Dual RNA-Seq of Human Leprosy Lesions Identifies Bacterial Determinants Linked to Host Immune Response
Dennis J. Montoya,
Priscila Andrade,
Bruno J.A. Silva,
Rosane M.B. Teles,
Feiyang Ma,
Bryan Bryson,
Saheli Sadanand,
Teia Noel,
Jing Lu,
Euzenir Sarno,
Kristine B. Arnvig,
Douglas Young,
Ramanuj Lahiri,
Diana L. Williams,
Sarah Fortune,
Barry R. Bloom,
Matteo Pellegrini,
Robert L. Modlin
Affiliations
Dennis J. Montoya
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA
Priscila Andrade
Division of Dermatology, David Geffen School of Medicine, Los Angeles, CA, USA
Bruno J.A. Silva
Division of Dermatology, David Geffen School of Medicine, Los Angeles, CA, USA
Rosane M.B. Teles
Division of Dermatology, David Geffen School of Medicine, Los Angeles, CA, USA
Feiyang Ma
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA
Bryan Bryson
Harvard T.H. Chan School of Public Health, Department of Immunology and Infectious Diseases, Boston, MA, USA
Saheli Sadanand
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
Teia Noel
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA
Jing Lu
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA
Euzenir Sarno
Department of Mycobacteriosis, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
Kristine B. Arnvig
Institute for Structural and Molecular Biology, University College London, London WC1E 6BT, UK
Douglas Young
National Institute for Medical Research, Mycobacterial Research Division, London NW7 1AA, UK; The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London NW7 1AA, UK
Ramanuj Lahiri
Health Resources and Services Administration (HRSA), National Hansen’s Disease Program (NHDP), Baton Rouge, LA, USA
Diana L. Williams
Health Resources and Services Administration (HRSA), National Hansen’s Disease Program (NHDP), Baton Rouge, LA, USA; Department of Pathobiological Sciences, Louisiana State University (LSU), Baton Rouge, LA, USA
Sarah Fortune
Harvard T.H. Chan School of Public Health, Department of Immunology and Infectious Diseases, Boston, MA, USA
Barry R. Bloom
Harvard T.H. Chan School of Public Health, Department of Immunology and Infectious Diseases, Boston, MA, USA
Matteo Pellegrini
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA
Robert L. Modlin
Division of Dermatology, David Geffen School of Medicine, Los Angeles, CA, USA; Corresponding author
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
