Cell Wall Integrity and Pathogenesis

Coxiella burnetii, the intracellular bacterial pathogen the causes Q fever, has few described virulence factors. Using a unique cellular model of Coxiella infection, we discovered that multiple genes related to the bacterial cell wall are  required for replication in macrophages. These genes represent a novel class of cell type-specific virulence determinants for C. burnetii.

The Case Lab is investigating how the cell wall contributes to Coxiella's unique ability to withstand the extreme environment of the Coxiella-containing vacuole (CCV) in which it resides. We discovered some mutant strains of C. burnetii with disruptions in the structure and synthesis of cell wall components cannot replicate in the CCV of macrophages. The CCV contains degradative enzymes, a  very low pH, and potentially, antimicrobial peptides that could attack its cell membrane. We suspect that these cell wall mutants have vulnerabilities that render Coxiella vulnerable to the harsh conditions of this compartment. We plan to use these mutant strains as a tool to understand how Coxiella can resist the conditions within its CCV.

In addition to investigating how the cell wall helps Coxiella survive in the macrophage, we also predict it allows the bacterium to hide from its host. If, because of their weakened cell walls, these mutants release bacterial molecules (pathogen-associated molecular markers, or PAMPS) that can be detected by the host via toll-like receptors (TLRs). The host might then respond with antibacterial defense measures, like cytokine/chemokine secretion, or generation of reactive oxygen or nitrogen species (ROS/RNS). This also may contribute to the host's ability to control the infection.

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