Chair, Department of PediatricsDepartments / Divisions
Durham, NC 27710
Pediatric infectious diseases; antibiotic resistance; infections of the respiratory tract and central nervous system; tick-borne infections; vaccine development; microbial pathogenesis
ST. GEME LAB
My laboratory is interested in host-pathogen interactions and is using genetic methods, protein chemistry, X-ray crystallography, high resolution microscopy, and microarray analysis to study the molecular and cellular determinants of disease due to Haemophilus influenzae, a model mucosal pathogen and a common cause of local respiratory tract disease and serious invasive infection. H. influenzae expresses a number of adhesive proteins that mediate interaction with host epithelium, and we are studying the biogenesis, adhesive specificity, and regulation of these proteins. In addition, we are examining the host determinants of H. influenzae interaction with respiratory epithelium. Recent evidence indicates that H. influenzae forms biofilms, complex communities of organisms that likely facilitate persistence on the respiratory epithelial surface. We are seeking to understand the bacterial and host factors that influence H. influenzae biofilm formation, and we are beginning to study the relationship between biofilms and evasion of innate immune mechanisms, such as cationic peptides, lactoferrin, and phagocytosis. From a practical perspective, our work has relevance to development of novel antimicrobial compounds and to generation of a vaccine broadly effective against H. influenzae.
In a new line of investigation, we have initiated studies of Kingella kingae, an emerging pathogen that has been recognized in recent years as a common cause of invasive disease in young children, especially bone and joint infections. K. kingae initiates infection by colonizing the upper respiratory tract, then invades the bloodstream and disseminates to distant sites. We have focused on defining the bacterial and host determinants of colonization, invasion of the bloodstream, survival in the intravascular space, and induction of an inflammatory response.
Haemophilus Influenzae Adherence
Most bacterial diseases begin with microbial colonization of a particular mucosal surface. Bacterial attachment to host epithelial cells is a key event in this process and is mediated by specific interactions between microbial adhesins and complementary receptor structures on the epithelial cell surface.
Virtually all strains of H. influenzae express one or two high-molecular weight non-pilus adhesins, either Hia/Hsf or HMW1 and HMW2. We are characterizing the structure, biogenesis, adhesive properties, and regulation of these adhesins. We are also defining the host cell receptors with which these adhesins interact and the host cell pathways that are activated by H. influenzae adherence.
H. influenzae Hap-meditated Microcolony Formation
Microbial biofilms are structured microbial communities that are being recognized increasingly in human disease and appear to promote bacterial persistence on mucosal surfaces. Several reports indicate that Haemophilus influenzae is capable of forming biofilms, in particular in patients with otitis media and probably in adults with chronic bronchitis. We have identified an H. influenzae adhesive protein called Hap, which was first discovered based on the capacity to promote intimate interaction with cultured epithelial cells. More recent evidence indicates that Hap mediates bacterial aggregation and microcolony formation. Hap adhesive activity is augmented by a soluble host serine protease inhibitor called secretory leukocyte protease inhibitor (SLPI). At the same time, Hap is a target for degradation by lactoferrin, a host protein present in a number of secretions and capable of cleaving arginine-rich sequences. Our data suggest that Hap-mediated microcolony formation is a precursor to biofilm formation.
The interaction between pathogenic bacteria and host cells is largely determined by microbial proteins presented on the bacterial surface or rel
This faculty member has no reported relationships with industry.