Michael Otto, Ph.D.
Chief, Pathogen Molecular Genetics Section
Senior Investigator
M.Sc., 1993, University of Tuebingen, Germany (Biochemistry)
Ph.D., 1998, University of Tuebingen, Germany (Microbiology)
Editorial Board Member PLoS ONE, Recent Patents on Anti-Infective Drug Discovery
Pathogen Molecular Genetics Section
The Pathogen Molecular Genetics Section is located on the NIH main campus in Bethesda, MD (Building 33).
Description of Research Program
The Gram-positive bacteria Staphylococcus epidermidis and Staphylococcus aureus are the most common pathogens in hospital-acquired infections. The costs related to infections caused by these strains in the hospital setting are enormous and represent a major health care burden. Furthermore, the more recent combination of extraordinary virulence and multiple antibiotic resistance in community-acquired methicillin-resistant strains of S. aureus (CA-MRSA) poses an additional severe threat to public health.
S. aureus may cause a multitude of serious infections, including toxic shock and scalded skin syndromes, endocarditis, and pneumonia, to name but a few. In contrast, infections with S. epidermidis are usually chronic and less severe. The most important type of disease caused by S. epidermidis is the colonization and infection of indwelling medical devices.
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 chronic infections with staphylococci. 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.
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Scanning electron microscopy of Staphylococcus epidermidis cluster embedded in exopolysaccharide matrix |
Major Areas of Research
Phenol-soluble modulins (PSM): a novel class of staphylococcal virulence determinants
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. Furthermore, the PSM-mec peptide represents the first known example of a staphylococcal toxin gene that is transferred together with antibiotic resistance. PSMs may represent promising targets for anti-staphylococcal drug and vaccine development.
Evolution of virulence in CA-MRSA
We are investigating the molecular determinants responsible for the exceptional success of CA-MRSA in causing severe disease and spreading sustainably in the human population. In particular, our laboratory explores differential expression of core genome-encoded virulence determinants as a basis for CA-MRSA virulence.
Gene regulatory processes during pathogen-host interaction
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
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. Further work is focused on the interaction of staphylococci with the anionic human antimicrobial peptide dermcidin.
Physiology of staphylococcal biofilms and biofilm-associated infection
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 have developed real-time monitoring of S. epidermidis infection using bioluminescent imaging. We are currently focusing on the mechanism of biofilm detachment and its role in biofilm-associated infection.
Role of staphylococcal exopolymers in immune evasion
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.
Research Group Members
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| Gordon Yiu Chong Cheung, Ph.D. |
Burhan Khan |
Hwang-Soo Joo, Ph.D. |
Kevin Rigby, Ph.D. |
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| Amer Villaruz, Ph.D. |
Som Subra Chatterjee, Ph.D. |
June Chan |
Former laboratory members and current affiliations: Shu Yeong Queck, Ph.D. (Nanyang Polytechnic, Singapore); Min Li, Ph.D. (Fudan University, Shanghai); Rong Wang, Ph.D. (LICP, NIAID, Hamilton, MT); Yuping Lai, Ph.D. (UCSD); Cuong Vuong, Ph.D. (Aicuris, Wuppertal, Germany); Yufeng Yao, Ph.D. (Jiaotong University, Shanghai); Stanislava Kocianova, Ph.D.; Viveka Vadyvaloo, Ph.D. (LZP, Hamilton, MT); Max Jameson-Lee (University of Virginia), David J. Cha (SUNY Stony Brook), Thanh-Huy Bach (University of Arizona); Kok-Fai Kong (Yale University); Aaron Carmody (RTB, NIAID, Hamilton, MT).
Selected Publications
(View list in PubMed)
Queck SY, Khan BA, Wang R, Bach TH, Kretschmer D, Chen L, Kreiswirth BN, Peschel A, DeLeo FR, Otto M. Mobile genetic element-encoded cytolysin connects virulence to methicillin resistance in MRSA. PLoS Pathog. 2009 Jul;5(7):e1000533.
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.
Li M, Lai Y, Villaruz AE, Cha DJ, Sturdevant DE, Otto M. Gram-positive three-component antimicrobial peptide-sensing system. Proc Natl Acad Sci U S A. 2007 May 29;104(22):9469-74
Kocianova S, Vuong C, Yao Y, Voyich JM, Fischer ER, DeLeo FR, Otto M. Key role of poly-gamma-DL-glutamic acid in immune evasion and virulence of Staphylococcus epidermidis. J Clin Invest. 2005 Mar;115(3):688-94.
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