Pulmonary Immunopathogenesis of Granulibacter bethesdensis

Abstract

Abstract Granulibacter bethesdensis (Gb) is a Gram negative bacterial pathogen reported to cause disease exclusively in patients with Chronic Granulomatous Disease harboring mutations in one of the five subunits of NADPH oxidase complex. The pathogen has been shown to cause chronic as well as recurrent infections in CGD patients that can be fatal. Although systemic and septic infection have been reported, the pathogenesis of Gb in respiratory microenvironment is completely unknown. Here we compared the disease progression and infection outcome of wild-type (WT) and murine CGD model Gp91 −/−mice following intranasal infection with a clinical isolate of Gb. We found that compared to the WT mice, Gp91 −/−CGD mice are highly susceptible to respiratory infection with Gb. While the WT mice displayed transient increase in inflammatory cytokines and moderate leukocyte infiltration characteristic of a mild, resolving infection, CGD mice displayed hypercytokinemia but attenuated antimicrobial function of phagocytic cells. A significant upregulation of Type 2 inflammatory cytokine IFN-γ in lungs Gb infected gp91−/− prompted investigation the its role in GB pathogenesis. Neutralization of this cytokine mitigated the inflammatory response and reduced bacterial burden in infected Gp91−/− CGD mice resulting in significantly improved overall survival. Mechanistically, IFN-γ neutralization improved antimicrobial function of neutrophils. Taken together, our findings suggest that in the absence of a functional superoxide production machinery, G. bethesdensis is capable of causing a chronic respiratory infection with fulminant sepsis and IFN-γ produced during the infection has a detrimental effect on the bacterial clearance.