NIH Reporter #2P20GM130448-06

Impact of the Borrelia burgdorferi adenylate cyclase cyaB at the host-pathogen interface

This award funds research to understand how the Borrelia burgdorferi adenylate cyclase cyaB influences gene expression and host interaction to promote Lyme disease pathogenesis, aiming to elucidate the cAMP signaling pathway at the host-pathogen interface.

Description

Lyme disease is the most common vector-borne illness in the United States with rapidly increasing incidence. The symptoms of Lyme disease range from mild flu-like illness with fatigue and nausea to debilitating headaches and arthritis that can persist for years. The longstanding and severe morbidity of Lyme disease makes it a significant public health concern, especially considering a human vaccine is currently not available. Lyme disease is caused by the spirochete Borrelia burgdorferi, transmitted to humans through the bite of an infected Ixodes scapularis tick. Our long-term research goal is to characterize the pathogenic mechanisms utilized by B. burgdorferi to sense and adapt to the host environment to promote virulence. We have previously established a role for B. burgdorferi cyaB, an adenylate cyclase responsible for producing the important second messenger cAMP, in pathogenesis. We found that B. burgdorferi cyaB modulates gene expression and protein production to promote virulence and dissemination in the mammalian host. Moreover, after investigating the role of B. burgdorferi cyaB during host cell interaction by co-cultivating the bacteria with human cell lines, we found that expression of cyaB is influenced by cellular factors unique to the cell line. The objective of this proposal is to investigate targets downstream of B. burgdorferi cyaB in both the pathogen and the host to continue elucidating the cAMP signaling pathway and its role at the B. burgdorferi-host interface. Based on preliminary and published data, we hypothesize that interaction with host epithelial-like cells induces cyaB expression, impacting both the B. burgdorferi and the host. To test this hypothesis, in Aim 1 we will analyze the B. burgdorferi cyaB regulon during host cell exposure through investigating the B. burgdorferi WT and cyaB mutant transcriptomes following co-cultivation. In Aim 2 we will analyze the host transcriptome impacted by cyaB during B. burgdorferi exposure to better understand the impact of cyaB on the host cell response. The results from this proposal will provide significant insight into the mechanisms of B. burgdorferi-host interaction and the dynamic transcriptional regulation taking place at the B. burgdorferi-host interface. Moreover, the data generated may provide a deeper understanding of the genetic changes being initiated upon exposure to the host to promote B. burgdorferi pathogenesis.

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