Iron limitation in M. tuberculosis has broad impact on central carbon metabolism DOI Creative Commons
Monique E. Theriault, Davide Pisu, Kaley M. Wilburn

et al.

Communications Biology, Journal Year: 2022, Volume and Issue: 5(1)

Published: July 9, 2022

Abstract Mycobacterium tuberculosis ( Mtb ), the cause of human pulmonary disease (TB), contributes to approximately 1.5 million deaths every year. Prior work has established that lipids are actively catabolized by in vivo and fulfill major roles physiology pathogenesis. We conducted a high-throughput screen identify inhibitors survival its host macrophage. One hit compounds identified this screen, sAEL057, demonstrates highest activity on growth conditions where cholesterol was primary carbon source. Transcriptional functional data indicate sAEL057 limits ’s access iron acting as an chelator. Furthermore, pharmacological genetic inhibition acquisition results dysregulation catabolism, revealing previously unappreciated linkage between these pathways. Characterization sAEL057’s mode action argues metabolic regulation reveals vulnerabilities those pathways impact central metabolism.

Language: Английский

Mycobacterium tuberculosis infection drives a type I IFN signature in lung lymphocytes DOI
Sadia Akter, Kuldeep S Chauhan, Micah Dunlap

et al.

Cell Reports, Journal Year: 2022, Volume and Issue: 39(12), P. 110983 - 110983

Published: June 1, 2022

Language: Английский

Citations

44
The interaction of macrophages and CD8 T cells in bronchoalveolar lavage fluid is associated with latent tuberculosis infection DOI Creative Commons
Qianting Yang, Furong Qi, Taosheng Ye

et al.

Emerging Microbes & Infections, Journal Year: 2023, Volume and Issue: 12(2)

Published: July 20, 2023

Mycobacterium tuberculosis (Mtb) infection, including active (TB) and latent Mtb infection (LTBI), leads to diverse outcomes owing different host immune responses. However, the mechanisms that govern progression from LTBI TB remain poorly defined in humans. Here, we profiled lung cell populations within bronchoalveolar lavage fluid (BALF) patients with or using single-cell RNA sequencing (scRNA-seq). We found substantially changed compartments BALF, especially for three subsets of macrophages, monocyte macrophage (MM)-CCL23, MM-FCN1, MM-SPP1, which were be associated disease status infection. Notably, MM-CCL23 cells derived monocytes after stimulation characterized by high levels chemokine (CCL23 CXCL5) production might serve as a marker The population mainly recruited CD8-CCR6 T through CCL20/CCR6, was prominent feature protection immunity LTBI. This study improves our understanding landscape during may inform future vaccine design protective immunity.

Language: Английский

Citations

26
Mycobacterium tuberculosis resides in lysosome-poor monocyte-derived lung cells during chronic infection DOI Creative Commons
Weihao Zheng,

I-Chang Chang,

Jason Limberis

et al.

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(5), P. e1012205 - e1012205

Published: May 3, 2024

Mycobacterium tuberculosis (Mtb) infects lung myeloid cells, but the specific Mtb-permissive cells and host mechanisms supporting Mtb persistence during chronic infection are incompletely characterized. We report that after development of T cell responses, CD11c lo monocyte-derived harbor more live than alveolar macrophages (AM), neutrophils, hi cells. Transcriptomic functional studies revealed lysosome pathway is underexpressed in this highly permissive subset, characterized by less content, acidification, proteolytic activity AM, along with nuclear TFEB, a regulator biogenesis. does not drive deficiency promotes recruitment monocytes develop into mediated ESX-1 secretion system. The c-Abl tyrosine kinase inhibitor nilotinib activates TFEB enhances functions vitro vivo, improving control infection. Our results suggest exploits lysosome-poor for targeting biogenesis potential host-directed therapy tuberculosis.

Language: Английский

Citations

15
Metabolically active neutrophils represent a permissive niche for Mycobacterium tuberculosis DOI
J. Tucker Andrews, Zijing Zhang, Gauri Prasad

et al.

Mucosal Immunology, Journal Year: 2024, Volume and Issue: 17(5), P. 825 - 842

Published: June 5, 2024

Language: Английский

Citations

15
Host stress drives tolerance and persistence: The bane of anti-microbial therapeutics DOI Creative Commons
Sophie Hélaine, Brian P. Conlon, Kimberly M. Davis

et al.

Cell Host & Microbe, Journal Year: 2024, Volume and Issue: 32(6), P. 852 - 862

Published: June 1, 2024

Antibiotic resistance, typically associated with genetic changes within a bacterial population, is frequent contributor to antibiotic treatment failures. persistence and tolerance, which we collectively term recalcitrance, represent transient phenotypic in the population that prolong survival presence of lethal concentrations antibiotics. recalcitrance challenging detect investigate-traditionally studied under vitro conditions, our understanding during infection its contribution failure limited. Recently, significant progress has been made study antibiotic-recalcitrant populations pathogenic species, including Mycobacterium tuberculosis, Staphylococcus aureus, Salmonella enterica, Yersiniae, context host environment. Despite diversity these pathogens models, shared signals responses promote common features vulnerabilities persisters tolerant bacteria have emerged. These will be discussed here, along toward developing therapeutic interventions better treat recalcitrant pathogens.

