Identification of scavenger receptor B1 as the airway microfold cell receptor for Mycobacterium tuberculosis
- University of Texas Southwestern Medical School, United States
- University of Texas Southwestern Medical Center, United States
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.
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Identification of scavenger receptor B1 as the airway microfold cell receptor for Mycobacterium tuberculosisNCBI Sequence Read Archive, PRJNA605439.
Article and author information
Author details
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.
Reviewing Editor
- Christina L Stallings, Washington University School of Medicine, United States
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).
Version history
- Received: October 8, 2019
- Accepted: March 4, 2020
- Accepted Manuscript published: March 5, 2020 (version 1)
- Version of Record published: March 11, 2020 (version 2)
- 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.
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Identification of scavenger receptor B1 as the airway microfold cell receptor for Mycobacterium tuberculosis
eLife 9:e52551.
https://doi.org/10.7554/eLife.52551
Further reading
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- Immunology and Inflammation
- Medicine
Background:
Prinflammatory extracellular chromatin from neutrophil extracellular traps (NETs) and other cellular sources is found in COVID-19 patients and may promote pathology. We determined whether pulmonary administration of the endonuclease dornase alfa reduced systemic inflammation by clearing extracellular chromatin.
Methods:
Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors.
Results:
We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01–2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 μg/mL, p=0.004).
Conclusions:
Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin.
Funding:
LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust).
Clinical trial number:
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- Immunology and Inflammation
Trained immunity is the long-term functional reprogramming of innate immune cells, which results in altered responses toward a secondary challenge. Despite indoxyl sulfate (IS) being a potent stimulus associated with chronic kidney disease (CKD)-related inflammation, its impact on trained immunity has not been explored. Here, we demonstrate that IS induces trained immunity in monocytes via epigenetic and metabolic reprogramming, resulting in augmented cytokine production. Mechanistically, the aryl hydrocarbon receptor (AhR) contributes to IS-trained immunity by enhancing the expression of arachidonic acid (AA) metabolism-related genes such as arachidonate 5-lipoxygenase (ALOX5) and ALOX5 activating protein (ALOX5AP). Inhibition of AhR during IS training suppresses the induction of IS-trained immunity. Monocytes from end-stage renal disease (ESRD) patients have increased ALOX5 expression and after 6 days training, they exhibit enhanced TNF-α and IL-6 production to lipopolysaccharide (LPS). Furthermore, healthy control-derived monocytes trained with uremic sera from ESRD patients exhibit increased production of TNF-α and IL-6. Consistently, IS-trained mice and their splenic myeloid cells had increased production of TNF-α after in vivo and ex vivo LPS stimulation compared to that of control mice. These results provide insight into the role of IS in the induction of trained immunity, which is critical during inflammatory immune responses in CKD patients.
