1. Immunology and Inflammation
  2. Microbiology and Infectious Disease

Identification of scavenger receptor B1 as the airway microfold cell receptor for Mycobacterium tuberculosis

  1. Haaris S Khan
  2. Vidhya R Nair
  3. Cody R Ruhl
  4. Samuel Alvarez-Arguedas
  5. Jorge L Galvan Rendiz
  6. Luis H Franco
  7. Linzhang Huang
  8. Philip W Shaul
  9. Jiwoong Kim
  10. Yang Xie
  11. Ron B Mitchell
  12. Michael U Shiloh  Is a corresponding author
  1. University of Texas Southwestern Medical School, United States
  2. University of Texas Southwestern Medical Center, United States
https://doi.org/10.7554/eLife.52551
Share this article
Cite this article
  1. Haaris S Khan
  2. Vidhya R Nair
  3. Cody R Ruhl
  4. Samuel Alvarez-Arguedas
  5. Jorge L Galvan Rendiz
  6. Luis H Franco
  7. Linzhang Huang
  8. Philip W Shaul
  9. Jiwoong Kim
  10. Yang Xie
  11. Ron B Mitchell
  12. Michael U Shiloh
(2020)
Identification of scavenger receptor B1 as the airway microfold cell receptor for Mycobacterium tuberculosis
eLife 9:e52551.
https://doi.org/10.7554/eLife.52551
  2. Download BibTeX
  3. Download .RIS

Abstract

Mycobacterium tuberculosis (Mtb) can enter the body through multiple routes, including via specialized transcytotic cells called microfold cells (M cell). However, the mechanistic basis for M cell entry remains undefined. Here, we show that M cell transcytosis depends on the Mtb Type VII secretion machine and its major virulence factor EsxA. We identify scavenger receptor B1 (SR-B1) as an EsxA receptor on airway M cells. SR-B1 is required for Mtb binding to and translocation across M cells in mouse and human tissue. Together, our data demonstrate a previously undescribed role for Mtb EsxA in mucosal invasion and identify SR-B1 as the airway M cell receptor for Mtb.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Whole genome sequencing data have been deposited at NCBI Sequence Read Archive, Accession #PRJNA605439.

The following data sets were generated

Article and author information

Author details

  1. Haaris S Khan

    Internal Medicine, University of Texas Southwestern Medical School, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Vidhya R Nair

    Internal Medicine and Microbiology, University of Texas Southwestern Medical School, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Cody R Ruhl

    Internal Medicine, University of Texas Southwestern Medical School, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Samuel Alvarez-Arguedas

    Internal Medicine, University of Texas Southwestern Medical School, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Jorge L Galvan Rendiz

    Internal Medicine, University of Texas Southwestern Medical School, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Luis H Franco

    Internal Medicine and Microbiology, University of Texas Southwestern Medical School, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Linzhang Huang

    Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical School, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Philip W Shaul

    Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical School, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Jiwoong Kim

    Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical School, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Yang Xie

    Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. Ron B Mitchell

    Otolaryngology, University of Texas Southwestern Medical School, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  12. Michael U Shiloh

    Internal Medicine and Microbiology, University of Texas Southwestern Medical School, Dallas, United States
    For correspondence
    michael.shiloh@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4329-2253

Funding

National Institute of Allergy and Infectious Diseases (AI125939)

  • Michael U Shiloh

National Institute of Allergy and Infectious Diseases (AI142784)

  • Michael U Shiloh

National Institute of Allergy and Infectious Diseases (5T32AI005284)

  • Haaris S Khan

National Heart, Lung, and Blood Institute (HK131597)

  • Philip W Shaul

Burroughs Wellcome Fund (1017894)

  • Michael U Shiloh

Welch Foundation (I-1964-20180324)

  • Michael U Shiloh

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal experiments were reviewed and approved by the Institutional Animal Care and Use Committee at the University of Texas Southwestern (protocol 2017-101836) and followed the eighth edition of the Guide for the Care and Use of Laboratory Animals. The University of Texas Southwestern is accredited by the American Association for Accreditation of Laboratory Animal Care (AAALAC).

Human subjects: Human adenoids were obtained from children undergoing elective adenoidectomy for sleep apnea after informed consent was obtained from parents or guardians. This study was reviewed by the University of Texas Southwestern Institutional Review Board (protocol STU 062016-087).