Language: Английский

Citations

12
Single-cell analysis reveals Mycobacterium tuberculosis ESX-1–mediated accumulation of permissive macrophages in infected mouse lungs DOI Creative Commons
Weihao Zheng, Michael Borja, Leah C. Dorman

et al.

Science Advances, Journal Year: 2025, Volume and Issue: 11(3)

Published: Jan. 15, 2025

Mycobacterium tuberculosis (MTB) ESX-1, a type VII secretion system, is key virulence determinant contributing to MTB’s survival within lung mononuclear phagocytes (MNPs), but its effect on MNP recruitment and differentiation remains unknown. Here, using multiple single-cell RNA sequencing techniques, we studied the role of ESX-1 in heterogeneity response mice murine bone marrow–derived macrophages (BMDM). We found that required for MTB recruit diverse subsets with high burden. Further, induces transcriptional signature immune evasion BMDM an ESX-1–dependent manner. Spatial transcriptomics revealed up-regulation permissive features lesions, where monocyte-derived concentrate near MTB-infected cells. Together, our findings suggest facilitates MNPs, which can infect manipulate survival. Our dataset across various models methods could contribute broader understanding recruited cell during infection.

Language: Английский

Citations

1
Alveolar macrophages: Achilles’ heel of SARS-CoV-2 infection DOI Creative Commons
Zhenfeng Wang,

Shunshun Li,

Bo Huang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: July 19, 2022

Abstract The coronavirus disease 2019 (COVID-19) pandemic has caused more than 6.3 million deaths to date. Despite great efforts curb the spread of severe acute respiratory syndrome 2 (SARS-CoV-2), vaccines and neutralizing antibodies are in gloom due persistent viral mutations antiviral compounds face challenges specificity safety. In addition, unable treat already-infected individuals, drugs cannot be used prophylactically. Therefore, exploration unconventional strategies current is highly urgent. Alveolar macrophages (AMs) residing on surface alveoli first immune cells that dispose alveoli-invading viruses. Our findings demonstrate M1 AMs have an acidic endosomal pH, thus favoring SARS-CoV-2 leave endosomes release into cytosol where virus initiates replication; contrast, M2 increased which dampens escape facilitates delivery for lysosomal degradation. this review, we propose Achilles’ heel infection modulation pH potential eliminate invaded SARS-CoV-2; same strategy might also suitable other lethal

Language: Английский

Citations

34
Single cell genomics as a transformative approach for aquaculture research and innovation DOI Creative Commons
Rose Ruiz Daniels, Richard S. Taylor, Diego Robledo

et al.

Reviews in Aquaculture, Journal Year: 2023, Volume and Issue: 15(4), P. 1618 - 1637

Published: March 7, 2023

Abstract Single cell genomics encompasses a suite of rapidly maturing technologies that measure the molecular profiles individual cells within target samples. These approaches provide large up‐step in biological information compared to long‐established ‘bulk’ methods profile average all sample, and have led transformative advances understanding cellular biology, particularly humans model organisms. The application single is fast expanding non‐model taxa, including aquaculture species, where numerous research applications are underway with many more envisaged. In this review, we highlight potential research, considering barriers solutions broad uptake these technologies. Focusing on transcriptomics, outline considerations for experimental design, essential requirement obtain high quality cells/nuclei sequencing ectothermic aquatic species. We further data analysis bioinformatics considerations, tailored studies under‐characterized genomes our knowledge heterogeneity marker genes immature. Overall, review offers useful source researchers aiming apply address challenges faced by global sector though an improved biology.

Language: Английский

Citations

23
Early innate cell interactions with Mycobacterium tuberculosis in protection and pathology of tuberculosis DOI Creative Commons

Poornima Sankar,

Bibhuti B. Mishra

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Oct. 27, 2023

Tuberculosis (TB) remains a significant global health challenge, claiming the lives of up to 1.5 million individuals annually. TB is caused by human pathogen

Language: Английский

Citations

23
Protective intravenous BCG vaccination induces enhanced immune signaling in the airways DOI Open Access
Joshua M. Peters, Edward B. Irvine, Jacob M. Rosenberg

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 18, 2023

Abstract Intradermal (ID) Bacillus Calmette–Guérin (BCG) is the most widely administered vaccine in world. However, ID-BCG fails to achieve level of protection needed adults alter course tuberculosis epidemic. Recent studies non-human primates have demonstrated high levels against Mycobacterium ( Mtb ) following intravenous (IV) administration BCG. protective immune features that emerge IV BCG vaccination remain incompletely defined. Here we used single-cell RNA-sequencing (scRNAseq) transcriptionally profile 157,114 unstimulated and purified protein derivative (PPD)-stimulated bronchoalveolar lavage (BAL) cells from 29 rhesus macaques immunized with across routes doses uncover cell composition-, gene expression-, biological network-level signatures associated BCG-mediated protection. Our analyses revealed high-dose drove an influx polyfunctional T macrophages into airways. These exhibited a basal activation phenotype even absence PPD-stimulation, defined part by IFN TNF-α signaling up 6 months immunization. Furthermore, intercellular pathways between key myeloid subsets were enhanced PPD-stimulation BCG-vaccinated macaques. High-dose also engendered quantitatively qualitatively stronger transcriptional responses robust Th1-Th17 cells, augmented reactive oxygen species production, hypoxia, IFN-γ response within alveolar macrophages. Collectively, this work supports immunization creates unique cellular ecosystem airways, which primes enables local effectively clear upon challenge.

Language: Английский

Citations

18