Michael Otto, Ph.D.
Chief, Pathogen Molecular Genetics Section, LHBP
The Gram-positive bacteria Staphylococcus epidermidis and Staphylococcus aureus are the most common pathogens in hospital-acquired infections. The costs related to staphylococcal infections are enormous and represent a major healthcare burden. Furthermore, frequent antibiotic resistance, in particular when combined with extraordinary virulence such as in community-acquired methicillin-resistant strains of S. aureus (CA-MRSA), poses an additional severe threat to public health (see review article Otto M. Ann Rev Microbiol 64:143-62, 2010).
S. aureus may cause a multitude of serious and acute infections, while infections with S. epidermidis are usually chronic and often involve the colonization and infection of indwelling medical devices (see review article Otto M. Nat Rev Microbiol 7:555-62, 2009).
The outcome of infections with S. epidermidis and S. aureus is closely linked to their interaction with human host defenses. Thus, mechanisms of immune evasion such as the formation of biofilms represent significant virulence determinants in staphylococcal infections. The long-term objective of our research is to provide the scientific basis for the development of drugs interfering with these mechanisms. To that end, we are investigating the molecular biology, biochemistry, and epidemiology of the interaction of staphylococci with host defenses.
PSMs are a family of alpha-helical, amphipathic peptides that are secreted by many staphylococcal species. We discovered that S. aureus and particularly CA-MRSA produce strongly cytolytic PSMs that lyse human neutrophils and have a key role in virulence. Moreover, PSMs function to structure staphylococcal biofilms and facilitate dissemination of biofilm-associated infection. PSMs and the dedicated PSM secretion mechanism that we recently discovered may represent promising targets for anti-staphylococcal drug and vaccine development.
Evolution of virulence in hospital- and community-associated MRSA
We are investigating the molecular determinants responsible for the exceptional success of MRSA in causing severe disease and spreading sustainably in the human population and in hospitals. In particular, our laboratory explores differential expression of core genome-encoded virulence determinants as a basis for CA-MRSA virulence. Furthermore, in collaboration with researchers from Shanghai, we determined that a prophage-encoded surface protein termed SasX contributes to the MRSA epidemic seen in Asian hospitals.
Our work has provided important insight into the role of the agr and luxS quorum-sensing systems during biofilm formation and inflammation. Furthermore, our findings on agr control of psm genes have allowed a glimpse on how quorum-sensing dependent regulation of virulence in S. aureus has evolved.
Antimicrobial peptides are a key part of innate host defense to bacterial infections. We have identified the first antimicrobial peptide-sensing system in Gram-positive bacteria and investigated its role in S. epidermidis and CA-MRSA.
The formation of sticky, multicellular bacterial agglomerations called biofilms dramatically complicates the treatment of staphylococcal infections. Using genome-wide transcriptional profiling, we have shown that gene-regulated processes in an S. epidermidis biofilm lead to a non-aggressive and protected form of bacterial growth with low metabolic activity, optimally suited to guarantee long-term survival during chronic infection and resistance to antibiotics. Furthermore, we recently discovered that PSM peptides of S. epidermidis and S. aureus are key contributors to the quorum-sensing controlled maturation of biofilms and dissemination of biofilm-associated infection (see review article Otto M. Ann Rev Microbiol 64:175-88, 2013).
Polysaccharide intercellular adhesin (PIA). We have shown that the exopolysaccharide PIA contributes to S. epidermidis resistance to innate host defense. Furthermore, we identified enzymatic modification of PIA by the IcaB enzyme as a crucial factor determining the biological function of PIA in biofilm formation, colonization, and immune evasion.
Poly-gamma-glutamic acid (PGA). Our research has shown that S. epidermidis PGA is crucial for survival in the human host during commensal life on the skin and infection. PGA might be a promising antigen for vaccine development against S. epidermidis infection.
Former laboratory members and current affiliations: Shu Yeong Queck, Ph.D. (Biomerieux Ltd., Singapore); Min Li, Ph.D. (Fudan University, Shanghai); Saravanan Periasamy, Ph. D. (Nanyang Technical University, Singapore); Rong Wang, Ph.D. (USDA, Clay Center, NE); Yuping Lai, Ph.D. (East China Normal University, Shanghai); Cuong Vuong, Ph.D. (Aicuris, Wuppertal, Germany); Yufeng Yao, Ph.D. (Jiaotong University, Shanghai); Stanislava Kocianova, Ph.D.; Viveka Vadyvaloo, Ph.D. (Idaho State University, Moscow, ID); Kevin R. Rigby, Ph.D., (LHBP, NIAID, Hamilton, MT); June Chan (Johns Hopkins University, Baltimore, MD); Tony Pang (Dartmouth Medical College, NH); Burhan A. Khan (Southcentral Foundation, Anchorage, AK); Max Jameson-Lee (University of Virginia); David J. Cha (SUNY Stony Brook); Thanh-Huy Bach; Kok-Fai Kong (La Jolla Institute for Allergy and Immunology, La Jolla, CA); Kwame Tuffour; Thomas Dieringer (University at Buffalo); Aaron Carmody (RTB, NIAID, Hamilton, MT).
Chatterjee SS, Joo HS, Duong AC, Dieringer TD, Tan VY, Song Y, Fischer ER, Cheung GY, Li M, Otto M. Essential Staphylococcus aureus toxin export system . Nat Med. Epub 2013 Feb 12.
Li M, Du X, Villaruz AE, Diep BA, Wang D, Song Y, Tian Y, Hu F, Yu F, Lu Y, Otto M. MRSA epidemic linked to a quickly spreading colonization and virulence determinant . Nat Med. 2012 May;18(5): 816-819.
Wang R, Khan BA, Cheung GY, Bach TH, Jameson-Lee M, Kong KF, Queck SY, Otto M. Staphylococcus epidermidis surfactant peptides promote biofilm maturation and dissemination of biofilm-associated infection in mice. J Clin Invest. 2011 Jan 4;121(1):238-48.
Li M, Diep BA, Villaruz AE, Braughton KR, Jiang X, DeLeo FR, Chambers HF, Lu Y, Otto M. Evolution of virulence in epidemic community-associated methicillin-resistant Staphylococcus aureus. Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5883-8.
Queck SY, Jameson-Lee M, Villaruz AE, Bach TH, Khan BA, Sturdevant DE, Ricklefs SM, Li M, Otto M. RNAIII-independent target gene control by the agr quorum-sensing system: insight into the evolution of virulence regulation in Staphylococcus aureus. Mol Cell. 2008 Oct 10;32(1):150-8.
Wang R, Braughton KR, Kretschmer D, Bach TH, Queck SY, Li M, Kennedy AD, Dorward DW, Klebanoff SJ, Peschel A, DeLeo FR, Otto M. Identification of novel cytolytic peptides as key virulence determinants for community-associated MRSA. Nat Med. 2007 Dec;13(12):1510-4.
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Last Updated March 28, 2013