A metabolically engineered bacterial vaccine protects against arthritis in mice
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AbstractArthritis is an autoimmune disease that adversely affects the quality of life of patients. Treatment options for autoimmunity include the use of chemical and biologic agents that suppress inflammation. However, these can result in patients being vulnerable to opportunistic infections. Adoptive T regulatory (Treg) cell transfer can specifically block auto-inflammatory immune cells in an antigen-specific manner while maintaining an intact immune response to pathogens. However, isolating sufficient Treg cells for adoptive cell transfer therapy is challenging; therefore, improving Treg cell survival and function could have important impacts on adoptive Treg transfer therapy. To explore the use of bacterial vaccines as autoimmune therapies, we engineered an attenuated brucellosis vaccine (Brucella melitensis vjbR Tna) to produce indole, a bacterial metabolite that induces Treg expansion. In the collagen induced arthritis (CIA) murine model, Treg transfer following BmvjbR Tna treatment decreased arthritis incidence and score. CD4+FoxP3+ T regulatory cells and CD8+ T cells in spleen and lymph nodes were increased in BmvjbR Tna treated CIA mice. BmvjbR Tna injection also promoted CD4+ cell proliferation, and increased IL-2 and IFN-g expression. The levels of some pro-inflammatory cytokines (IL-1 and IL-6) were also dramatically reduced in BmvjbR Tna infected bone marrow derived macrophages (BMDMs). Taken together, these findings indicate that the indole-producing BmvjbR Tna strain increases Treg cell populations and proliferation, suppresses proinflammatory cytokine secretion, and reduces autoimmune responses.
