Path-seq identifies an essential mycolate remodeling program for mycobacterial host adaptation

Peterson, Eliza J. R.; Bailo, Rebeca; Rothchild, Alissa C.; Arrieta‐Ortiz, Mario L.; Kaur, Amardeep; Pan, Min; Mai, Dat; Abidi, Abrar A.; Cooper, Charlotte; Aderem, Alan; Bhatt, Apoorva; Baliga, Nitin S.

doi:10.15252/msb.20188584

Path-seq identifies an essential mycolate remodeling program for mycobacterial host adaptation

Journal Article · Fri Mar 01 00:00:00 EST 2019 · Molecular Systems Biology

DOI:https://doi.org/10.15252/msb.20188584· OSTI ID:1627939

^[1]; ^[2]; ^[3]; Arrieta‐Ortiz, Mario L. ^[4]; Kaur, Amardeep ^[5]; Pan, Min ^[4]; Mai, Dat ^[3]; Abidi, Abrar A. ^[4]; Cooper, Charlotte ^[2]; Aderem, Alan ^[3]; ^[2]; ^[6]

Inst. for Systems Biology, Seattle, WA (United States); DOE/OSTI
Univ. of Birmingham (United Kingdom)
Seattle Children's Research Inst., Seattle, WA (United States)
Inst. for Systems Biology, Seattle, WA (United States)
IInst. for Systems Biology, Seattle, WA (United States)
Inst. for Systems Biology, Seattle, WA (United States); Univ. of Washington, Seattle, WA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

The success of Mycobacterium tuberculosis (MTB) stems from its ability to remain hidden from the immune system within macrophages. Here, we report a new technology (Path-seq) to sequence miniscule amounts of MTB transcripts within up to million-fold excess host RNA. Using Path-seq and regulatory network analyses, we have discovered a novel transcriptional program for in vivo mycobacterial cell wall remodeling when the pathogen infects alveolar macrophages in mice. We have discovered that MadR transcriptionally modulates two mycolic acid desaturases desA1/desA2 to initially promote cell wall remodeling upon in vitro macrophage infection and, subsequently, reduces mycolate biosynthesis upon entering dormancy. We demonstrate that disrupting MadR program is lethal to diverse mycobacteria making this evolutionarily conserved regulator a prime antitubercular target for both early and late stages of infection

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: Biotechnology and Biological Sciences Research Council (BBSRC); National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH); National Science Foundation (NSF); USDOE

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1627939

Journal Information:: Molecular Systems Biology, Journal Name: Molecular Systems Biology Journal Issue: 3 Vol. 15; ISSN 1744-4292

Publisher:: WileyCopyright Statement

Country of Publication:: United States

Language:: English

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NbClust : An R Package for Determining the Relevant Number of Clusters in a Data Set Charrad, Malika; Ghazzali, Nadia; Boiteau, Véronique Journal of Statistical Software, Vol. 61, Issue 6 https://doi.org/10.18637/jss.v061.i06	journal	January 2014
Type I interferons in tuberculosis: Foe and occasionally friend Moreira-Teixeira, Lúcia; Mayer-Barber, Katrin; Sher, Alan The Francis Crick Institute https://doi.org/10.25418/crick.15178128	text	January 2021
Type I interferons in tuberculosis: Foe and occasionally friend Moreira-Teixeira, Lúcia; Mayer-Barber, Katrin; Sher, Alan The Francis Crick Institute https://doi.org/10.25418/crick.15178128.v1	text	January 2021
A comprehensive map of genome-wide gene regulation in Mycobacterium tuberculosis Turkarslan, Serdar figshare https://doi.org/10.6084/m9.figshare.1249805	dataset	January 2014
A comprehensive map of genome-wide gene regulation in Mycobacterium tuberculosis Turkarslan, Serdar figshare https://doi.org/10.6084/m9.figshare.1249805.v1	dataset	January 2014

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Dual RNA-Seq of Mtb-Infected Macrophages In Vivo Reveals Ontologically Distinct Host-Pathogen Interactions Pisu, Davide; Huang, Lu; Grenier, Jennifer K. Cell Reports, Vol. 30, Issue 2 https://doi.org/10.1016/j.celrep.2019.12.033	journal	January 2020
Hybridization-based capture of pathogen mRNA enables paired host-pathogen transcriptional analysis Betin, Viktoria; Penaranda, Cristina; Bandyopadhyay, Nirmalya Scientific Reports, Vol. 9, Issue 1 https://doi.org/10.1038/s41598-019-55633-6	journal	December 2019
The mycobacterial cell envelope — a moving target Dulberger, Charles L.; Rubin, Eric J.; Boutte, Cara C. Nature Reviews Microbiology, Vol. 18, Issue 1 https://doi.org/10.1038/s41579-019-0273-7	journal	November 2019
The sensor kinase MtrB of Mycobacterium tuberculosis regulates hypoxic survival and establishment of infection Banerjee, Srijon Kaushik; Lata, Suruchi; Sharma, Arun Kumar Journal of Biological Chemistry, Vol. 294, Issue 52 https://doi.org/10.1074/jbc.ra119.009449	journal	October 2019
Alveolar macrophages generate a noncanonical NRF2-driven transcriptional response to Mycobacterium tuberculosis in vivo Rothchild, Alissa C.; Olson, Gregory S.; Nemeth, Johannes Science Immunology, Vol. 4, Issue 37 https://doi.org/10.1126/sciimmunol.aaw6693	journal	July 2019

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59 BASIC BIOLOGICAL SCIENCES
Mycobacterium tuberculosis
Path-seq
biochemistry & molecular biology
gene regulatory networks
host–pathogen interactions
systems biology

Path-seq identifies an essential mycolate remodeling program for mycobacterial host adaptation

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