Dual RNA-Seq of Human Leprosy Lesions Identifies Bacterial Determinants Linked to Host Immune Response

Abstract

Summary: To understand how the interaction between an intracellular bacterium and the host immune system contributes to outcome at the site of infection, we studied leprosy, a disease that forms a clinical spectrum, in which progressive infection by the intracellular bacterium Mycobacterium leprae is characterized by the production of type I IFNs and antibody production. Dual RNA-seq on patient lesions identifies two independent molecular measures of M. leprae, each of which correlates with distinct aspects of the host immune response. The fraction of bacterial transcripts, reflecting bacterial burden, correlates with a host type I IFN gene signature, known to inhibit antimicrobial responses. Second, the bacterial mRNA:rRNA ratio, reflecting bacterial viability, links bacterial heat shock proteins with the BAFF-BCMA host antibody response pathway. Our findings provide a platform for the interrogation of host and pathogen transcriptomes at the site of infection, allowing insight into mechanisms of inflammation in human disease. : Montoya et al. utilizes dual RNA-seq to define the bacterial burden and transcriptional state within leprosy skin lesions. These molecular measures vary across patients and provide separate but informative metrics about the pathogenesis of mycobacterial disease, revealing that the immune system responds to bacterial states and not just their abundance. Keywords: mycobacteria, immunology, systems immunology, microbiology, plasma cell, host-pathogen, tuberculosis, heat shock, humoral, translational, transcriptome, sequencing, bioinformatics, computational biology