Homeostatic Regulation of Salmonella-Induced Mucosal Inflammation and Injury by IL-23

IL-12 and IL-23 regulate innate and adaptive immunity to microbial pathogens through influencing the expression of IFN-γ, IL-17, and IL-22. Herein we define the roles of IL-12 and IL-23 in regulating host resistance and intestinal inflammation during acute Salmonella infection. We find that IL-23 alone is dispensable for protection against systemic spread of bacteria, but synergizes with IL-12 for optimal protection. IL-12 promotes the production of IFN-γ by NK cells, which is required for resistance against Salmonella and also for induction of intestinal inflammation and epithelial injury. In contrast, IL-23 controls the severity of inflammation by inhibiting IL-12A expression, reducing IFN-γ and preventing excessive mucosal injury. Our studies demonstrate that IL-23 is a homeostatic regulator of IL-12-dependent, IFN-γ-mediated intestinal inflammation

An Oral Vaccine Based on U-Omp19 Induces Protection against B. abortus Mucosal Challenge by Inducing an Adaptive IL-17 Immune Response in Mice

As Brucella infections occur mainly through mucosal surfaces, the development of mucosal administered vaccines could be radical for the control of brucellosis. In this work we evaluated the potential of Brucella abortus 19 kDa outer membrane protein (U-Omp19) as an edible subunit vaccine against brucellosis. We investigated the protective immune response elicited against oral B. abortus infection after vaccination of mice with leaves from transgenic plants expressing U-Omp19; or with plant-made or E. coli-made purified U-Omp19. All tested U-Omp19 formulations induced protection against Brucella when orally administered without the need of adjuvants. U-Omp19 also induced protection against a systemic challenge when parenterally administered. This built-in adjuvant ability of U-Omp19 was independent of TLR4 and could be explained at least in part by its capability to activate dendritic cells in vivo. While unadjuvanted U-Omp19 intraperitoneally administered induced a specific Th1 response, following U-Omp19 oral delivery a mixed specific Th1-Th17 response was induced. Depletion of CD4+ T cells in mice orally vaccinated with U-Omp19 resulted in a loss of the elicited protection, indicating that this cell type mediates immune protection. The role of IL-17 against Brucella infection has never been explored. In this study, we determined that if IL-17A was neutralized in vivo during the challenge period, the mucosal U-Omp19 vaccine did not confer mucosal protection. On the contrary, IL-17A neutralization during the infection did not influence at all the subsistence and growth of this bacterium in PBS-immunized mice. All together, our results indicate that an oral unadjuvanted vaccine based on U-Omp19 induces protection against a mucosal challenge with Brucella abortus by inducing an adaptive IL-17 immune response. They also indicate different and important new aspects i) IL-17 does not contribute to reduce the bacterial burden in non vaccinated mice and ii) IL-17 plays a central role in vaccine mediated anti-Brucella mucosal immunity

High-Resolution Diffusion Tensor Spinal Cord MRI Measures as Biomarkers of Disability Progression in a Rodent Model of Progressive Multiple Sclerosis

<div><p>Disease in the spinal cord is a major component of disability in multiple sclerosis, yet current techniques of imaging spinal cord injury are insensitive and nonspecific. This study seeks to remove this major impediment to research in multiple sclerosis and other spinal cord diseases by identifying reliable biomarkers of disability progression using diffusion tensor imaging (DTI), a magnetic resonance imaging technique, to evaluate the spinal cord in a model of multiple sclerosis, i.e. the Theiler’s Murine Encephalitis Virus-Induced Demyelinating Disease (TMEV-IDD). Mice with TMEV-IDD with varying levels of clinical disease were imaged using a 9.4T small animal MRI scanner. Axial diffusivity, radial diffusivity, and fractional anisotropy were calculated. Disability was assessed periodically using Rotarod assay and data were expressed as a neurological function index. Correlation was performed between DTI measurements and disability scores. TMEV-IDD mice displayed significant increased neurological deficits over time when compared with controls (<i>p</i><0.0001). Concurrently, the values of fractional anisotropy and axial diffusivity were both decreased compared to controls (both <i>p</i><0.0001), while radial diffusivity was increased (<i>p</i><0.0001). Overall, fractional anisotropy changes were larger in white matter than in grey matter and differences were more pronounced in the ventral region. Lower disability scores were associated with decreased fractional anisotropy values measured in the ventral (r = 0.68; <i>p</i><0.0001) and ventral-lateral (r = 0.70; <i>p</i><0.0001) regions of the white matter. These data demonstrate that DTI measures of the spinal cord contribute to strengthening the association between neuroradiological markers and clinical disability, and support the use of DTI measures in spinal cord imaging in MS patients.</p></div