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)

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.

Scanning electron microscopy of Staphylococcus epidermidis cluster embedded in exopolysaccharide matrix.

Major Areas of Research

• Physiology of S. epidermidis biofilms and biofilm-associated infection
  

  We are using genome-wide approaches to determine the specific physiology of S. epidermidis biofilms. Our research has 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 high-level resistance to antibiotics. We have used comparative genomic hybridization to identify factors that determine the success of S. epidermidis during biofilm-associated infection. 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 the resistance of S. epidermidis 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-g-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.  

• Phenol-soluble modulins (PSM): a novel class of staphylococcal virulence determinants
  We are investigating the double role of the amphipathic PSM peptides in inflammation and biofilm development. We have shown that S. aureus PSMs are key virulence determinants during infection by CA-MRSA strains. These peptides have an extraordinary capacity to lyse human neutrophils. 
• Gene regulatory processes during pathogen-host interaction
  Quorum-sensing systems. Our work has provided important insight into the role of the agr and luxS quorum-sensing systems during biofilm formation and inflammation.
• Antimicrobial peptides
  We have identified the Gram-positive counterpart (termed Aps) of the Gram-negative PhoP/PhoQ antimicrobial peptide-sensing system 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.

Research Group Members

Front, left to right: Shu Yeong Queck, Ph.D., Visiting Fellow; Min Li, Ph.D., Visiting Fellow; Yuping Lai; Rong Wang, Ph.D., Visiting Fellow.  Back, left to right: Max Jameson-Lee, Postbaccalaureate IRTA Fellow; Michael Otto; Amer Villaruz, Ph.D., Microbiologist.  Not pictured: Thanh-Huy Bach, Postbaccalaureate IRTA Fellow

Former laboratory members: Cuong Vuong, Ph.D.;Yufeng Yao, Ph.D.; Stanislava Kocianova, Ph.D.; Viveka Vadyvaloo, Ph.D.; Kok-Fai Kong; Aaron Carmody

Selected Publications

(View list in PubMed)

Li M, Cha DJ, Lai Y, Villaruz AE, Sturdevant DE, Otto M. The antimicrobial peptide-sensing system aps of Staphylococcus aureus. Mol Microbiol. 2007 Dec;66(5):1136-47.

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

Lai Y, Villaruz AE, Li M, Cha DJ, Sturdevant DE, Otto M. The human anionic antimicrobial peptide dermcidin induces proteolytic defence mechanisms in staphylococci. Mol Microbiol. 2007 Jan;63(2):497-506.

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.

Vuong C, Kocianova S, Voyich JM, Yao Y, Fischer ER, DeLeo FR, Otto M. A crucial role for exopolysaccharide modification in bacterial biofilm formation, immune evasion, and virulence. J Biol Chem. 2004 Dec 24;279(52):54881-6. 

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