2021年
No. 6
Medical Abstracts
Filters applied: from 2021/5/1 - 2021/5/31
1. CA Cancer J Clin. 2021 Jul;71(4):299-314. doi: 10.3322/caac.21671. Epub 2021 May
20.
Racial and socioeconomic disparities in lung cancer screening in the United
States: A systematic review.
Sosa E(1), D'Souza G(2), Akhtar A(2), Sur M(1), Love K(3), Duffels J(3), Raz
DJ(2), Kim JY(2), Sun V(1)(2), Erhunmwunsee L(1)(2).
Author information:
(1)Department of Populations Sciences, City of Hope National Medical Center,
Duarte, California.
(2)Department of Surgery, City of Hope Comprehensive Cancer Center, Duarte,
California.
(3)Division of Library Services, City of Hope National Medical Center, Duarte,
California.
Nonsmall cell lung cancer (NSCLC) is the leading cause of cancer deaths. Lung
cancer screening (LCS) reduces NSCLC mortality; however, a lack of diversity in
LCS studies may limit the generalizability of the results to marginalized groups
who face higher risk for and worse outcomes from NSCLC. Identifying sources of
inequity in the LCS pipeline is essential to reduce disparities in NSCLC
outcomes. The authors searched 3 major databases for studies published from
January 1, 2010 to February 27, 2020 that met the following criteria: 1)
included screenees between ages 45 and 80 years who were current or former
smokers, 2) written in English, 3) conducted in the United States, and 4)
discussed socioeconomic and race-based LCS outcomes. Eligible studies were
assessed for risk of bias. Of 3721 studies screened, 21 were eligible. Eligible
studies were evaluated, and their findings were categorized into 3 themes
related to LCS disparities faced by Black and socioeconomically disadvantaged
individuals: 1) eligibility; 2) utilization, perception, and utility; and 3)
postscreening behavior and care. Disparities in LCS exist along racial and
socioeconomic lines. There are several steps along the LCS pipeline in which
Black and socioeconomically disadvantaged individuals miss the potential
benefits of LCS, resulting in increased mortality. This study identified
potential sources of inequity that require further investigation. The authors
recommend the implementation of prospective trials that evaluate eligibility
criteria for underserved groups and the creation of interventions focused on
improving utilization and follow-up care to decrease LCS disparities.
© 2021 The Authors. CA: A Cancer Journal for Clinicians published by Wiley
Periodicals LLC on behalf of American Cancer Society.
DOI: 10.3322/caac.21671
PMCID: PMC8266751
PMID: 34015860
2. Nature. 2021 May;593(7859):445-448. doi: 10.1038/s41586-021-03517-z. Epub 2021
May 12.
Structure and dynamics of a mycobacterial type VII secretion system.
Bunduc CM(1)(2)(3)(4), Fahrenkamp D(1)(2)(3), Wald J(1)(2)(3), Ummels R(5),
Bitter W(4)(5), Houben ENG(4), Marlovits TC(6)(7)(8).
Author information:
(1)Centre for Structural Systems Biology, Hamburg, Germany.
(2)Institute of Structural and Systems Biology, University Medical Centre
Hamburg-Eppendorf, Hamburg, Germany.
(3)Deutsches Elektron Synchrotron DESY, Hamburg, Germany.
…
Mycobacterium tuberculosis is the cause of one of the most important infectious
diseases in humans, which leads to 1.4 million deaths every year1. Specialized
protein transport systems-known as type VII secretion systems (T7SSs)-are
central to the virulence of this pathogen, and are also crucial for nutrient and
metabolite transport across the mycobacterial cell envelope2,3. Here we present
the structure of an intact T7SS inner-membrane complex of M. tuberculosis. We
show how the 2.32-MDa ESX-5 assembly, which contains 165 transmembrane helices,
is restructured and stabilized as a trimer of dimers by the MycP5 protease. A
trimer of MycP5 caps a central periplasmic dome-like chamber that is formed by
three EccB5 dimers, with the proteolytic sites of MycP5 facing towards the
cavity. This chamber suggests a central secretion and processing conduit.
Complexes without MycP5 show disruption of the EccB5 periplasmic assembly and
increased flexibility, which highlights the importance of MycP5 for complex
integrity. Beneath the EccB5-MycP5 chamber, dimers of the EccC5 ATPase assemble
into three bundles of four transmembrane helices each, which together seal the
potential central secretion channel. Individual cytoplasmic EccC5 domains adopt
two distinctive conformations that probably reflect different secretion states.
Our work suggests a previously undescribed mechanism of protein transport and
provides a structural scaffold to aid in the development of drugs against this
major human pathogen.
DOI: 10.1038/s41586-021-03517-z
PMCID: PMC8131196
PMID: 33981042
3. N Engl J Med. 2021 May 6;384(18):1705-1718. doi: 10.1056/NEJMoa2033400.
Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis.
Dorman SE(1), Nahid P(1), Kurbatova EV(1), Phillips PPJ(1), Bryant K(1), Dooley
KE(1), Engle M(1), Goldberg SV(1), Phan HTT(1), Hakim J(1), Johnson JL(1),
Lourens M(1), Martinson NA(1), Muzanyi G(1), Narunsky K(1), Nerette S(1), Nguyen
NV(1), Pham TH(1), Pierre S(1), Purfield AE(1), Samaneka W(1), Savic RM(1),
Sanne I(1), Scott NA(1), Shenje J(1), Sizemore E(1), Vernon A(1), Waja Z(1),
Weiner M(1), Swindells S(1), Chaisson RE(1); AIDS Clinical Trials Group;
Tuberculosis Trials Consortium.
