IFN-γ-deficient mice develop IL-1-dependent cutaneous and musculoskeletal inflammation during experimental brucellosis

Abstract

Human brucellosis exhibits diverse pathological manifestations that can affect almost any organ. In particular, osteoarticular complications are the most common focal manifestation of brucellosis and occur in 40-80% of patients. In immunocompetent mice, Brucella replication is generally restricted to the spleen, liver, and to a lesser extent, LNs, thereby limiting their use for study of focal inflammation often found in brucellosis. Here, we report that nasal, oral, or peritoneal infection of IFN-γ(-/-) mice with WT Brucella melitensis or Brucella abortus results in joint and periarticular tissue inflammation. Histological analysis of the affected joints revealed inflammatory infiltrates and debris within the joint space colocalizing with Brucella antigen. Osteoarthritis, necrosis, periarticular soft tissue inflammation, and substantial brucellae burdens were observed. Oral rifampicin was effective in clearing infection and halting further progression of focal inflammation from infected IFN-γ(-/-) mice, although some symptoms and swelling remained. Elevated IL-1 β, but not TNF-α, IL-6, or IL-17, was detected in joint homogenates from infected IFN-γ(-/-) mice. Whereas more susceptible to systemic infection, IL-1R(-/-) mice depleted of IFN-γ were more resistant to focal inflammation than WT mice similarly depleted of IFN-γ. Collectively, these results show IFN-γ(-/-) mice represent a potential model for study of focal inflammation attributed to Brucella infection and will allow evaluation of intervention strategies targeting IL-1, IL-1R, or other inflammatory mediators, with the potential to complement antibiotic-based therapies.

Identification of Immune Effectors Essential to the Control of Primary and Secondary Intranasal Infection with Brucella melitensis in Mice

“…Moreover, we demonstrated that mortality associated with a deficiency in IFN-g signaling is linked to uncontrolled Brucella growth in tissues and probably to severe neutrophilia, which causes multiple organ failure. We failed to (69). In an Ehrlichia muris infection model (70), IFN-g was shown to control infection by directly promoting the differentiation of myeloid cells into monocytes.…”

Temporal Role for MyD88 in a Model of Brucella-Induced Arthritis and Musculoskeletal Inflammation

“…Arthritis in this model was dependent on CXCR2 and interleukin-1 receptor (IL-1R), but adaptive immune cells were not required for the induction of inflammation (9,17). We suspected that IFN-␥ deficiency allowed for the hematogenous spread of Brucella, resulting in infection and inflammation of the joint (9). Other mouse models of infectious arthritis have utilized footpad inoculation to localize pathogens, such as Borrelia burgdorferi, chikungunya virus, and Candida albicans, to the joint and surrounding tissue to induce inflammation (19)(20)(21) Here we describe a model of Brucella-induced arthritis that is applicable in WT mice.…”

“…Brucella infection of gamma interferon (IFN-␥)-deficient mice resulted in arthritis of ankle joints as early as 15 days postinfection. Arthritis in this model was dependent on CXCR2 and interleukin-1 receptor (IL-1R), but adaptive immune cells were not required for the induction of inflammation (9,17). We suspected that IFN-␥ deficiency allowed for the hematogenous spread of Brucella, resulting in infection and inflammation of the joint (9).…”

“…Mechanisms underlying arthritic responses induced by Brucella have been hindered by the lack of relevant mouse models, as wild-type (WT) mice infected with conventional doses (10 4 to 10 6 CFU) by systemic routes do not develop joint inflammation (9,17). One study showed that BALB/c mice infected intraperitoneally (i.p.)…”

“…Osteoarticular and musculoskeletal inflammation are the most common focal complications of human brucellosis and occur in 40 to 80% of Brucella-infected patients (7,8). This arthritis is thought to arise from the hematogenous spread of Brucella to the joints, as viable brucellae can be found within the synovial fluid of infected patients (9,10). Arthritis can manifest as peripheral arthritis, sacroiliitis, and spondylitis, which are most common in children, young adults and older adults, respectively (7,8,11,12).…”