To understand how infection by Mycobacterium tuberculosis (Mtb) is modulated by host cell phenotype, we characterized those host phagocytes that controlled or supported bacterial growth during early infection, focusing on the ontologically distinct alveolar macrophage (AM) and interstitial macrophage (IM) lineages. Using fluorescent Mtb reporter strains, we found that bacilli in AM exhibited lower stress and higher bacterial replication than those in IM. Interestingly, depletion of AM reduced bacterial burden, whereas depletion of IM increased bacterial burden. Transcriptomic analysis revealed that IMs were glycolytically active, whereas AMs were committed to fatty acid oxidation. Intoxication of infected mice with the glycolytic inhibitor, 2-deoxyglucose, decreased the number of IMs yet increased the bacterial burden in the lung. Furthermore, in in vitro macrophage infections, 2-deoxyglucose treatment increased bacterial growth, whereas the fatty acid oxidation inhibitor etomoxir constrained bacterial growth. We hypothesize that different macrophage lineages respond divergently to Mtb infection, with IMs exhibiting nutritional restriction and controlling bacterial growth and AMs representing a more nutritionally permissive environment.

/pdf/growth-of-mycobacterium-tuberculosis-in-vivo-segregates-with-4pa5f09anu.pdf

Growth of Mycobacterium tuberculosis in vivo segregates with host macrophage metabolism and ontogeny.

It is generally regarded that the progression of an infection within host macrophages is the consequence of a failed immune response. However, recent appreciation of macrophage heterogeneity, with respect to both development and metabolism, indicates that the reality is more complex. Different lineages of tissue-resident macrophages respond divergently to microbial, environmental and immunological stimuli. The emerging picture that the developmental origin of macrophages determines their responses to immune stimulation and to infection stresses the importance of in vivo infection models. Recent investigations into the metabolism of infecting microorganisms and host macrophages indicate that their metabolic interface can be a major determinant of pathogen growth or containment. This Review focuses on the integration of data from existing studies, the identification of challenges in generating and interpreting data from ongoing studies and a discussion of the technologies and tools that are required to best address future questions in the field. Different lineages of macrophages respond divergently to immune stimuli and microbial infection. This Review explores our current knowledge of how the different metabolic states of macrophage lineages impact the control or progression of intracellular bacterial infections.

Immunometabolism at the interface between macrophages and pathogens.

Metabolism was once relegated to the supply of energy and biosynthetic precursors, but it has now become clear that it is a specific mediator of nearly all physiological processes. In the context of microbial pathogenesis, metabolism has expanded outside its canonical role in bacterial replication. Among human pathogens, this expansion has emerged perhaps nowhere more visibly than for Mycobacterium tuberculosis, the causative agent of tuberculosis. Unlike most pathogens, M. tuberculosis has evolved within humans, which are both host and reservoir. This makes unrestrained replication and perpetual quiescence equally incompatible strategies for survival as a species. In this Review, we summarize recent work that illustrates the diversity of metabolic functions that not only enable M. tuberculosis to establish and maintain a state of chronic infection within the host but also facilitate its survival in the face of drug pressure and, ultimately, completion of its life cycle.

/pdf/metabolic-principles-of-persistence-and-pathogenicity-in-1f3midzmgt.pdf

Metabolic principles of persistence and pathogenicity in Mycobacterium tuberculosis

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

Tuberculosis is a distinctive disease in which the causative agent, Mycobacterium tuberculosis, can persist in humans for decades by avoiding clearance from host immunity. During infection, M. tuberculosis maintains viability by extracting and utilizing essential nutrients from the host, and this is a prerequisite for all of the pathogenic activities that are deployed by the bacterium. In particular, M. tuberculosis preferentially acquires and metabolizes host-derived lipids (fatty acids and cholesterol), and the bacterium utilizes these substrates to cause and maintain disease. In this review, we discuss our current understanding of lipid utilization by M. tuberculosis, and we describe how these pathways promote pathogenesis to fuel metabolic processes in the bacillus. Finally, we highlight weaknesses in these pathways that potentially can be targeted for drug discovery.

Cholesterol and fatty acids grease the wheels of Mycobacterium tuberculosis pathogenesis.

