Most individuals exposed to Mycobacterium tuberculosis either never become infected or are able control infection maintaining the bacteria in a latent state walled off inside structures called granulomas. Active tuberculosis occurs in a subset of infected subjects when immunologic control breaks down. Immunologic approaches for preventing infection or disease have focussed on the critical role played by CD4+T cells and macrophages in host resistance to mycobacteria although there has been less information concerning the function of the latter cell population in disease exacerbation. Evidence for such a role was obtained this year in a project aimed at studying the effects of exogeneously induced Type 1 IFN on murine tuberculosis. In this study, we treated mice infected by the aerosol route intranasally with poly-ICLC, an agent designed to stimulate prolonged, high-level production of type I IFN. Drug-treated, infected wild-type, but not IFN alpha, beta receptor deficient animals, displayed marked elevations in lung bacillary loads accompanied by widespread pulmonary necrosis without detectable impairment of Th1 effector function. Importantly, lungs from Poly-ICLC-treated mice exhibited a striking increase in CD11b+F4/80+Gr1int monocyte/macrophages. These cells displayed decreased MHC II expression and enhanced bacterial levels relative to the same subset purified from infected, untreated controls. Moreover, both the Poly-ICLC triggered pulmonary recruitment of the CD11b+F4/80+Gr1int population and the accompanying exacerbation of infection correlated with type I IFN-induced upregulation of mRNA for the chemokine Ccl2 and required host expression of its receptor, CCR2. The above findings suggest that type I IFN induction, by promoting the accumulation of a permissive myeloid population in the lung, can detrimentally affect the outcome of M. tuberculosis infection and suggest that drugs that stimulate type I IFN should be utilized with caution in patients exposed to this pathogen. Immune Reconstitution Inflammatory Syndrome (IRIS) is the rapid and paradoxical worsening of pathology seen in HIV-1 infected individuals after initiation of anti-retroviral therapy (ART). With the increasing use of ART for mass treatment of AIDS in developing regions, this complication has emerged as a major problem in the management of HIV infection. IRIS is more common in patients with severe CD4 T cell lymphopenia and patients with mycobacterial and other opportunistic infection are at particularly high risk of developing this severe pathologic response. The factors that lead to the induction of IRIS and the mechanisms of its immunopathogenesis are poorly understood, so currently patient treatment during IRIS episodes is limited to supportive care and broad steroid based immunosuppression. In a collaborative study study initiated with Drs.Irini Sereti and Mario Roederer we have been using multiparameter flow cytometry to characterize T cell populations in ART treated HIV patients at the NIH clinical center in order to identify phenotypic changes predictive of IRIS development. The initial study population consists of a group of 45 HIV+1 individuals with low CD4 T cell counts and a variety of potential IRIS pre-disposing conditions. The T cell phenotypic data gathered so far comparing the sub-set of patients developing IRIS with those that did not, indicate higher levels of the activation marker PD-1 on CD4+ T cells in the IRIS group at the start of ART treatment. This data supports the hypothesis that the presence of a highly activated T cell phenotype at the time of ART initiation, possibly due to excessive antigenic stimulation from co-infection, may be a pre-disposing factor for IRIS.
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