Human polymorphonuclear leukocytes (PMNs or neutrophils) are essential to the innate immune response against invading microorganisms. In contrast to the acquired immune response, which requires time to develop and is dependent on previous interaction with specific pathogens, the ability of PMNs to ingest and kill infectious microorganisms is immediate, non-specific, and not dependent on previous pathogen exposure. My laboratory studies the interaction of human PMNs with bacterial pathogens. A key aspect of the research investigates how PMNs ingest and kill bacteria, and elucidates post-phagocytosis sequelae such as programmed cell death, processes essential for the resolution of infection. Notably, we discovered a genetic program that links phagocytosis of bacterial pathogens in human PMNs with programmed cell death (apoptosis) using cutting edge microarray technology to screen thousands of human genes. Although most human pathogens are killed readily by PMNs, some have evolved mechanisms to inhibit phagocytosis and death resulting from exposure to ROS and microbicidal products. For example, Streptococcus pyogenes (Group A Streptococcus or GAS) successfully evades PMN phagocytosis and killing to cause human infections such as pharyngitis, cellulitis, and necrotizing fasciitis (flesh-eating syndrome). These infections and post-infection sequelae are responsible for high morbidity and mortality globally. A second focus of research in my laboratory investigates how bacterial pathogens such as GAS evade PMN killing to cause disease. Using DNA microarrays, we discovered a genome-wide protective response used by GAS to evade PMN phagocytosis and killing. In these studies, we identified 349 GAS genes that were differentially regulated during phagocytic interaction with human PMNs. We found that 11 novel GAS secreted proteins were up-regulated during PMN phagocytosis, and discovered that a previously uncharacterized two-component gene regulatory system facilitates immune evasion to promote GAS survival and cause disease in humans.
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