Persistent articular infection and host reactive response contribute to Brucella-induced spondyloarthritis in SKG mice

Abstract

Brucellosis, one of the most prevalent zoonotic diseases worldwide, often results in osteoarticular complications including large joint and axial arthritis mimicking spondyloarthritis. To model this chronic manifestation, we infected autoimmunity-prone SKG mice containing a mutation in the T-cell adaptor ZAP-70 with Brucella species. B. melitensis infection resulted in a fully penetrant, readily scoreable disease involving large joint wrist and foot arthritis, peri-ocular inflammation, and less frequent scaly paw rash. Infection with B. abortus resulted in delayed arthritis onset, and B. neotomae revealed sex differences, with more severe disease and a dose response in females. Heat-killed Brucella did not induce arthritis, evincing a requirement for viable infection. Across species, splenic CFU correlated well with final clinical score at 12 weeks ({rho}=0.79 and p<0.001). In vivo imaging using luminescent B. neotomae revealed rapid colonization of the paws by one-week post-infection, more than a month prior to arthritis onset. Paw luminescence levels decreased after 2 weeks and then remained relatively static, even as clinical scores increased. Thus, the degree of arthritis did not strictly correlate with degree of paw infection but suggested an additional reactive component. Further, in examining a Brucella {Delta}tcpB mutant lacking a Type IV secretion system-dependent mediator, mice displayed an intermediate phenotype without significant differences in splenic CFU. Together these data suggest Brucella induced spondyloarthritis reflects both persistent colonization as well as excess host reactivity. Moreover, the sensitivity of the SKG model to different species and mutants will provide new opportunities for dissecting correlates of Brucella virulence and host immunity. ImportanceBrucellosis, a bacterial infection acquired from herd animals, remains one of the most common zoonotic diseases worldwide. Chronic infection often results in spondyloarthritis-like complications. Investigation into pathogenesis has been limited by the lack of overt disease in standard lab mice. We addressed this issue using spondyloarthritis-susceptible SKG mice. Upon infection with B. melitensis, SKG mice develop robust, fully penetrant large joint arthritis. Arthritis development required viable bacteria. Moreover, studies of colonization, gene expression and anatomic distribution using bioluminescent bacteria revealed active persistent infection in the mouse paws. However, peak paw infection occurred much earlier than arthritis onset, suggesting an added immune reactive component. Disease onset, severity and manifestations varied upon infection with different Brucella species and mutants. Together these results suggest this new model will be very useful to the scientific community for determining correlates of bacterial virulence leading to clinical disease.