Author information:
(1)From the Medical University of South Carolina, Charleston (S.E.D.); the UCSF
Center for Tuberculosis, University of California, San Francisco, San Francisco
(P.N., P.P.J.P., R.M.S.); the Vietnam National Tuberculosis Program-University
of California, San Francisco Research Collaboration Unit (P.N., P.P.J.P.,
…
Comment in
N Engl J Med. 2021 May 6;384(18):1764-1765.
BACKGROUND: Rifapentine-based regimens have potent antimycobacterial activity
that may allow for a shorter course in patients with drug-susceptible pulmonary
tuberculosis.
METHODS: In an open-label, phase 3, randomized, controlled trial involving
persons with newly diagnosed pulmonary tuberculosis from 13 countries, we
compared two 4-month rifapentine-based regimens with a standard 6-month regimen
consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (control) using
a noninferiority margin of 6.6 percentage points. In one 4-month regimen,
rifampin was replaced with rifapentine; in the other, rifampin was replaced with
rifapentine and ethambutol with moxifloxacin. The primary efficacy outcome was
survival free of tuberculosis at 12 months.
RESULTS: Among 2516 participants who had undergone randomization, 2343 had a
culture positive for Mycobacterium tuberculosis that was not resistant to
isoniazid, rifampin, or fluoroquinolones (microbiologically eligible population;
768 in the control group, 791 in the rifapentine-moxifloxacin group, and 784 in
the rifapentine group), of whom 194 were coinfected with human immunodeficiency
virus and 1703 had cavitation on chest radiography. A total of 2234 participants
could be assessed for the primary outcome (assessable population; 726 in the
control group, 756 in the rifapentine-moxifloxacin group, and 752 in the
rifapentine group). Rifapentine with moxifloxacin was noninferior to the control
in the microbiologically eligible population (15.5% vs. 14.6% had an unfavorable
outcome; difference, 1.0 percentage point; 95% confidence interval [CI], -2.6 to
4.5) and in the assessable population (11.6% vs. 9.6%; difference, 2.0
percentage points; 95% CI, -1.1 to 5.1). Noninferiority was shown in the
secondary and sensitivity analyses. Rifapentine without moxifloxacin was not
shown to be noninferior to the control in either population (17.7% vs. 14.6%
with an unfavorable outcome in the microbiologically eligible population;
difference, 3.0 percentage points [95% CI, -0.6 to 6.6]; and 14.2% vs. 9.6% in
the assessable population; difference, 4.4 percentage points [95% CI, 1.2 to
7.7]). Adverse events of grade 3 or higher occurred during the on-treatment
period in 19.3% of participants in the control group, 18.8% in the
rifapentine-moxifloxacin group, and 14.3% in the rifapentine group.
CONCLUSIONS: The efficacy of a 4-month rifapentine-based regimen containing
moxifloxacin was noninferior to the standard 6-month regimen in the treatment of
tuberculosis. (Funded by the Centers for Disease Control and Prevention and
others; Study 31/A5349 ClinicalTrials.gov number, NCT02410772.).
Copyright © 2021 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2033400
PMCID: PMC8282329
PMID: 33951360 [Indexed for MEDLINE]
4. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb
4.
Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality
Worldwide for 36 Cancers in 185 Countries.
Sung H(1), Ferlay J(2), Siegel RL(1), Laversanne M(2), Soerjomataram I(2), Jemal
A(1), Bray F(2).
Author information:
(1)Surveillance and Health Equity Science, American Cancer Society, Atlanta,
Georgia.
(2)Section of Cancer Surveillance, International Agency for Research on Cancer,
Lyon, France.
This article provides an update on the global cancer burden using the GLOBOCAN
2020 estimates of cancer incidence and mortality produced by the International
Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer
cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million
cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020.
Female breast cancer has surpassed lung cancer as the most commonly diagnosed
cancer, with an estimated 2.3 million new cases (11.7%), followed by lung
(11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung
cancer remained the leading cause of cancer death, with an estimated 1.8 million
deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and
female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher
in transitioned versus transitioning countries for both sexes, whereas mortality
varied<2-fold for men and little for women. Death rates for female breast and
cervical cancers, however, were considerably higher in transitioning versus
transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000,
respectively). The global cancer burden is expected to be 28.4 million cases in
2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%)
versus transitioned (32% to 56%) countries due to demographic changes, although
this may be further exacerbated by increasing risk factors associated with
globalization and a growing economy. Efforts to build a sustainable
infrastructure for the dissemination of cancer prevention measures and provision
of cancer care in transitioning countries is critical for global cancer control.
© 2021 American Cancer Society.
DOI: 10.3322/caac.21660
PMID: 33538338
5. Nat Immunol. 2021 Jun;22(6):781-793. doi: 10.1038/s41590-021-00933-1. Epub 2021
May 24.
Multimodally profiling memory T cells from a tuberculosis cohort identifies cell
state associations with demographics, environment and disease.
Nathan A(1)(2)(3)(4)(5), Beynor JI(1)(2)(3)(4)(5), Baglaenko Y(1)(2)(3)(4)(5),
Suliman S(2), Ishigaki K(1)(2)(3)(4)(5), Asgari S(1)(2)(3)(4)(5), Huang
CC(6)(7), Luo Y(1)(2)(3)(4)(5), Zhang Z(6)(7), Lopez K(2)(8), Lindestam Arlehamn
CS(9), Ernst JD(10), Jimenez J(8), Calderón RI(8)(11), Lecca L(6)(8), Van Rhijn
I(2)(12), Moody DB(2), Murray MB(6)(7), Raychaudhuri S(13)(14)(15)(16)(17)(18).
