Laboratory of Human Bacterial Pathogenesis

Program Description

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 healthcare 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 (see review article Otto M. Ann Rev Microbiol 64:143-62, 2010).

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 (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 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.

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. Moreover, we recently discovered that PSMs also function to structure staphylococcal biofilms. 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. Moreover, we recently identified the PSMbeta peptides of S. epidermidis as key contributors to the quorum-sensing controlled maturation of biofilms and dissemination of 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.

Biography

Dr. Otto received his M.S. in biochemistry in 1993 from the University of Tuebingen, Germany. In 1998, he earned his Ph.D. in microbiology from the same institution. Dr. Otto joined the Laboratory of Human Bacterial Pathogenesis in July 2001 as a principal investigator. In 2008, he became a tenured senior investigator and moved his laboratory to the NIH Bethesda main campus (Building 33).

Research Group Members

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. (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); 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); Aaron Carmody (RTB, NIAID, Hamilton, MT).

Selected Publications

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.

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

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