While not life-threatening, Brucella infections can cause debilitating disease with relapses of an undulating fever and lifelong complications, including arthritis, endocarditis, and possible neurological complications, even with antibiotic treatment. Moreover, in many parts of the world, brucellosis remains problematic, and it is estimated that approximately 500,000 new cases occur annually, making brucellosis the most common zoonotic infection in the world. While early immune responses to Brucella have been studied in murine models, brucellosis in humans is a chronic disease, and wild-type mice are naturally resistant to Brucella infection and do not develop disease in the same way as humans. Infection of the joints is the most frequent localized manifestation of brucellosis (occurring in u to 80% of patients) and a common cause of infectious arthritis in countries where the disease is endemic. To our knowledge, no experimental murine model of osteoarticular brucellosis has been reported in the literature; however, we have found that infection of IFN-?-deficient mice with wild-type B. melitensis or B. abortus results in joint and periarticular tissue inflammation. s no murine model of osteoarticular brucellosis has been reported, little is known about the pathogenic immune response that leads to arthritis. Interestingly, we found that IL-1R-/- mice depleted of IFN-? were more resistant to joint inflammation than wild-type mice similarly depleted of IFN-?, implicating IL-1 in the manifestation of osteoarticular brucellosis. In our preliminary data, we show that neutrophils are the main source of IL-1 in Brucella infected joints. In the proposed studies, we will determine the mechanisms of IL-1 signaling in brucellosis and their role in articular inflammation.
In many parts of the world, brucellosis remains problematic, and it is estimated that approximately 500,000 new cases occur annually, making brucellosis one of the most common zoonotic infections in the world. Infection of the joints is the most frequent localized manifestation of brucellosis (occurring in up to 80% of patients) and a common cause of infectious arthritis in countries where the disease is endemic. The proposed studies will determine mechanisms of IL-1 signaling in Brucella-induced articular inflammation in order to identify targets that can be exploited via immunomodulatory strategies to augment antibiotic resolution of Brucella-induced arthritis in humans.
| Lacey, Carolyn A; Mitchell, William J; Dadelahi, Alexis S et al. (2018) Caspases-1 and caspase-11 mediate pyroptosis, inflammation, and control of Brucella joint infection. Infect Immun : |
| Lacey, Carolyn A; Mitchell, William J; Brown, Charles R et al. (2017) Temporal Role for MyD88 in a Model of Brucella-Induced Arthritis and Musculoskeletal Inflammation. Infect Immun 85: |
| Lacey, Carolyn A; Keleher, Lauren L; Mitchell, William J et al. (2016) CXCR2 Mediates Brucella-Induced Arthritis in Interferon ?-Deficient Mice. J Infect Dis 214:151-60 |