Author information:
(1)Center for Data Sciences, Brigham and Women's Hospital and Harvard Medical
School, Boston, MA, USA.
(2)Division of Rheumatology, Inflammation, and Immunity, Department of Medicine,
Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
(3)Division of Genetics, Department of Medicine, Brigham and Women's Hospital
and Harvard Medical School, Boston, MA, USA.
…
Comment in
Nat Immunol. 2021 Jun;22(6):675-676.
Multimodal T cell profiling can enable more precise characterization of elusive
cell states underlying disease. Here, we integrated single-cell RNA and surface
protein data from 500,089 memory T cells to define 31 cell states from 259
individuals in a Peruvian tuberculosis (TB) progression cohort. At immune steady
state >4 years after infection and disease resolution, we found that, after
accounting for significant effects of age, sex, season and genetic ancestry on T
cell composition, a polyfunctional type 17 helper T (TH17) cell-like effector
state was reduced in abundance and function in individuals who previously
progressed from Mycobacterium tuberculosis (M.tb) infection to active TB
disease. These cells are capable of responding to M.tb peptides. Deconvoluting
this state-uniquely identifiable with multimodal analysis-from public data
demonstrated that its depletion may precede and persist beyond active disease.
Our study demonstrates the power of integrative multimodal single-cell profiling
to define cell states relevant to disease and other traits.
DOI: 10.1038/s41590-021-00933-1
PMCID: PMC8162307
PMID: 34031617 [Indexed for MEDLINE]
6. Nat Med. 2021 Jul;27(7):1171-1177. doi: 10.1038/s41591-021-01358-x. Epub 2021
May 24.
Prisons as ecological drivers of fitness-compensated multidrug-resistant
Mycobacterium tuberculosis.
Gygli SM(#)(1)(2), Loiseau C(#)(1)(2), Jugheli L(1)(2)(3), Adamia N(3), Trauner
A(1)(2), Reinhard M(1)(2), Ross A(1)(2), Borrell S(1)(2), Aspindzelashvili R(3),
Maghradze N(1)(2)(3), Reither K(1)(2), Beisel C(4), Tukvadze N(1)(2)(3),
Avaliani Z(3), Gagneux S(5)(6).
Author information:
(1)Swiss Tropical and Public Health Institute, Basel, Switzerland.
(2)University of Basel, Basel, Switzerland.
(3)National Center for Tuberculosis and Lung Diseases (NCTLD), Tbilisi, Georgia.
…
Erratum in
Nat Med. 2021 Jun 1;:
Multidrug-resistant tuberculosis (MDR-TB) accounts for one third of the annual
deaths due to antimicrobial resistance1. Drug resistance-conferring mutations
frequently cause fitness costs in bacteria2-5. Experimental work indicates that
these drug resistance-related fitness costs might be mitigated by compensatory
mutations6-10. However, the clinical relevance of compensatory evolution remains
poorly understood. Here we show that, in the country of Georgia, during a 6-year
nationwide study, 63% of MDR-TB was due to patient-to-patient transmission.
Compensatory mutations and patient incarceration were independently associated
with transmission. Furthermore, compensatory mutations were overrepresented
among isolates from incarcerated individuals that also frequently spilled over
into the non-incarcerated population. As a result, up to 31% of MDR-TB in
Georgia was directly or indirectly linked to prisons. We conclude that prisons
fuel the epidemic of MDR-TB in Georgia by acting as ecological drivers of
fitness-compensated strains with high transmission potential.
© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
DOI: 10.1038/s41591-021-01358-x
PMID: 34031604
7. Lancet Oncol. 2021 Jun;22(6):824-835. doi: 10.1016/S1470-2045(21)00149-2. Epub
2021 May 18.
Neoadjuvant durvalumab with or without stereotactic body radiotherapy in
patients with early-stage non-small-cell lung cancer: a single-centre,
randomised phase 2 trial.
Altorki NK(1), McGraw TE(2), Borczuk AC(3), Saxena A(4), Port JL(5), Stiles
BM(5), Lee BE(5), Sanfilippo NJ(6), Scheff RJ(4), Pua BB(7), Gruden JF(7),
Christos PJ(8), Spinelli C(5), Gakuria J(5), Uppal M(9), Binder B(9), Elemento
O(3), Ballman KV(8), Formenti SC(6).
Author information:
(1)Department of Cardiothoracic Surgery, Weill Cornell Medicine-New York
Presbyterian Hospital, New York, NY, USA. Electronic address:
nkaltork@med.cornell.edu.
(2)Department of Biochemistry, Weill Cornell Medicine-New York Presbyterian
Hospital, New York, NY, USA.
(3)Department of Pathology and Laboratory Medicine, Weill Cornell Medicine-New
York Presbyterian Hospital, New York, NY, USA.
…
Comment in
Lancet Oncol. 2021 Jun;22(6):744-746.
BACKGROUND: Previous phase 2 trials of neoadjuvant anti-PD-1 or anti-PD-L1
monotherapy in patients with early-stage non-small-cell lung cancer have
reported major pathological response rates in the range of 15-45%. Evidence
suggests that stereotactic body radiotherapy might be a potent immunomodulator
in advanced non-small-cell lung cancer (NSCLC). In this trial, we aimed to
evaluate the use of stereotactic body radiotherapy in patients with early-stage
NSCLC as an immunomodulator to enhance the anti-tumour immune response
associated with the anti-PD-L1 antibody durvalumab.
