1. Immunology and Inflammation
  2. Microbiology and Infectious Disease
Download icon

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
Research Article
  • Cited 5
  • Views 1,486
  • Annotations
Cite this article as: eLife 2020;9:e52551 doi: 10.7554/eLife.52551

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).

Reviewing Editor

  1. Christina L Stallings, Washington University School of Medicine, United States

Publication history

  1. Received: October 8, 2019
  2. Accepted: March 4, 2020
  3. Accepted Manuscript published: March 5, 2020 (version 1)
  4. Version of Record published: March 11, 2020 (version 2)
  5. Version of Record updated: March 11, 2020 (version 3)

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

  • 1,486
    Page views
  • 253
    Downloads
  • 5
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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)

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

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

Categories and tags

Research organisms

Further reading

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease

    Rapid and sensitive detection of SARS-CoV-2 infection using quantitative peptide enrichment LC-MS analysis

    Andreas Hober et al.
    Research Article Updated

    Reliable, robust, large-scale molecular testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is essential for monitoring the ongoing coronavirus disease 2019 (COVID-19) pandemic. We have developed a scalable analytical approach to detect viral proteins based on peptide immuno-affinity enrichment combined with liquid chromatography-mass spectrometry (LC-MS). This is a multiplexed strategy, based on targeted proteomics analysis and read-out by LC-MS, capable of precisely quantifying and confirming the presence of SARS-CoV-2 in phosphate-buffered saline (PBS) swab media from combined throat/nasopharynx/saliva samples. The results reveal that the levels of SARS-CoV-2 measured by LC-MS correlate well with their correspondingreal-time polymerase chain reaction (RT-PCR) read-out (r = 0.79). The analytical workflow shows similar turnaround times as regular RT-PCR instrumentation with a quantitative read-out of viral proteins corresponding to cycle thresholds (Ct) equivalents ranging from 21 to 34. Using RT-PCR as a reference, we demonstrate that the LC-MS-based method has 100% negative percent agreement (estimated specificity) and 95% positive percent agreement (estimated sensitivity) when analyzing clinical samples collected from asymptomatic individuals with a Ct within the limit of detection of the mass spectrometer (Ct ≤ 30). These results suggest that a scalable analytical method based on LC-MS has a place in future pandemic preparedness centers to complement current virus detection technologies.

    1. Immunology and Inflammation
    2. Structural Biology and Molecular Biophysics

    Neutrophil-mediated oxidative stress and albumin structural damage predict COVID-19-associated mortality

    Mohamed A Badawy et al.
    Research Article

    Human serum albumin (HSA) is the frontline antioxidant protein in blood with established anti-inflammatory and anticoagulation functions. Here we report that COVID-19-induced oxidative stress inflicts structural damages to HSA and is linked with mortality outcome in critically ill patients. We recruited 39 patients who were followed up for a median of 12.5 days (1-35 days), among them 23 had died. Analyzing blood samples from patients and healthy individuals (n=11), we provide evidence that neutrophils are major sources of oxidative stress in blood and that hydrogen peroxide is highly accumulated in plasmas of non-survivors. We then analyzed electron paramagnetic resonance (EPR) spectra of spin labelled fatty acids (SLFA) bound with HSA in whole blood of control, survivor, and non-survivor subjects (n=10-11). Non-survivor' HSA showed dramatically reduced protein packing order parameter, faster SLFA correlational rotational time, and smaller S/W ratio (strong-binding/weak-binding sites within HSA), all reflecting remarkably fluid protein microenvironments. Following loading/unloading of 16-DSA we show that transport function of HSA maybe impaired in severe patients. Stratified at the means, Kaplan–Meier survival analysis indicated that lower values of S/W ratio and accumulated H2O2 in plasma significantly predicted in-hospital mortality (S/W≤0.15, 81.8% (18/22) vs. S/W>0.15, 18.2% (4/22), p=0.023; plasma [H2O2]>8.6 mM, 65.2% (15/23) vs. 34.8% (8/23), p=0.043). When we combined these two parameters as the ratio ((S/W)/[H2O2]) to derive a risk score, the resultant risk score lower than the mean (< 0.019) predicted mortality with high fidelity (95.5% (21/22) vs. 4.5% (1/22), logrank c2 = 12.1, p=4.9x10-4). The derived parameters may provide a surrogate marker to assess new candidates for COVID-19 treatments targeting HSA replacements and/or oxidative stress.

    1. Immunology and Inflammation

    The alpha/B.1.1.7 SARS-CoV-2 variant exhibits significantly higher affinity for ACE-2 and requires lower inoculation doses to cause disease in K18-hACE2 mice

    Rafael Bayarri-Olmos et al.
    Research Article

    The alpha/B.1.1.7 SARS-CoV-2 lineage emerged in autumn 2020 in the United Kingdom and transmitted rapidly until winter 2021 when it was responsible for most new COVID-19 cases in many European countries. The incidence domination was likely due to a fitness advantage that could be driven by the RBD residue change (N501Y), which also emerged independently in other Variants of Concern such as the beta/B.1.351 and gamma/P.1 strains. Here we present a functional characterization of the alpha/B.1.1.7 variant and show an eight-fold affinity increase towards human ACE-2. In accordance with this, transgenic hACE-2 mice showed a faster disease progression and severity after infection with a low dose of B.1.1.7, compared to an early 2020 SARS-CoV-2 isolate. When challenged with sera from convalescent individuals or anti-RBD monoclonal antibodies, the N501Y variant showed a minor, but significant elevated evasion potential of ACE-2/RBD antibody neutralization. The data suggest that the single asparagine to tyrosine substitution remarkable rise in affinity may be responsible for the higher transmission rate and severity of the B.1.1.7 variant.