Associate Physician
Brigham and Women's Hospital

mwessels@channing.harvard.edu

Work in Dr. Wessels's laboratory focuses on mechanisms of pathogenesis of diseases caused by two important bacterial pathogens, group B Streptococcus (GBS) and group A Streptococcus (GAS, or Streptococcus pyogenes), with particular emphasis on the roles of the capsular polysaccharides of these organisms in pathogenesis and immunity.

Group B Streptococcus (GBS). GBS is an important cause of bacterial sepsis and meningitis among newborns and of invasive infections in immunocompromised adults. Virtually all strains of GBS isolated from human infections are encapsulated by one of the nine identified GBS capsular polysaccharides. Studies of mutant strains of type III GBS with altered capsule phenotypes have shown that the type III capsule confers animal virulence and resistance to phagocytic killing. This virulence function is attributable largely to the effect of capsular sialic acid residues that regulate activation of the alternative complement pathway and deposition of C3 on the bacterial surface (Marques et al., 1992). In serotype III GBS, the genes required for capsule biosynthesis are clustered in a 16-gene operon involved in assembly of the polysaccharide subunits, polymerization, and export (Wessels et al., 1992; Rubens et al., 1993; Haft and Wessels, 1994; Haft et al., 1996). Certain genes are conserved among all capsular types of GBS, while those that specify serotype-specific glycosyltransferases are unique. Current studies are investigating the genetic mechanisms through which a novel capsule type may evolve, leading to the emergence of a new virulent serotype in a nonimmune population.

Another area of investigation is the identification of host factors involved in innate immunity to GBS infection. GBS is a pathogen of neonates, pregnant women, and immunocompromised adults, but rarely causes infection in otherwise healthy adults, despite the fact that most adults lack antibodies the GBS capsular polysaccharides. Current studies are investigating the potential role in innate immunity of humoral factors including complement proteins and natural antibodies to noncapsular GBS antigens (Wessels et al., 1998; Butko et al., 1999). These studies may provide insight into the precise immunologic deficiencies associated with susceptibility to GBS infection.

Group A Streptococcus (GAS). GAS remains an important cause of morbidity and mortality as a result of infections and as a consequence of the postinfectious sequelae of acute rheumatic fever. Attention has focused recently on invasive GAS infections including necrotizing fasciitis and streptococcal toxic shock.

Research in Dr. Wessels's lab has defined the hyaluronic acid capsular polysaccharide as a critical virulence determinant in GAS infection . A 3-gene operon encodes the enzymes uniquely required for hyaluronic acid synthesis in GAS. The capsule synthesis gene cluster appears to be present in all strains of GAS; however, the level of hyaluronic acid capsule production varies widely among isolates of GAS and may vary in an individual strain under different circumstances. Capsule biosynthesis is regulated by the fine structure of the has operon promoter (Albert’ et al., 1998) and by a 2-component regulatory system that controls transcription of the has genes (Levin and Wessels, 1998). Current studies are directed toward definition of the mechanisms through which the organisms sense different environments within the host and adapt to those environments by regulating capsule production.

Mutant strains derived by targeted knockout mutations of the genes required for synthesis of specific virulence determinants have helped define the importance of the capsule and other virulence factors in GAS disease. The hyaluronic acid capsule mediates adherence of the organisms to the hyaluronate-binding protein CD44 on human pharyngeal keratinocytes (Schrager et al., 1998), a finding that may explain the importance of the capsule in the capacity of the GAS to colonize the pharynx (Wessels and Bronze, 1994). The hyaluronic acid capsule also protects GAS from ingestion by epithelial cells and phagocytes, allowing the organisms to proliferate extracellularly and to invade into deeper tissues and the blood (Wessels et al., 1994; Schrager et al., 1996; Ashbaugh et al., 1998). Ongoing studies are investigating the role of the capsule and other GAS extracellular products in mediating tissue invasion and as stimuli for host cellular responses important in streptococcal disease syndromes. These studies will lead to a better understanding of the pathogenesis of streptococcal infection and of the immune responses of the host which may play a role in acute rheumatic fever.