Copyright

© 2020, Khan et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,151
    views
  • 337
    downloads
  • 18
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Haaris S Khan
  2. Vidhya R Nair
  3. Cody R Ruhl
  4. Samuel Alvarez-Arguedas
  5. Jorge L Galvan Rendiz
  6. Luis H Franco
  7. Linzhang Huang
  8. Philip W Shaul
  9. Jiwoong Kim
  10. Yang Xie
  11. Ron B Mitchell
  12. Michael U Shiloh
(2020)
Identification of scavenger receptor B1 as the airway microfold cell receptor for Mycobacterium tuberculosis
eLife 9:e52551.
https://doi.org/10.7554/eLife.52551

Share this article

https://doi.org/10.7554/eLife.52551

Categories and tags

Research organisms

Further reading

    1. Chromosomes and Gene Expression
    2. Immunology and Inflammation

    Dynamic chromatin architecture identifies new autoimmune-associated enhancers for IL2 and novel genes regulating CD4+ T cell activation

    Matthew C Pahl, Prabhat Sharma ... Andrew D Wells
    Research Article

    Genome-wide association studies (GWAS) have identified hundreds of genetic signals associated with autoimmune disease. The majority of these signals are located in non-coding regions and likely impact cis-regulatory elements (cRE). Because cRE function is dynamic across cell types and states, profiling the epigenetic status of cRE across physiological processes is necessary to characterize the molecular mechanisms by which autoimmune variants contribute to disease risk. We localized risk variants from 15 autoimmune GWAS to cRE active during TCR-CD28 co-stimulation of naïve human CD4+ T cells. To characterize how dynamic changes in gene expression correlate with cRE activity, we measured transcript levels, chromatin accessibility, and promoter–cRE contacts across three phases of naive CD4+ T cell activation using RNA-seq, ATAC-seq, and HiC. We identified ~1200 protein-coding genes physically connected to accessible disease-associated variants at 423 GWAS signals, at least one-third of which are dynamically regulated by activation. From these maps, we functionally validated a novel stretch of evolutionarily conserved intergenic enhancers whose activity is required for activation-induced IL2 gene expression in human and mouse, and is influenced by autoimmune-associated genetic variation. The set of genes implicated by this approach are enriched for genes controlling CD4+ T cell function and genes involved in human inborn errors of immunity, and we pharmacologically validated eight implicated genes as novel regulators of T cell activation. These studies directly show how autoimmune variants and the genes they regulate influence processes involved in CD4+ T cell proliferation and activation.

    1. Cell Biology
    2. Immunology and Inflammation

    Arpin deficiency increases actomyosin contractility and vascular permeability

    Armando Montoya-Garcia, Idaira M Guerrero-Fonseca ... Michael Schnoor
    Research Article

    Arpin was discovered as an inhibitor of the Arp2/3 complex localized at the lamellipodial tip of fibroblasts, where it regulated migration steering. Recently, we showed that arpin stabilizes the epithelial barrier in an Arp2/3-dependent manner. However, the expression and functions of arpin in endothelial cells (EC) have not yet been described. Arpin mRNA and protein are expressed in EC and downregulated by pro-inflammatory cytokines. Arpin depletion in Human Umbilical Vein Endothelial Cells causes the formation of actomyosin stress fibers leading to increased permeability in an Arp2/3-independent manner. Instead, inhibitors of ROCK1 and ZIPK, kinases involved in the generation of stress fibers, normalize the loss-of-arpin effects on actin filaments and permeability. Arpin-deficient mice are viable but show a characteristic vascular phenotype in the lung including edema, microhemorrhage, and vascular congestion, increased F-actin levels, and vascular permeability. Our data show that, apart from being an Arp2/3 inhibitor, arpin is also a regulator of actomyosin contractility and endothelial barrier integrity.

    1. Immunology and Inflammation

    The common Sting1 HAQ, AQ alleles rescue CD4 T cellpenia, restore T-regs, and prevent SAVI (N153S) inflammatory disease in mice

    Alexandra a Aybar-Torres, Lennon A Saldarriaga ... Lei Jin
    Research Article

    The significance of STING1 gene in tissue inflammation and cancer immunotherapy has been increasingly recognized. Intriguingly, common human STING1 alleles R71H-G230A-R293Q (HAQ) and G230A-R293Q (AQ) are carried by ~60% of East Asians and ~40% of Africans, respectively. Here, we examine the modulatory effects of HAQ, AQ alleles on STING-associated vasculopathy with onset in infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused by gain-of-function human STING1 mutations. CD4 T cellpenia is evident in SAVI patients and mouse models. Using Sting1 knock-in mice expressing common human STING1 alleles HAQ, AQ, and Q293, we found that HAQ, AQ, and Q293 splenocytes resist STING1-mediated cell death ex vivo, establishing a critical role of STING1 residue 293 in cell death. The HAQ/SAVI(N153S) and AQ/SAVI(N153S) mice did not have CD4 T cellpenia. The HAQ/SAVI(N153S), AQ/SAVI(N153S) mice have more (~10-fold, ~20-fold, respectively) T-regs than WT/SAVI(N153S) mice. Remarkably, while they have comparable TBK1, IRF3, and NFκB activation as the WT/SAVI, the AQ/SAVI mice have no tissue inflammation, regular body weight, and normal lifespan. We propose that STING1 activation promotes tissue inflammation by depleting T-regs cells in vivo. Billions of modern humans have the dominant HAQ, AQ alleles. STING1 research and STING1-targeting immunotherapy should consider STING1 heterogeneity in humans.