Haemophilus parainfluenzae and cardiopulmonary disease

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DESCRIPTION (provided by applicant): Haemophilus parainfluenzae is a Gram-negative pleomorphic bacillus that is found exclusively associated with human hosts. Multiple clinical reports have shown the bacterium to be the most frequent cause of Gram-negative infective endocarditis (IE). Infective Endocarditis is a bacterial infection of the heart typically involving the valves. H. parainfluenzae IE has been associated with a high frequency of septic embolism in which vegetative masses, comprising bacteria and platelets, break off from the main site of infection and travel through the bloodstream. While IE caused by Gram-negative bacteria is essentially unstudied, more is known about Gram-positive IE. These studies have shown a strong correlation between the ability of the bacteria to bind to components of the extracellular matrix (ECM) and the ability of the bacteria to cause IE. This is consistent with data showing that IE is much more common when there is preexisting damage to the heart, resulting in ECM at the site of injury. The bacteria bind to the heart via adherence to ECM molecules. The adherent bacteria then come into contact with platelets and bind them. Thus, a vegetative body of bacteria and host platelets begin to expand. If part of this vegetative body breaks off, a septic embolism may result. The specific aims of this research are 1) to characterize the adherence of H. parainfluenzae to human ECM and to identify the molecules involved; and 2) to characterize the attachment of H. parainfluenzae to human platelets and the molecules involved. To accomplish these aims we will utilize wild type strains of H. parainfluenzae in a series of adherence assays using ECM components and human platelets. After characterization of the binding has been performed, identification of molecules involved will be done using a bank of random transposon insertion mutants of H. parainfluenzae. Finally, two candidate adhesions have already been identified by this group, Haa and Hap. The role of these specific proteins in bacterial adherence will be examined. PUBLIC HEALTH RELEVANCE: Haemophilus pararinfluenzae has been implicated as an opportunistic pathogen of the human cardiopulmonary system. In particular, it is has been implicated in infective endocarditis. The proposed research will examine the molecular mechanisms of adherence of H. parainfluenzae to components of the extracellular matrix and cardiac valves as well as Hia-like adhesin proteins Haa and Hap.