Immune responses against Mycobacterium tuberculosis targets associated to latent and active tuberculosis infection

Sammanfattning: Background: Tuberculosis is a worldwide problem particularly in developing countries. Different clinical outcomes, such as the asymptomatic phase during infection or the symptomatic stage during active disease leads to activation and expansion of cellular immune responses in order to control the infection. This process of latency and active TB infection is a highly dynamic interaction between the host and the immunogenicity of M.tb. The detailed antigen specific analysis of the M.tb host response will likely lead to a better understanding of the pathogenesis of TB in human subjects and may help to identify markers of immune protection. There is a need to develop an effective TB vaccine and biomarkers of protection. Currently, different TB vaccine candidates contain M.tb components that are able to induce T cell activation and subsequent IFN-γ release. For instance, TB10.4 is such a novel vaccine candidate, it is highly immunogenic and present in M.tb and in the BCG vaccine strain. We characterized immune recognition patterns from Honduran patients with TB with a particularly focus on TB10.4 in order to better understand the infection biology, heterologous immune responses and the role of memory T cell formation. Aims: i) Defining and comparing M.tb specific immune responses in individuals with active and latent tuberculosis infection using cell based immune assays and a panel of specific M.tb target antigens; ii) Characterization of the recognition pattern of the humoral and cellular responses towards TB10.4 (Rv0288); and iii) Studying the relationship between molecular mimicry and tuberculosis using TB10.4 as a paradigm. Methodology: We selected a clinically well-defined population in order to perform cell- based immune assays (i.e Interferon gamma release assay), microarray peptide technology, and a bioplex assay, to gauge immune responses against a panel of recombinant or synthetic M.tb target antigens. Results and discussion: Paper I. This work represents the first analysis of cellular immune responses directed against M.tb associated targets in individuals from Honduras and provides a robust concept for identification of TB targets; we were able to identify differential target recognition patterns in TB+ patients vs TB exposed health care workers. Comprehensive pattern recognition analysis using biologically relevant targets revealed that enzymes involved in M.tb lipid synthesis serve as targets for T cells, defined by IFN-γ and IL-17 production. Paper II. We mapped humoral and cellular immune responses against the TB10.4 protein in non-human primates (NHPs) as well as in TB patients from Honduras. Immune responses in NHP were very focused, in contrast toTB10.4 directed immune responses in humans. We postulated that cross recognition of closely related antigens could be one possible explanation. The report shows substantial differences in cellular recognition comparing NHP and human immune responses. This T cell responses may be sustained via cross reactive immune responses recognizing the TB10.4 target and non-M.tb related target antigens.

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