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Dual RNA-Seq of Human Leprosy Lesions Identifies Bacterial Determinants Linked to Host Immune Response
Dennis J Montoya1, Priscila Andrade2, Bruno J A Silva2
1Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA.
Abstract:
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.
Insights
Leprosy research reveals two key measures of Mycobacterium leprae infection. Bacterial burden correlates with immune-inhibiting type I IFNs, while bacterial viability links to host antibody pathways, offering insights into disease mechanisms.
Area of Science:
- Immunology
- Microbiology
- Genomics
Background:
- Leprosy is a complex disease caused by Mycobacterium leprae.
- The host immune response to M. leprae dictates disease outcome.
- Understanding host-pathogen interactions at the infection site is crucial.
Purpose of the Study:
- To investigate the relationship between M. leprae and the host immune system in leprosy.
- To identify molecular markers of M. leprae infection and their correlation with host responses.
- To explore the mechanisms of inflammation in human leprosy.
Main Methods:
- Dual RNA-sequencing (RNA-seq) was performed on patient lesions.
- Analysis focused on bacterial transcripts and mRNA:rRNA ratios.
- Correlations between bacterial measures and host immune responses were assessed.
Main Results:
- Two independent molecular measures of M. leprae were identified.
- Bacterial fraction correlated with a host type I interferon (IFN) gene signature.
- Bacterial mRNA:rRNA ratio linked M. leprae heat shock proteins to the BAFF-BCMA antibody pathway.
Conclusions:
- Host and pathogen transcriptomes at the infection site provide insights into leprosy pathogenesis.
- Type I IFNs may inhibit host antimicrobial responses in M. leprae infection.
- Bacterial viability is associated with specific host antibody response pathways.
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