Dual RNA-Seq of Mtb-Infected Macrophages In Vivo Reveals Ontologically Distinct Host-Pathogen Interactions

• Published in: Cell reports (Cambridge) Vol. 30; no. 2; pp. 335 - 350.e4
• Main Authors: Pisu, Davide, Huang, Lu, Grenier, Jennifer K., Russell, David G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.01.2020; Elsevier
• Subjects: alveolar macrophage; Animals; dual RNA-seq; Host-Pathogen Interactions; Humans; interstitial macrophage; Lung - pathology; macrophage; Macrophages - microbiology; Mice; Mycobacterium tuberculosis; Mycobacterium tuberculosis - genetics; nutritional immunity; RNA-Seq - methods; tuberculosis; interstitial macrophage; alveolar macrophage; Mycobacterium tuberculosis; nutritional immunity; dual RNA-seq; tuberculosis; macrophage
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.12.033

Dissecting the in vivo host-pathogen interplay is crucial to understanding the molecular mechanisms governing control or progression of intracellular infections. In this work, we explore the in vivo molecular dynamics of Mtb infection by performing dual RNA-seq on Mycobacterium tuberculosis-infected, ontogenetically distinct macrophage lineages isolated directly from murine lungs. We first define an in vivo signature of 180 genes specifically upregulated by Mtb in mouse lung macrophages, then we uncover a divergent transcriptional response of the bacteria between alveolar macrophages that appear to sustain Mtb growth through increased access to iron and fatty acids and interstitial macrophages that restrict Mtb growth through iron sequestration and higher levels of nitric oxide. We use an enrichment protocol for bacterial transcripts, which enables us to probe Mtb physiology at the host cell level in an in vivo environment, with broader application in understanding the infection dynamics of intracellular pathogens in general. [Display omitted] •Dual RNA-seq analysis of M. tuberculosis infected macrophages•Infected macrophages were isolated directly from mouse lung•Transcriptional signatures of host and pathogen varied with macrophage ontogeny•Data highlighted a key role for nutritional immunity in limiting bacterial growth In this study Pisu et al. performed dual RNA-seq on Mycobacterium tuberculosis-infected, ontogenetically distinct macrophage lineages isolated directly from infected murine lungs. The transcriptional response of host and bacteria diverged between alveolar macrophages that sustain Mtb growth and interstitial macrophages that restrict Mtb growth.