METHODS: We did a single-centre, open-label, randomised, controlled, phase 2
trial, comparing neoadjuvant durvalumab alone with neoadjuvant durvalumab plus
stereotactic radiotherapy in patients with early-stage NSCLC, at
NewYork-Presbyterian and Weill Cornell Medical Center (New York, NY, USA). We
enrolled patients with potentially resectable early-stage NSCLC (clinical stages
I-IIIA as per the 7th edition of the American Joint Committee on Cancer) who
were aged 18 years or older with an Eastern Cooperative Oncology Group
performance status of 0 or 1. Eligible patients were randomly assigned (1:1) to
either neoadjuvant durvalumab monotherapy or neoadjuvant durvalumab plus
stereotactic body radiotherapy (8 Gy × 3 fractions), using permuted blocks with
varied sizes and no stratification for clinical or molecular variables.
Patients, treating physicians, and all study personnel were unmasked to
treatment assignment after all patients were randomly assigned. All patients
received two cycles of durvalumab 3 weeks apart at a dose of 1·12 g by
intravenous infusion over 60 min. Those in the durvalumab plus radiotherapy
group also received three consecutive daily fractions of 8 Gy stereotactic body
radiotherapy delivered to the primary tumour immediately before the first cycle
of durvalumab. Patients without systemic disease progression proceeded to
surgical resection. The primary endpoint was major pathological response in the
primary tumour. All analyses were done on an intention-to-treat basis. This
trial is registered with ClinicalTrial.gov, NCT02904954, and is ongoing but
closed to accrual.
FINDINGS: Between Jan 25, 2017, and Sept 15, 2020, 96 patients were screened and
60 were enrolled and randomly assigned to either the durvalumab monotherapy
group (n=30) or the durvalumab plus radiotherapy group (n=30). 26 (87%) of 30
patients in each group had their tumours surgically resected. Major pathological
response was observed in two (6·7% [95% CI 0·8-22·1]) of 30 patients in the
durvalumab monotherapy group and 16 (53·3% [34·3-71·7]) of 30 patients in the
durvalumab plus radiotherapy group. The difference in the major pathological
response rates between both groups was significant (crude odds ratio 16·0 [95%
CI 3·2-79·6]; p<0·0001). In the 16 patients in the dual therapy group with a
major pathological response, eight (50%) had a complete pathological response.
The second cycle of durvalumab was withheld in three (10%) of 30 patients in the
dual therapy group due to immune-related adverse events (grade 3 hepatitis,
grade 2 pancreatitis, and grade 3 fatigue and thrombocytopaenia). Grade 3-4
adverse events occurred in five (17%) of 30 patients in the durvalumab
monotherapy group and six (20%) of 30 patients in the durvalumab plus
radiotherapy group. The most frequent grade 3-4 events were hyponatraemia (three
[10%] patients in the durvalumab monotherapy group) and hyperlipasaemia (three
[10%] patients in the durvalumab plus radiotherapy group). Two patients in each
group had serious adverse events (pulmonary embolism [n=1] and stroke [n=1] in
the durvalumab monotherapy group, and pancreatitis [n=1] and fatigue [n=1] in
the durvalumab plus radiotherapy group). No treatment-related deaths or deaths
within 30 days of surgery were reported.
INTERPRETATION: Neoadjuvant durvalumab combined with stereotactic body
radiotherapy is well tolerated, safe, and associated with a high major
pathological response rate. This neoadjuvant strategy should be validated in a
larger trial.
FUNDING: AstraZeneca.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(21)00149-2
PMID: 34015311 [Indexed for MEDLINE]
8. Acc Chem Res. 2021 May 18;54(10):2361-2376. doi: 10.1021/acs.accounts.0c00878.
Epub 2021 Apr 22.
Strategies to Combat Multi-Drug Resistance in Tuberculosis.
Singh V(1)(2), Chibale K(1)(2).
Author information:
(1)Drug Discovery and Development Centre (H3D), University of Cape Town,
Rondebosch 7701, South Africa.
(2)South African Medical Research Council Drug Discovery and Development
Research Unit, Department of Chemistry and Institute of Infectious Disease and
Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa.
"Drug resistance is an unavoidable consequence of the use of drugs; however, the
emergence of multi-drug resistance can be managed by accurate diagnosis and
tailor-made regimens."Antimicrobial resistance (AMR), is one of the most
paramount health perils that has emerged in the 21st century. The global
increase in drug-resistant strains of various bacterial pathogens prompted the
World Health Organization (WHO) to develop a priority list of AMR pathogens.
Mycobacterium tuberculosis (Mtb), an acid-fast bacillus that causes tuberculosis
(TB), merits being one of the highest priority pathogens on this list since
drug-resistant TB (DR-TB) accounts for ∼29% of deaths attributable to AMR. In
recent years, funded collaborative efforts of researchers from academia,
not-for-profit virtual R&D organizations and industry have resulted in the
continuous growth of the TB drug discovery and development pipeline. This has so
far led to the accelerated regulatory approval of bedaquiline and delamanid for
the treatment of DR-TB. However, despite the availability of drug regimes, the
current cure rate for multi-drug-resistant TB (MDR-TB) and extensively
drug-resistant TB (XDR-TB) treatment regimens is 50% and 30%, respectively. It
is to be noted that these regimens are administered over a long duration and
have a serious side effect profile. Coupled with poor patient adherence, this
has led to further acquisition of drug resistance and treatment failure. There
is therefore an urgent need to develop new TB drugs with novel mechanism of
actions (MoAs) and associated regimens.This Account recapitulates drug
resistance in TB, existing challenges in addressing DR-TB, new drugs and
regimens in development, and potential ways to treat DR-TB. We highlight our
research aimed at identifying novel small molecule leads and associated targets
against TB toward contributing to the global TB drug discovery and development
pipeline. Our work mainly involves screening of various small molecule chemical
libraries in phenotypic whole-cell based assays to identify hits for medicinal
chemistry optimization, with attendant deconvolution of the MoA. We discuss the
identification of small molecule chemotypes active against Mtb and subsequent
structure-activity relationships (SAR) and MoA deconvolution studies. This is
followed by a discussion on a chemical series identified by whole-cell
cross-screening against Mtb, for which MoA deconvolution studies revealed a
pathway that explained the lack of in vivo efficacy in a mouse model of TB and
reiterated the importance of selecting an appropriate growth medium during
phenotypic screening. We also discuss our efforts on drug repositioning toward
addressing DR-TB. In the concluding section, we preview some promising future
directions and the challenges inherent in advancing the drug pipeline to address
DR-TB.
