Research

Approach

Our research is focused primarily on bacterial pathogens, which are a re-emerging threat to human health and welfare due to the increasing incidence of multidrug resistant strains.

We start by using structural biology (X-ray crystallography) to get a highly detailed view of how virulence factors produced by bacterial (or other microbial) pathogens interact with host cell targets. We then use this detailed picture as a basis for designing biochemical, structural, genetic, or cell biological experiments aimed at elucidating the physiological function of virulence factors. The results from our studies are potentially applicable to the creation of novel antimicrobials.

 

Surface proteins of Group A Streptococcus

M proteins have long been recognized as major virulence factors of Group A Streptococcus (GAS, S. pyogenes ), a Gram-positive bacterial pathogen that causes a wide variety of human disease spanning mild (e.g., pharyngitis and impetigo) to life-threatening (e.g., necrotizing fasciitis and streptococcal toxic shock syndrome).   Fibrils of M protein , which are ~500 Å in length and covalently attached to the GAS cell wall, form a dense coating on the streptococcal surface.   Host proteins, such as fibrinogen and C4BP, are recruited specifically by M protein to this surface, where they block deposition of opsonic antibodies and complement, thereby enabling M protein to inhibit phagocytic elimination of GAS by neutrophils and other immune cells. In collaboration with Victor Nizet, we are determining the structure and mechanism of action of M proteins.

 

Massive sequence variation in retroelement-encoded proteins

Bordetella bacteriophage retroelement is the prototype for a family of retroelements, called diversity-generating retroelements (DGR), implicated in generating sequence diversity in various phage and bacterial genomes.  This retroelement generates sequence diversity in a receptor-binding protein of the phage, major tropism determinant (Mtd).  Approximately 10e13 sequences of Mtd can be generated by the retroelement, rivaling the diversity of antibodies and T-cell receptors (~10e14-10e16). In essence, Mtd is a new kind antibody.

In collaboration with Jeff Miller, we are trying to understand how Mtd accommodates massive sequence variation and creates diverse receptor-binding sites.

 

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