Gene Expression Profiling Specifies Chemokine, Mitochondrial and Lipid Metabolism Signatures in Leprosy

<div><p>Herein, we performed microarray experiments in Schwann cells infected with live <i>M. leprae</i> and identified novel differentially expressed genes (DEG) in <i>M. leprae</i> infected cells. Also, we selected candidate genes associated or implicated with leprosy in genetic studies and biological experiments. Forty-seven genes were selected for validation in two independent types of samples by multiplex qPCR. First, an <i>in vitro</i> model using THP-1 cells was infected with live <i>Mycobacterium leprae</i> and <i>M. bovis</i> bacillus Calmette-Guérin (BCG). In a second situation, mRNA obtained from nerve biopsies from patients with leprosy or other peripheral neuropathies was tested. We detected DEGs that discriminate <i>M. bovis</i> BCG from <i>M. leprae</i> infection. Specific signatures of susceptible responses after <i>M. leprae</i> infection when compared to BCG lead to repression of genes, including <i>CCL2</i>, <i>CCL3</i>, <i>IL8</i> and <i>SOD2</i>. The same 47-gene set was screened in nerve biopsies, which corroborated the down-regulation of <i>CCL2</i> and <i>CCL3</i> in leprosy, but also evidenced the down-regulation of genes involved in mitochondrial metabolism, and the up-regulation of genes involved in lipid metabolism and ubiquitination. Finally, a gene expression signature from DEG was identified in patients confirmed of having leprosy. A classification tree was able to ascertain 80% of the cases as leprosy or non-leprous peripheral neuropathy based on the expression of only <i>LDLR</i> and <i>CCL4</i>. A general immune and mitochondrial hypo-responsive state occurs in response to <i>M. leprae</i> infection. Also, the most important genes and pathways have been highlighted providing new tools for early diagnosis and treatment of leprosy.</p>