DOI: 10.1021/acs.accounts.0c00878
PMCID: PMC8154215
PMID: 33886255
9. Nat Commun. 2021 May 20;12(1):2963. doi: 10.1038/s41467-021-23235-4.
Deep learning predicts cardiovascular disease risks from lung cancer screening
low dose computed tomography.
Chao H(1), Shan H(1), Homayounieh F(2), Singh R(2), Khera RD(2), Guo H(1), Su
T(3), Wang G(4), Kalra MK(5), Yan P(6).
Author information:
(1)Department of Biomedical Engineering, Biomedical Imaging Center, Rensselaer
Polytechnic Institute, Troy, NY, USA.
(2)Department of Radiology, Massachusetts General Hospital, Harvard Medical
School, Boston, MA, USA.
(3)Niskayuna High School, Niskayuna, NY, USA.
…
Cancer patients have a higher risk of cardiovascular disease (CVD) mortality
than the general population. Low dose computed tomography (LDCT) for lung cancer
screening offers an opportunity for simultaneous CVD risk estimation in at-risk
patients. Our deep learning CVD risk prediction model, trained with 30,286 LDCTs
from the National Lung Cancer Screening Trial, achieves an area under the curve
(AUC) of 0.871 on a separate test set of 2,085 subjects and identifies patients
with high CVD mortality risks (AUC of 0.768). We validate our model against
ECG-gated cardiac CT based markers, including coronary artery calcification
(CAC) score, CAD-RADS score, and MESA 10-year risk score from an independent
dataset of 335 subjects. Our work shows that, in high-risk patients, deep
learning can convert LDCT for lung cancer screening into a dual-screening
quantitative tool for CVD risk estimation.
DOI: 10.1038/s41467-021-23235-4
PMCID: PMC8137697
PMID: 34017001 [Indexed for MEDLINE]
10. Am J Respir Crit Care Med. 2021 May 20. doi: 10.1164/rccm.202101-0032OC. Online
ahead of print.
µCT Analysis of the Human Tuberculous Lung Reveals Remarkable Heterogeneity in
3D Granuloma Morphology.
Wells G(1), Glasgow JN(2), Nargan K(1), Lumamba K(1), Madansein R(3), Maharaj
K(3), Hunter RL(4), Naidoo T(5), Coetzer L(6), Le Roux S(6), du Plessis A(6),
Steyn AJC(2)(7).
Author information:
(1)Africa Health Research Institute, 560159, Durban, South Africa.
(2)The University of Alabama at Birmingham, 9968, Microbiology, Birmingham,
Alabama, United States.
(3)Inkosi Albert Luthuli Central Hospital, 37709, Mayville, South Africa.
…
Rationale: Our current understanding of tuberculosis pathophysiology is limited
by a reliance on animal models, the paucity of human tuberculosis lung tissue,
and traditional histopathological analysis, a destructive two-dimensional
approach that provides limited spatial insight. Determining the
three-dimensional (3D) structure of the necrotic granuloma, a characteristic
feature of tuberculosis, will more accurately inform preventative TB strategies.
Objectives: To ascertain the 3D shape of the human tuberculous granuloma and its
spatial relationship with airways and vasculature within large lung tissues.
Methods: We characterized the 3D microanatomic environment of human tuberculous
lungs using micro-computed tomography (µCT), histopathology and
immunohistochemistry. Using 3D segmentation software, we accurately
reconstructed TB granulomas, vasculature, and airways in 3D and confirmed our
findings using histopathology and immunohistochemistry. Measurements and main
results: We observed marked heterogeneity in the morphology, volume, and number
of TB granulomas in human lung sections. Unlike depictions of granulomas as
simple spherical structures, human necrotic granulomas exhibit complex,
cylindrical, branched morphologies which are connected to the airways and shaped
by the bronchi. 3D imaging of human tuberculosis lung sections provides
unanticipated insight into the spatial organization of tuberculosis granulomas
in relation to airways and the vasculature. Conclusions: Our findings highlight
the likelihood that a single structurally complex lesion could be mistakenly
viewed as multiple independent lesions when evaluated in 2D. Also, lack of
vascularization within obstructed bronchi establishes a paradigm for
antimycobacterial drug tolerance. Lastly, our results suggest that bronchogenic
spread of Mycobacterium tuberculosis re-seeds the lung.
DOI: 10.1164/rccm.202101-0032OC
PMID: 34015247
11. Nat Commun. 2021 May 18;12(1):2899. doi: 10.1038/s41467-021-22833-6.
Mycobacterium tuberculosis precursor rRNA as a measure of treatment-shortening
activity of drugs and regimens.
