Group A Streptococcus (GAS, S. pyogenes), which is responsible for ~500 million cases of strep throat annually, is also capable of causing severe invasive diseases (10,000 US cases annually) with high mortality rates (>30%), such as streptococcal toxic shock syndrome (STSS). Untreated GAS infection can also lead to serious autoimmune sequelae, including acute rheumatic fever. The M protein, the major surface-associated virulence factor of GAS, has a significant role in each of these disease processes. The M protein impairs phagocytic clearance of GAS by recruiting specific host factors to the GAS surface, the most common being fibrinogen (Fg) and C4b-binding protein (C4BP), that interfere with the deposition of opsonic antibodies and the activation of complement. Furthermore, the M1 type of M protein, after proteolytic release from the GAS surface, forms a proinflammatory complex with fibrinogen that contributes to STSS. Capitalizing on our recent structural discoveries on the M1 protein and its interactions with Fg, the goals of the project are to define the rules governing the interactions of various M protein types with Fg and with C4BP. In vitro and in vivo experiments will be carried out to determine how the M1 protein forms a pathogenic complex with Fg (Aim 1);whether other M types form pathogenic complexes with Fg, and if they do so, how this occurs (Aim 2);and how a remarkably broad variety of M protein types recruit C4BP to the GAS surface for protection through a region that is non-conserved and lacks apparent sequence homology (Aim 3). Once completed, these studies will provide essential knowledge applicable to the design of novel therapeutics or preventive strategies against GAS. This multi-PI proposal draws on the distinct yet highly complementary sorts of expertise in the Ghosh and Nizet laboratories. The Ghosh laboratory has extensive experience with the biochemistry and structural biology of bacterial virulence factors, and the Nizet laboratory has extensive experience in the molecular genetics of group A Streptococcus (GAS) and the study of GAS interactions with host innate immunity in vitro and in vivo. This five-year project will extend a successful approach of joint mentorship and collaboration that has yielded two manuscripts describing the crystal structures of M1 protein and the M1 protein-fibrinogen complex, and another joint manuscript detailing novel mechanisms by which M1 protein promotes GAS resistance to host neutrophil killing. Dr. Ghosh will directly supervise three postdoctoral researchers focusing on biochemical and structural approaches, and Dr. Nizet will directly supervise one postdoctoral researcher focusing on microbiological and immunological approaches.

Public Health Relevance

The group A strep bacterium, which is responsible for strep throat, also causes serious, life-threatening diseases. We are investigating the action of a protein of group A strep, called the M protein, that protects the bacterium from being killed by the immune system. Our studies on the M protein will provide knowledge that will be applicable to the design of novel therapeutics or preventive strategies aimed at group A strep infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI096837-02
Application #
8288048
Study Section
Special Emphasis Panel (ZRG1-IDM-N (02))
Program Officer
GU, Xin-Xing
Project Start
2011-07-01
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$524,859
Indirect Cost
$186,240
Name
University of California San Diego
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Stewart, Chelsea M; Buffalo, Cosmo Z; Valderrama, J Andrés et al. (2016) Coiled-coil destabilizing residues in the group A Streptococcus M1 protein are required for functional interaction. Proc Natl Acad Sci U S A 113:9515-20
Buffalo, Cosmo Z; Bahn-Suh, Adrian J; Hirakis, Sophia P et al. (2016) Conserved patterns hidden within group A Streptococcus M protein hypervariability recognize human C4b-binding protein. Nat Microbiol 1:16155
Cole, Jason N; Nizet, Victor (2016) Bacterial Evasion of Host Antimicrobial Peptide Defenses. Microbiol Spectr 4:
Rivera-Hernandez, Tania; Pandey, Manisha; Henningham, Anna et al. (2016) Differing Efficacies of Lead Group A Streptococcal Vaccine Candidates and Full-Length M Protein in Cutaneous and Invasive Disease Models. MBio 7:
Henningham, Anna; Döhrmann, Simon; Nizet, Victor et al. (2015) Mechanisms of group A Streptococcus resistance to reactive oxygen species. FEMS Microbiol Rev 39:488-508
Lin, Ann E; Beasley, Federico C; Keller, Nadia et al. (2015) A group A Streptococcus ADP-ribosyltransferase toxin stimulates a protective interleukin 1β-dependent macrophage immune response. MBio 6:e00133
LaRock, Christopher N; Nizet, Victor (2015) Cationic antimicrobial peptide resistance mechanisms of streptococcal pathogens. Biochim Biophys Acta 1848:3047-54
Wilkinson, Deepti S; Jariwala, Jinel S; Anderson, Ericka et al. (2015) Phosphorylation of LC3 by the Hippo kinases STK3/STK4 is essential for autophagy. Mol Cell 57:55-68
Kristian, Sascha A; Hwang, John H; Hall, Bradley et al. (2015) Retargeting pre-existing human antibodies to a bacterial pathogen with an alpha-Gal conjugated aptamer. J Mol Med (Berl) 93:619-31
LaRock, Christopher N; Döhrmann, Simon; Todd, Jordan et al. (2015) Group A Streptococcal M1 Protein Sequesters Cathelicidin to Evade Innate Immune Killing. Cell Host Microbe 18:471-7

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