Host response to intracellular pathogens
As accidental pathogens of humans, Legionella species are an excellent tool to investigate the mammalian innate immune response to bacterial pathogens. The study of Legionella restriction by the mammalian immune system has led to multiple breakthroughs, including the detection of bacterial flagellin by the NAIP5/NLRC4 inflammasome. A major component of research in our lab is to understand how effector proteins contribute to bacterial clearance by healthy hosts. Effector translocation by the Dot/Icm secretion system is required for bacterial replication but also contributes to immune clearance of Legionella by a process termed 'Effector-Triggered Immunity'. An excellent example of this enhanced pro-inflammatory gene expression in macrophages resulting from effector-mediated inhibition of host cell protein translation by several L. pneumophila effectors. We are currently working on elucidating the molecular mechanism(s) by which Legionella effectors enhance host defense against Legionella species. This work will reveal mechanisms of pathogen detection and host defense in addition to providing avenues for therapeutics against a range of pathogens.
Molecular mechanisms of metaeffector function
Legionella pneumophila encodes and translocates over three hundred individual effector proteins into infected host cells. How these effectors are regulated following translocation into host cells is poorly understood. Canonically, bacterial effectors have been associated exclusively with subversion of host factors. However, Legionella encodes multiple effectors that function exclusively to regulate other effectors, called metaeffectors. We have identified an essential metaeffector called Lpg2505 (MesI), which must regulate its cognate effector, SidI, for Legionella intracellular replication. We are interested in defining the mechanism by which MesI regulates SidI and how SidI impairs intracellular replication in the absence of SidI. We are also exploring how other metaeffectors function to regulate their cognate effectors and the role of these proteins in Legionella pathogenesis of natural and accidental hosts.
Antimicrobial action of sorghum polyphenols
Polyphenols derived from a variety of plants have demonstrated antimicrobial activity against diverse microbial pathogens. In collaboration with the U.S. Department of Agriculture and the K-State Agricultural research center, we discovered that activation of holy-polyphenol extracts from Sorghum bicolor bran augment macrophage killing of L. pneumophila. We are currently working towards understanding the molecular mechanism by which this occurs and the potential for Sorghum polyphenols to augment macrophage restriction of broad bacterial pathogens.