Walter ND(#)(1)(2)(3), Born SEM(#)(4), Robertson GT(#)(5)(6), Reichlen M(4),
Dide-Agossou C(7), Ektnitphong VA(6), Rossmassler K(8)(9), Ramey ME(6), Bauman
AA(6), Ozols V(8)(9), Bearrows SC(8)(9), Schoolnik G(10), Dolganov G(10), Garcia
B(11)(12), Musisi E(13)(14), Worodria W(13),…
Author information:
(1)Rocky Mountain Regional VA Medical Center, Aurora, CO, USA.
nicholas.walter@cuanschutz.edu.
(2)Division of Pulmonary Sciences and Critical Care Medicine, University of
Colorado Anschutz Medical Campus, Aurora, CO, USA.
nicholas.walter@cuanschutz.edu.
(3)Consortium for Applied Microbial Metrics, Aurora, CO, USA.
nicholas.walter@cuanschutz.edu.
…
There is urgent need for new drug regimens that more rapidly cure tuberculosis
(TB). Existing TB drugs and regimens vary in treatment-shortening activity, but
the molecular basis of these differences is unclear, and no existing assay
directly quantifies the ability of a drug or regimen to shorten treatment. Here,
we show that drugs historically classified as sterilizing and non-sterilizing
have distinct impacts on a fundamental aspect of Mycobacterium tuberculosis
physiology: ribosomal RNA (rRNA) synthesis. In culture, in mice, and in human
studies, measurement of precursor rRNA reveals that sterilizing drugs and highly
effective drug regimens profoundly suppress M. tuberculosis rRNA synthesis,
whereas non-sterilizing drugs and weaker regimens do not. The rRNA synthesis
ratio provides a readout of drug effect that is orthogonal to traditional
measures of bacterial burden. We propose that this metric of drug activity may
accelerate the development of shorter TB regimens.
DOI: 10.1038/s41467-021-22833-6
PMCID: PMC8131613
PMID: 34006838 [Indexed for MEDLINE]
12. Nat Commun. 2021 May 11;12(1):2716. doi: 10.1038/s41467-021-22705-z.
Genomic analyses of Mycobacterium tuberculosis from human lung resections reveal
a high frequency of polyclonal infections.
Moreno-Molina M(1), Shubladze N(2), Khurtsilava I(2), Avaliani Z(2), Bablishvili
N(2), Torres-Puente M(1), Villamayor L(3), Gabrielian A(4), Rosenthal A(4),
Vilaplana C(5)(6)(7), Gagneux S(8)(9), Kempker RR(10), Vashakidze S(2), Comas
I(11)(12).
Author information:
(1)Instituto de Biomedicina de Valencia IBV-CSIC, Valencia, Spain.
(2)National Center for Tuberculosis and Lung Diseases of Georgia, Tbilisi,
Georgia.
(3)FISABIO Public Health, Valencia, Spain.
…
Polyclonal infections occur when at least two unrelated strains of the same
pathogen are detected in an individual. This has been linked to worse clinical
outcomes in tuberculosis, as undetected strains with different antibiotic
resistance profiles can lead to treatment failure. Here, we examine the amount
of polyclonal infections in sputum and surgical resections from patients with
tuberculosis in the country of Georgia. For this purpose, we sequence and
analyse the genomes of Mycobacterium tuberculosis isolated from the samples,
acquired through an observational clinical study (NCT02715271). Access to the
lung enhanced the detection of multiple strains (40% of surgery cases) as
opposed to just using a sputum sample (0-5% in the general population). We show
that polyclonal infections often involve genetically distant strains and can be
associated with reversion of the patient's drug susceptibility profile over
time. In addition, we find different patterns of genetic diversity within
lesions and across patients, including mutational signatures known to be
associated with oxidative damage; this suggests that reactive oxygen species may
be acting as a selective pressure in the granuloma environment. Our results
support the idea that the magnitude of polyclonal infections in high-burden
tuberculosis settings is underestimated when only testing sputum samples.
DOI: 10.1038/s41467-021-22705-z
PMCID: PMC8113332
PMID: 33976135 [Indexed for MEDLINE]
13. Nat Commun. 2021 May 10;12(1):2606. doi: 10.1038/s41467-021-22875-w.
Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy
resistance in KRAS/p53 mutant lung cancers.
Peng DH(#)(1)(2), Rodriguez BL(#)(1), Diao L(3), Gaudreau PO(1)(4), Padhye
A(1)(5), Konen JM(1), Ochieng JK(1), Class CA(6), Fradette JJ(1), Gibson L(1),
Chen L(1), Wang J(3), Byers LA(1), Gibbons DL(7)(8).
Author information:
(1)Department of Thoracic/Head and Neck Medical Oncology, The University of
Texas MD Anderson Cancer Center, Houston, TX, USA.
(2)Perlmutter Cancer Center, NYU Langone Health, 550 First Avenue, Smilow
Building 10th Floor, Suite 1010, New York, NY, USA.
(3)Department of Bioinformatics and Computational Biology, The University of
Texas MD Anderson Cancer Center, Houston, TX, USA.
…
Understanding resistance mechanisms to targeted therapies and immune checkpoint
blockade in mutant KRAS lung cancers is critical to developing novel combination
therapies and improving patient survival. Here, we show that MEK inhibition
enhanced PD-L1 expression while PD-L1 blockade upregulated MAPK signaling in
mutant KRAS lung tumors. Combined MEK inhibition with anti-PD-L1 synergistically
reduced lung tumor growth and metastasis, but tumors eventually developed
resistance to sustained combinatorial therapy. Multi-platform profiling revealed
that resistant lung tumors have increased infiltration of Th17 cells, which
secrete IL-17 and IL-22 cytokines to promote lung cancer cell invasiveness and
MEK inhibitor resistance. Antibody depletion of IL-17A in combination with MEK
inhibition and PD-L1 blockade markedly reduced therapy-resistance in vivo.
