain length. J. Bacteriol. 194:3841-3850.
- Kern, J. W., and O. Schneewind. 2009. BslA, the S-layer adhesin of Bacillus anthracis, is a virulence factor for anthrax pathogenesis. Mol. Microbiol. 75:324-332.
- Richter, G. S., V. J. Anderson, G. Garufi, L. Lu, A. Joachimiak, C. He, O. Schneewind, and D. Missiakas. 2009. Capsule anchoring in Bacillus anthracis occurs by a transpeptidation mechanism that is inhibited by capsidin. Mol. Microbiol. 71:404-420.
- Lunderberg, J. M., S. M. Nguyen-Mau, G. S. Richter, Y. T. Wang, J. Dworkin, D. M. Missiakas, and O. Schneewind. 2013. Bacillus anthracis acetyltransferases PatA1 and PatA2 modify the secondary cell wall polysaccharide and affect the assembly of S-layer proteins. J. Bacteriol. 195:977-989.
- Liszewski Zilla, M., Y. G. Chan, J. M. Lunderberg, O. Schneewind, and D. Missiakas. 2015. LytR-CpsA-Psr enzymes as determinants of Bacillus anthracis secondary cell wall polysaccharide assembly. J. Bacteriol. 196:EPub ahead of press.
- Richter, G. S., D. Elli, H. K. Kim, A. P. Hendrickx, J. A. Sorg, O. Schneewind, and D. M. Missiakas. 2013. Small molecule inhibitor of lipoteichoic acid synthesis is an antibiotic for Gram-positive bacteria. Proc. Natl. Acad. Sci. USA 110:3531-3536.
- Garufi, G., Y.-T. Wang, S.-Y. Oh, H. Maier, D. M. Missiakas, and O. Schneewind. 2012. Sortase-conjugation generates a capsule vaccine that protects guinea pigs against Bacillus anthracis. Vaccine 30:3435-3444.
- Tam, C., O. Demke, T. Hermanas, A. Mitchell, A. Hendrickx, P., and O. Schneewind. 2014. YfbA, a Yersinia pestis regulator required for colonization and biofilm formation in the gut of cat fleas. J. Bacteriol. 196:1165-1173.
- Marketon, M. M., R. W. DePaolo, K. L. DeBord, B. Jabri, and O. Schneewind. 2005. Plague bacteria target immune cells during infection. Science 309:1739-1741.
- Quenee, L. E., N. A. Ciletti, D. Elli, T. Hermanas, and O. Schneewind. 2011. Prevention of pneumonic plague in mice, rats, guinea pigs and non-human primates with clinical grade rV10, rV10-2 or F1-V vaccines. Vaccine 29:6572-6583.
- Cornelius, C. A., L. E. Quenee, D. Elli, N. A. Ciletti, and O. Schneewind. 2009. Yersinia pestis IS1541 transposition provides for escape from plague immunity. Infect. Immun. 77:1807-1816.