Pathogenic bacteria have evolved highly specialized systems to extract essential nutrients from their hosts. Mycobacterium tuberculosis (Mtb) scavenges lipids (cholesterol and fatty acids) to maintain infections in mammals but mechanisms and proteins responsible for the import of fatty acids in Mtb were previously unknown. Here, we identify and determine that the previously uncharacterized protein Rv3723/LucA, functions to integrate cholesterol and fatty acid uptake in Mtb. Rv3723/LucA interacts with subunits of the Mce1 and Mce4 complexes to coordinate the activities of these nutrient transporters by maintaining their stability. We also demonstrate that Mce1 functions as a fatty acid transporter in Mtb and determine that facilitating cholesterol and fatty acid import via Rv3723/LucA is required for full bacterial virulence in vivo. These data establish that fatty acid and cholesterol assimilation are inexorably linked in Mtb and reveals a key function for Rv3723/LucA in in coordinating thetransport of both these substrates.

Rv3723/LucA coordinates fatty acid and cholesterol uptake in Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb) imports and metabolizes fatty acids to maintain infection within human macrophages. Although this is a well-established paradigm, the bacterial factors required for fatty acid import are poorly understood. Previously, we found that LucA and Mce1 are required for fatty acid import in Mtb (Nazarova et al., 2017). Here, we identified additional Mtb mutants that have a reduced ability to import a fluorescent fatty acid substrate during infection within macrophages. This screen identified the novel genes as rv2799 and rv0966c as be necessary for fatty acid import and confirmed the central role for Rv3723/LucA and putative components of the Mce1 fatty acid transporter (Rv0200/OmamB, Rv0172/Mce1D, and Rv0655/MceG) in this process.

The genetic requirements of fatty acid import by Mycobacterium tuberculosis within macrophages.

SUMMARY Linking genotype with phenotype is a fundamental goal in biology and requires robust data for both. Recent advances in plant‐genome sequencing have expedited comparisons among multiple‐related individuals. The abundance of structural genomic within‐species variation that has been discovered indicates that a single reference genome cannot represent the complete sequence diversity of a species, leading to the expansion of the pan‐genome concept. For high‐resolution forward genetics, this unprecedented access to genomic variation should be paralleled and integrated with phenotypic characterization of genetic diversity. We developed a multi‐parental framework for trait dissection in melon (Cucumis melo), leveraging a novel pan‐genome constructed for this highly variable cucurbit crop. A core subset of 25 diverse founders (MelonCore25), consisting of 24 accessions from the two widely cultivated subspecies of C. melo, encompassing 12 horticultural groups, and 1 feral accession was sequenced using a combination of short‐ and long‐read technologies, and their genomes were assembled de novo. The construction of this melon pan‐genome exposed substantial variation in genome size and structure, including detection of ~300 000 structural variants and ~9 million SNPs. A half‐diallel derived set of 300 F2 populations, representing all possible MelonCore25 parental combinations, was constructed as a framework for trait dissection through integration with the pan‐genome. We demonstrate the potential of this unified framework for genetic analysis of various melon traits, including rind color intensity and pattern, fruit sugar content, and resistance to fungal diseases. We anticipate that utilization of this integrated resource will enhance genetic dissection of important traits and accelerate melon breeding.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/tpj.16021

Pan‐genome and multi‐parental framework for high‐resolution trait dissection in melon (Cucumis melo)

Pathogenic bacteria have evolved highly specialized systems to extract essential nutrients from their hosts and Mycobacterium tuberculosis (Mtb) scavenges lipids (cholesterol and fatty acids) to maintain infection in mammals. While the uptake of cholesterol by Mtb is mediated by the Mce4 transporter, the route(s) of uptake of fatty acids remain unknown. Here, we demonstrate that an uncharacterized protein LucA, integrates the assimilation of both cholesterol and fatty acids in Mtb. LucA interacts with subunits of the Mce1 and Mce4 complexes to coordinate the activities of these nutrient transporters. We also demonstrate that Mce1 functions as an important fatty acid transporter in Mtb and we determine that the integration of cholesterol and fatty acid transport by LucA is required for full bacterial virulence in vivo . These data establish that fatty acid and cholesterol assimilation are inexorably linked in Mtb and reveals a key role for LucA in coordinating both transport activities.

https://www.biorxiv.org/content/biorxiv/early/2017/03/29/121780.full.pdf

Rv3723/LucA coordinates fatty acid and cholesterol uptake in Mycobacterium tuberculosis

Author response: The genetic requirements of fatty acid import by Mycobacterium tuberculosis within macrophages

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Thuy La

Author Tools

Chat about Author