Clinically, increased expression of Th17-associated genes in patients treated
with PD-1 blockade predicted poorer overall survival and response in melanoma
and predicated poorer response to anti-PD1 in NSCLC patients. Here we show a
triple combinatorial therapeutic strategy to overcome resistance to combined MEK
inhibitor and PD-L1 blockade.
DOI: 10.1038/s41467-021-22875-w
PMCID: PMC8110980
PMID: 33972557 [Indexed for MEDLINE]
14. Nat Commun. 2021 May 10;12(1):2581. doi: 10.1038/s41467-021-22676-1.
Lung cancer organoids analyzed on microwell arrays predict drug responses of
patients within a week.
Hu Y(#)(1), Sui X(#)(2), Song F(3), Li Y(3), Li K(1), Chen Z(1), Yang F(2), Chen
X(2), Zhang Y(3), Wang X(4), Liu Q(5), Li C(6), Zou B(6), Chen X(7)(8), Wang
J(9), Liu P(10).
Author information:
(1)Department of Biomedical Engineering, School of Medicine, Tsinghua
University, Beijing, China.
(2)Department of Thoracic Surgery, People's Hospital, Peking University,
Beijing, China.
(3)Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education,
School of Biological Science and Medical Engineering, Beihang University,
Beijing, China.
…
While the potential of patient-derived organoids (PDOs) to predict patients'
responses to anti-cancer treatments has been well recognized, the lengthy time
and the low efficiency in establishing PDOs hamper the implementation of
PDO-based drug sensitivity tests in clinics. We first adapt a mechanical sample
processing method to generate lung cancer organoids (LCOs) from surgically
resected and biopsy tumor tissues. The LCOs recapitulate the histological and
genetic features of the parental tumors and have the potential to expand
indefinitely. By employing an integrated superhydrophobic microwell array chip
(InSMAR-chip), we demonstrate hundreds of LCOs, a number that can be generated
from most of the samples at passage 0, are sufficient to produce clinically
meaningful drug responses within a week. The results prove our one-week drug
tests are in good agreement with patient-derived xenografts, genetic mutations
of tumors, and clinical outcomes. The LCO model coupled with the microwell
device provides a technically feasible means for predicting patient-specific
drug responses in clinical settings.
DOI: 10.1038/s41467-021-22676-1
PMCID: PMC8110811
PMID: 33972544 [Indexed for MEDLINE]
15. PLoS Med. 2021 May 6;18(5):e1003628. doi: 10.1371/journal.pmed.1003628.
eCollection 2021 May.
Digital adherence technology for tuberculosis treatment supervision:
A stepped-wedge cluster-randomized trial in Uganda.
Cattamanchi A(1)(2), Crowder R(1), Kityamuwesi A(2), Kiwanuka N(3), Lamunu M(2),
Namale C(2), Tinka LK(2), Nakate AS(2), Ggita J(2), Turimumahoro P(2), Babirye
D(2), Oyuku D(2), Berger C(1), Tucker A(4), Patel D(5), Sammann A(5), Turyahabwe
S(6), Dowdy D(2)(4), Katamba A(2)(7).
Author information:
(1)Center for Tuberculosis and Division of Pulmonary and Critical Care Medicine,
San Francisco General Hospital, University of California San Francisco, San
Francisco, California, United States of America.
(2)Uganda Tuberculosis Implementation Research Consortium, Walimu, Kampala,
Uganda.
(3)Department of Epidemiology and Biostatistics, School of Public Health,
Makerere University College of Health Sciences, Kampala, Uganda.
…
BACKGROUND: Adherence to and completion of tuberculosis (TB) treatment remain
problematic in many high-burden countries. 99DOTS is a low-cost digital
adherence technology that could increase TB treatment completion.
METHODS AND FINDINGS: We conducted a pragmatic stepped-wedge cluster-randomized
trial including all adults treated for drug-susceptible pulmonary TB at 18
health facilities across Uganda over 8 months (1 December 2018-31 July 2019).
Facilities were randomized to switch from routine (control period) to
99DOTS-based (intervention period) TB treatment supervision in consecutive
months. Patients were allocated to the control or intervention period based on
which facility they attended and their treatment start date. Health facility
staff and patients were not blinded to the intervention. The primary outcome was
TB treatment completion. Due to the pragmatic nature of the trial, the primary
analysis was done according to intention-to-treat (ITT) and per protocol (PP)
principles. This trial is registered with the Pan African Clinical Trials
Registry (PACTR201808609844917). Of 1,913 eligible patients at the 18 health
facilities (1,022 and 891 during the control and intervention periods,
respectively), 38.0% were women, mean (SD) age was 39.4 (14.4) years, 46.8% were
HIV-infected, and most (91.4%) had newly diagnosed TB. In total, 463 (52.0%)
patients were enrolled on 99DOTS during the intervention period. In the ITT
analysis, the odds of treatment success were similar in the intervention and
control periods (adjusted odds ratio [aOR] 1.04, 95% CI 0.68-1.58, p = 0.87).
