Their development is further driven by IL-12 and IFN-. a flu-like illness with fever, chills, fatigue, headache, and body aches (1). This form of the disease can be asymptomatic and is often self-limiting (2). Consequently, it is believed that disease incidence is significantly underreported (3). Chronic Q fever commonly presents as endocarditis (4,C6) and, when left untreated, is fatal in at least 25% of patients (1). Treatment involves dual antibiotic therapy with doxycycline and hydroxychloroquine for at least 18?months (7, 8). However, in Santonin one 24-month cohort study (9), more than 30% of Q fever patients retained an impaired health status despite following the prescribed antibiotic regimen. This globally distributed pathogen is transmitted to humans via aerosols from infected ruminants and thus serves as an occupational hazard for individuals working closely with livestock (10,C14). Its hardiness in the environment (15), aerosol route of transmission (16, 17), and low infectious dose (18, 19) make an important zoonotic pathogen. Furthermore, has been designated a National Institutes of Health (NIH) category B priority pathogen for its potential threat as a biowarfare agent (20). Considering the incapacitating effects of aerosolized and the shortcomings of current antibiotic therapies, the creation Santonin of a safe and effective new-generation Q fever vaccine remains critical. has two phase variants. Phase I organisms are found in nature and possess full-length lipopolysaccharide (LPS). In contrast, phase II organisms, generated by serial passage in eggs, tissue culture, or synthetic media, have a truncated LPS lacking the O-antigen and outer core regions (21, 22). Virulent phase I is capable of replicating in immunocompetent animals to cause disease, while avirulent phase II is rapidly cleared and does not cause disease (18). A formalin-inactivated whole-cell vaccine generated from Henzerling phase I (Q-VAX) elicits long-lasting protective immunity in animal models and human vaccinees (10, 23,C25); however, it is not approved for use in the United States due to a high incidence of adverse reactions in vaccine recipients (10, 23, 26,C29). Multiple screening procedures, including skin tests and serology, are required for safe use of this vaccine (30). Understanding the immunological mechanisms of vaccine protection, as well as the underlying triggers of hypersensitivity, is necessary to develop a vaccine that is both safe and effective. It has previously been demonstrated that both humoral and cell-mediated immunity contribute to host defense against (25, 31,C44). In a murine intraperitoneal (i.p.) infection model, B cells appear to contribute to the host inflammatory response, while T cells and interferon gamma (IFN-) are important for bacterial clearance (37). However, only adoptive transfer of immune T cells, not immune B cells, from Nine Mile phase I vaccine (PIV)-vaccinated Santonin BALB/c mice to SCID mice reduces disease severity following i.p. challenge (25). These data suggest an important role for T cells in both the primary and the Rabbit Polyclonal to MOV10L1 secondary host response against and show that MHC-II is important for PIV-mediated protection. The contribution of MHC-II to vaccine-induced protective immunity is only partially dependent on CD4+ T cells, since PIV-vaccinated MHC-II-deficient (MHC-II KO) mice have significantly worse disease than PIV-vaccinated CD4-deficient (CD4 KO) mice. CD4+ Santonin T cells are, however, sufficient for protection when they come from an antigen-experienced donor. This is demonstrated by a significant reduction in splenomegaly following adoptive transfer of PIV-vaccinated CD4+ T cells to naive CD4 KO mice. Furthermore, we demonstrate a role for Tbet in PIV protection that is partially dependent on Th1 subset CD4+ T cells. When we evaluated the contribution of IFN-, we found that, while IFN- does seem to affect inflammation, it does not appear to play a major role in bacterial clearance following secondary challenge. These findings provide novel information about the role of MHC-II, Tbet, CD4+ T cells, and IFN- in vaccine-induced protective immunity against a murine model of experimental Q fever. Furthermore, this study highlights key differences in the host response following primary infection and secondary challenge which can inform future Q fever vaccine development. RESULTS MHC-II is important for PIV-mediated protection against infection, with MHC-I being more critical (44). To determine the role of these complexes in vaccine-mediated protection, we vaccinated MHC-I-deficient (B2m KO) and MHC-II-deficient (MHC-II KO) mice subcutaneously (s.c.) with 10?g of PIV with Alhydrogel adjuvant followed by intraperitoneal (i.p.) challenge with 1??107 genomic copies of Nine Mile phase I (NMI) 28?days postvaccination (dpv). An aluminum hydroxide adjuvant was chosen for these studies based on its widely accepted use in commercially available human vaccines (45). Body weight loss, splenomegaly, and splenic bacterial burden were evaluated to assess the protective efficacy of PIV. PIV-vaccinated wild-type (WT) C57BL/6 mice were protected from body weight loss compared to WT adjuvant control mice, which had a significant drop in body weight 7?days postinfection (dpi; Fig. 1A). This correlated with a significant reduction in splenomegaly (Fig..