Host interferon-γ inducible protein contributes to Brucella survival

Brucella spp. are highly adapted intracellular pathogens of mammals that cause chronic infections while surving and replicating in host monocytes and macrophages. Although monocytes are normally susceptible to infection, pretreatment with pro-inflammatory cytokine interferon-γ (IFN-γ) activates cellular defense mechanisms that increase intracellular killing of Brucella and prevents bacterial replication. We examined the contribution of the IFN-γ inducible GTPase, LRG-47, to B. abortus 2308 infection in in vitro and in vivo murine models. Infecting non-activated macrophages from LRG-47(-/-) mice revealed that loss of this host protein negatively effected the intracellular survival and replication of IgG opsonized B. abortus. In contrast, survival and replication of non-opsonized B. abortus was the same in both C57/B6 and LRG-47(-/-) peritoneal macrophages. Following IFN-γ activation of LRG-47(-/-) monocytes, IgG opsonized B. abortus survived better than non-opsonized bacteria. The differential fate of opsonized and non-opsonized B. abortus was only observed in macrophages collected from LRG-47(-/-) mice. Given the specific nature of the relationship between this host protein and the mechanism of Brucella internalization, LRG-47(-/-) mice were infected with B. abortus to assess whether the loss of the lrg47 protein would affect the ability of the bacteria to colonize or persist within the host. B. abortus were able to establish and maintain similar numbers of bacteria in both C57/B6 mice and LRG-47(-/-) through 3 weeks post intraperitoneal infection. By 9 weeks p.i. fewer B. abortus were recovered from LRG-47(-/-) mice than controls, suggesting that the host protein has a positive role in maintaining long term persistence of the bacteria within the host. These observations demonstrating a positive role for a host IFN-γ induced protein defense protein has yet to be reported. These results provide interesting insight into the complex interaction between Brucella and their host.