Haemophilus ducreyi Inhibits Phagocytosis

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Haemophilus ducreyi is the etiologic agent of chancroid, a sexually transmitted genital ulcer disease. Very little is known about how this unencapsulated, Gram-negative bacterium evades host defenses and causes dermal lesion development. However, it has been shown that H. ducreyi has the ability to resist phagocytosis in vivo. Moreover, this bacterium can prevent phagocytosis of both itself and secondary targets by macrophages in vitro. We have identified two extremely large H. ducreyi proteins, designated LspAt and LspA2, that are released into H. ducreyi culture supernatant fluid and which are responsible for the observed inhibition of phagocytic activity. That these proteins are relevant to disease production was proven by the finding that a H. ducreyi mutant unable to express either LspA1 or LspA2 had drastically reduced virulence in both animal and human models of experimental chancroid. Nothing is known, however, about how the LspA proteins inhibit phagocytic activity. The proposed research project is focused on the structure, function, and expression of the LspA proteins. In the first Specific Aim, we will purify either a functional LspAt fusion protein or native LspA1 protein and determine the composition of the active form of this protein. In the second Specific Aim,we will elucidate the mechanism of action involved in the inhibition of phagocytic activity by the LspA proteins. We already have data which indicate that the LspA proteins can affect signaling pathways that control phagocytosis in macrophages. In the third Specific Aim, we will identify the H. ducreyi gene products that are responsible for control of expression of the LspA proteins by this bacterium. The relevance of this research to public health involves the new information that will be gained about phagocytosis, one of the primary defense mechanisms of the human body. The ability of phagocytes to engulf and kill bacteria is essential to preventing or curing infectious diseases. Information gained from this study will help us understand how phagocytes control this protective activity.