Integrative immune analysis in patients with leprosy reveals host factors associated with mycobacterial control

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BACKGROUND: Leprosy is a debilitating, chronic infectious disease, ranking second after tuberculosis in the order of severe human mycobacterial diseases. If timely treatment is not initiated, infection with its causative agent, Mycobacterium leprae, can result in severe nerve damage leading to life-long disabilities. Host immunity largely dictates the spectral disease presentation, ranging from multi- to paucibacillary. Studying the host response to M. leprae is, however, complicated by the inability to culture this mycobacterium in vitro. Immune correlates of protection in persons at risk of leprosy are, therefore, essentially unknown. METHODS: To identify host factors related to mycobacterial control, functional mycobacterial growth inhibition assays combined with extensive immunophenotyping by spectral flow cytometry were performed for patients with leprosy and their contacts. This integrative approach merged sampling of peripheral blood mononuclear cells in low resource areas with immune-analysis using cutting edge technology. FINDINGS: In contrast to the current dogma, no intrinsic differences in mycobacterial control in vitro between patients with high and low bacillary loads were observed. Immunophenotyping at consecutive levels revealed a significant link between the induction of chemokines to mycobacterial antigens and expression of CXCR3 and CCR4 on adaptive immune cells in contacts controlling M. leprae infection. INTERPRETATION: These results offer more detailed insights into protective immunity against M. leprae and define host factors associated with bacterial control, fuelling improved diagnosis and treatment of leprosy. FUNDING: Q.M. Gastmann-Wichers Foundation, the Leprosy Research Initiative & the Turing Foundation (ILEP#: 707.19.02), R2STOP; the Leprosy Mission Great Britain.

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