Abstract
Reversal reactions (RRs) in leprosy are characterized by a reduction in the number of bacilli in lesions associated with an increase in cell-mediated immunity against the intracellular bacterium Mycobacterium leprae, the causative pathogen of leprosy. To identify the mechanisms that contribute to cell-mediated immunity in leprosy, we measured changes in the whole blood-derived transcriptome of patients with leprosy before, during and after RR. We identified an ‘RR signature’ of 1017 genes that were upregulated at the time of the clinical diagnosis of RR. Using weighted gene correlated network analysis (WGCNA), we detected a module of 794 genes, bisque4, that was significantly correlated with RR, of which 434 genes were part of the RR signature. An enrichment for both IFN-γ and IFN-β downstream gene pathways was present in the RR signature as well as the RR upregulated genes in the bisque4 module, including those encoding proteins of the guanylate binding protein (GBP) family that contributes to antimicrobial responses against mycobacteria. Specifically, GBP1, GBP2, GBP3 and GBP5 mRNAs were upregulated in the RR peripheral blood transcriptome, with GBP1, GBP2 and GBP5 mRNAs also upregulated in the RR disease lesion transcriptome. These data indicate that RRs involve a systemic upregulation of IFN-γ downstream genes including GBP family members as part of the host antimicrobial response against mycobacteria.
Highlights
Leprosy is a poverty-related infectious disease caused by the intracellular pathogen Mycobacterium leprae that remains persistently present in pockets of developing countries causing 200,000 new cases each year, where it creates considerable health and economic burdens [1]
We show that GBP1, GBP2 and GBP5 mRNAs are upregulated at the site of disease in Reversal reactions (RRs) patients
We performed a longitudinal transcriptome analysis of blood from patients with RR to identify the mechanisms that contribute to cell-mediated immunity in leprosy (S1 Fig)
Summary
Leprosy is a poverty-related infectious disease caused by the intracellular pathogen Mycobacterium leprae that remains persistently present in pockets of developing countries causing 200,000 new cases each year, where it creates considerable health and economic burdens [1]. The disease offers a robust model of divergent immune responses correlating with the outcome of the host response to the pathogen [2]. At one end of the disease spectrum, tuberculoid leprosy (T-lep) patients typify the resistant response that restricts the growth of the pathogen, resulting in limited lesions and small bacilli numbers. Lepromatous leprosy (L-lep) patients represent susceptibility to disseminated infection, with numerous skin lesions and abundant bacilli. Whereas cell-mediated immunity against M. leprae is present in T-lep patients, humoral responses against the pathogen are characteristic of L-lep patients. Insights into human immune responses gained from investigations of leprosy include specific immune patterns based on cell-type- (CD4+ vs. CD8+) [3] and cytokine patterns of adaptive T cells (Th1 vs. Th2) [4,5,6] in host defense
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