Chemokine-mediated Antimicrobial Activity against Bacillus Anthracis: Bacterial Targets and Biological Relevance

Crawford, Matthew Anthony, Department of Microbiology, University of Virginia
Hewlett, Erik, Department of Microbiology, University of Virginia
Goldberg, Joanna, Department of Microbiology, University of Virginia

Innate immunity is central to host defense, playing a critical role in protecting the host from infection by pathogenic microorganisms. Among the mediators important in the innate response to infection are chemokines, a family of chemotactic cytokines. In addition to orchestrating cellular movement, many chemokines have also been found to exert direct antimicrobial activity against a broad range of microorganisms through an as yet undefined mechanism. Here, we hypothesized that the interferon-inducible ELR - CXC chemokines CXCL9, CXCL10, and CXCL11 exert direct antimicrobial effects against Bacillus anthracis and mediate a receptor-independent contribution to host defense against pulmonary B. anthracis infection; we also hypothesized that specific bacterial targets are critically involved in facilitating chemokine-mediated bactericidal activity against B. anthracis. In vitro analysis demonstrated that all three CXC chemokines exert direct antimicrobial effects against B. anthracis spores and bacilli including disruptions in spore germination and reductions in spore and vegetative cell viability. Using a murine model of inhalational anthrax, CXCL9, CXCL10, and CXCL11 induction within the lungs of sporechallenged animals was found to be associated with reduced levels of spore germination and increased resistance to pulmonary infection. Antibody-mediated neutralization of these CXC chemokines, but not their shared cellular receptor CXCR3, resulted in significantly increased host susceptibility to inhalational anthrax characterized by ii systemic bacterial dissemination, toxemia, and host death. To identify bacterial targets of chemokine-mediated antimicrobial activity, we screened a B. anthracis transposon mutant library for vegetative bacilli resistant to CXCL10-mediated bactericidal activity. Prominent among the bacterial components identified as being critical in the ability of CXCL10 to kill B. anthracis bacilli was FtsX, the transmembrane portion of a putative ATP-binding cassette transporter. Importantly, FtsX was found to share considerable homology with the N-terminal chemokine binding domain of CXCR3 and, in the absence of FtsX, CXCL10 was unable to localize to the bacterial cell membrane and mediate killing. Taken together, these data demonstrate an efficient, biologically relevant antimicrobial role for host chemokines and support the notion of chemokine-mediated antimicrobial activity as a foundation for the identification of novel, broad-spectrum therapeutic targets and innovative approaches for treating infections caused by pathogenic, potentially multidrug-resistant microorganisms.

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PHD (Doctor of Philosophy)
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