Marques MD, Kasper DL, Pangburn MK, Wessels MR. Prevention of C3 deposition is a virulence mechanism of type III group B Streptococcus capsular polysaccharide. Infect Immun 1992;60:3986-3993. [abstract]

Wessels MR, Haft RF, Heggen LM, Rubens CE. Identification of a genetic locus essential for capsule sialylation in type III group B streptococci. Infect Immun 1992;60:392-400.[abstract]

Rubens CE, Heggen LM, Haft RF, Wessels MR. Identification of cpsD, a gene essential for type III capsule expression in group B streptococci. Mol Microbiol 1993;8:843-855. [abstract]

Haft RF, Wessels MR. Characterization of CMP-N-acetylneuraminic acid synthetase of group B streptococci. J Bacteriol 1994;176:7372-7374. [abstract]

Wessels MR, Bronze MS. Critical role of the group A streptococcal capsule in pharyngeal colonization and infection in mice. Proc Natl Acad Sci USA 1994;91:12238-12242. [abstract]

Wessels MR, Goldberg JB, Moses AE, DiCesare TJ. Effects on virulence of mutations in a locus essential for hyaluronic acid capsule expression in group A streptococci. Infect Immun 1994;62:433-441. [abstract]

Wessels MR, Butko P, Ma M, Warren HB, Lage AL, Carroll MC. Studies of group B streptococcal infection in mice deficient in complement C3 or C4 demonstrate an essential role for complement in both innate and acquired immunity. Proc Natl Acad Sci USA 1995;92:11490-11494. [abstract]

Haft RF, Wessels MR, Mebane MF, Conaty N, Rubens CE. Characterization of cpsF and its product CMP-N-acetylneuraminic acid synthetase, a group B streptococcal enzyme that can function in K1 capsular polysaccharide biosynthesis in Escherichia coli. Mol Mircobiol 1996;19:555-563. [abstract]

Schrager HM, Rheinwald JG, Wessels MR. Hyaluronic acid capsule and the role of streptococcal entry into keratinocytes in invasive skin infection. J Clin Invest 1996;98:1954-1958. [abstract]

Alberti S, Ashbaugh CD, Wessels MR. Structure of the has operon promoter and regulation of hyaluronic acid capsule expression in group A Streptococcus. Mol Microbiol 1998;28:343-353. [abstract]

Ashbaugh CD, Alberti S, Wessels MR. Molecular analysis of the capsule gene region of group A Streptococcus: the hasAB genes are sufficient for capsule expression. J Bacteriol 1998;180:4955-4959. [abstract]

Ashbaugh CD, Warren HB, Carey VJ, Wessels MR. Molecular analysis of the role of the group A streptococcal cysteine protease, hyaluronic acid capsule, and M protein in a murine model of human invasive soft-tissue infection. J Clin Invest 1998;102:550-560. [abstract]

Levin JC, Wessels MR. Identification of csrR/csrS, a genetic locus that regulates hyaluronic acid capsule synthesis in group A Streptococcus. Mol Microbiol 1998;30:209-219. [abstract]

Schrager HM, Alberti S, Cywes C, Dougherty GJ, Wessels MR. Hyaluronic acid capsule modulates M protein-mediated adherence and acts as a ligand for attachment of group A Streptococcus to CD44 on human keratinocytes. J Clin Invest 1998;101:1708-1716. [abstract]

Wessels MR, Kasper DL, Johnson KD, Harrison LH. Antibody responses in invasive group B streptococcal infection in adults. J Infect Dis 1998;178:569-72. [abstract]

Butko P, Nicholson-Weller A, Wessels MR. Role of complement component C1q in the IgG independent opsonophagocytosis of group B Streptococcus. J Immunol 1999;163:2761-2768. [abstract]

Deng L, Kasper DL, Krick TP, Wessels MR. Characterization of the linkage between the type III capsular polysaccharide and the bacterial cell wall of group B Streptococcus. J. Biol. Chem 2000; 275:7497-7504. [abstract]