My research goal is to become an independent investigator that heads a research group aimed atunderstanding host immunity against vacuolar pathogens. To this end, I am using the respiratory pathogenLegionella pneumophila as a model organism to understand immune detection of pathogens and subsequentcontrol of infection. Upon host cell infection, L. pneumophila is able to prevent its transport to lysosomes, andremodels its vacuole into an endoplasmic reticulum-derived compartment that supports bacterial replication. Toaccomplish this, L. pneumophila utilizes a type IV secretion system (T4SS) to translocate bacterial effectorsinto the host cell. We have found that the host is able to discriminate between virulent and avirulent bacteria.We have identified host MAPK pathways activated only in response to virulent bacteria expressing a functionalT4SS that result in an increased proinflammatory cytokine response. This T4SS-dependent host response isdistinct from TLR, Nod1, Nod2, and inflammasome signaling. However, little is known about the identity of thebacterial factors that trigger this response and how this pathway contributes to immune gene expression andsubsequent control of bacterial infection in vivo. A multi-disciplinary approach will be taken to answer thesequestions.
In Aim 1, I will identify and characterize the bacterial components required for T4SS-dependentactivation of host MAP kinases.
In Aim 2, I will identify and characterize the contributions of TLR-dependentand T4SS-dependent signaling to immune gene expression. Finally, in Aim 3, I will dissect the contributions ofvarious cell types to the innate immune detection of L. pneumophila and subsequent control of infection.During the mentored phase, completion of Aim 1 will provide a series of relatively straightforward experimentsas well as screen-based approaches that will yield bacterial candidates that can be pursued during theindependent phase. Additionally, bacterial strains described in Aim 3 will be generated and mouse breeding forAim 3 will be started. During the independent phase, Aims 2 and 3 involving molecular immunology and in vivoinfection models will be pursued. These studies will provide a solid foundation for further investigations intounderstanding host responses to vacuolar pathogens that will be pursued during the independent phase of mycareer.
Understanding host responses to the respiratory pathogen L. pneumophila will advance our understanding of bacterial virulence and how the innate immune system distinguishes between virulent and avirulent bacteria and initiates antimicrobial immunity. This will ultimately aid in the design of effective antimicrobial therapies and vaccines.