The odds of treatment success did not increase in the intervention period for
either men (aOR 1.24, 95% CI 0.73-2.10) or women (aOR 0.67, 95% CI 0.35-1.29),
or for either patients with HIV infection (aOR 1.51, 95% CI 0.81-2.85) or
without HIV infection (aOR 0.78, 95% CI 0.46-1.32). In the PP analysis, the
99DOTS-based intervention increased the odds of treatment success (aOR 2.89, 95%
CI 1.57-5.33, p = 0.001). The odds of completing the intensive phase of
treatment and the odds of not being lost to follow-up were similarly improved in
PP but not ITT analyses. Study limitations include the likelihood of selection
bias in the PP analysis, inability to verify medication dosing in either arm,
and incomplete implementation of some components of the intervention.
CONCLUSIONS: 99DOTS-based treatment supervision did not improve treatment
outcomes in the overall study population. However, similar treatment outcomes
were achieved during the control and intervention periods, and those patients
enrolled on 99DOTS achieved high treatment completion. 99DOTS-based treatment
supervision could be a viable alternative to directly observed therapy for a
substantial proportion of patients with TB.
TRIAL REGISTRATION: Pan-African Clinical Trials Registry (PACTR201808609844917).
DOI: 10.1371/journal.pmed.1003628
PMCID: PMC8136841
PMID: 33956802
16. Immunol Rev. 2021 May;301(1):98-121. doi: 10.1111/imr.12968. Epub 2021 May 6.
A century of BCG: Impact on tuberculosis control and beyond.
Ahmed A(1), Rakshit S(1), Adiga V(1), Dias M(2), Dwarkanath P(3), D'Souza
G(2)(4), Vyakarnam A(1)(5).
Author information:
(1)Laboratory of Immunology of HIV-TB co-infection, Centre for Infectious
Disease Research, Indian Institute of Science, Bangalore, India.
(2)Division of Infectious Diseases, St John's Research Institute, Bangalore,
India.
(3)Division of Nutrition, St John's Research Institute, Bangalore, India.
(4)Department of Pulmonary Medicine, St John's Medical College, Bangalore,
India.
(5)Peter Gorer Department of Immunobiology, School of Immunology and Microbial
Sciences, Faculty of Life Sciences and Medicine, Guy's Hospital, King's College
London, London, UK.
BCG turns 100 this year and while it might not be the perfect vaccine, it has
certainly contributed significantly towards eradication and prevention of spread
of tuberculosis (TB). The search for newer and better vaccines for TB is an
ongoing endeavor and latest results from trials of candidate TB vaccines such as
M72AS01 look promising. However, recent encouraging data from BCG revaccination
trials in adults combined with studies on mucosal and intravenous routes of BCG
vaccination in non-human primate models have renewed interest in BCG for TB
prevention. In addition, several well-demonstrated non-specific effects of BCG,
for example, prevention of viral and respiratory infections, give BCG an added
advantage. Also, BCG vaccination is currently being widely tested in human
clinical trials to determine whether it protects against SARS-CoV-2 infection
and/or death with detailed analyses and outcomes from several ongoing trials
across the world awaited. Through this review, we attempt to bring together
information on various aspects of the BCG-induced immune response, its efficacy
in TB control, comparison with other candidate TB vaccines and strategies to
improve its efficiency including revaccination and alternate routes of
administration. Finally, we discuss the future relevance of BCG use especially
in light of its several heterologous benefits.
© 2021 The Authors. Immunological Reviews published by John Wiley & Sons Ltd.
DOI: 10.1111/imr.12968
PMID: 33955564 [Indexed for MEDLINE]
17. Nat Commun. 2021 May 5;12(1):2540. doi: 10.1038/s41467-021-22801-0.
Single-cell profiling of tumor heterogeneity and the microenvironment in
advanced non-small cell lung cancer.
Wu F(#)(1), Fan J(#)(2), He Y(1), Xiong A(1), Yu J(1), Li Y(2), Zhang Y(2), Zhao
W(1), Zhou F(1), Li W(1), Zhang J(1), Zhang X(1), Qiao M(1), Gao G(1), Chen
S(1), Chen X(1), Li X(1), Hou L(3), Wu C(3), Su C(1), Ren S(1), Odenthal
M(4)(5), Buettner R(4)(5), Fang N(2), Zhou C(6).
Author information:
(1)Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji
University School of Medicine, Shanghai, China.
(2)Singleron Biotechnologies, Nanjing, Jiangsu, China.
(3)Department of Pathology, Shanghai Pulmonary Hospital, Tongji University
School of Medicine, Shanghai, China.
(4)Institute of Pathology, University Hospital of Cologne, Cologne, Germany.
(5)Center for Molecular Medicine Cologne, University of Cologne, Cologne,
Germany.
(6)Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji
University School of Medicine, Shanghai, China. caicunzhoudr@163.com.
(#)Contributed equally
Lung cancer is a highly heterogeneous disease. Cancer cells and cells within the
tumor microenvironment together determine disease progression, as well as
response to or escape from treatment. To map the cell type-specific
transcriptome landscape of cancer cells and their tumor microenvironment in
advanced non-small cell lung cancer (NSCLC), we analyze 42 tissue biopsy samples
from stage III/IV NSCLC patients by single cell RNA sequencing and present the
large scale, single cell resolution profiles of advanced NSCLCs. In addition to
cell types described in previous single cell studies of early stage lung cancer,
we are able to identify rare cell types in tumors such as follicular dendritic
cells and T helper 17 cells. Tumors from different patients display large
heterogeneity in cellular composition, chromosomal structure, developmental
trajectory, intercellular signaling network and phenotype dominance. Our study
also reveals a correlation of tumor heterogeneity with tumor associated
neutrophils, which might help to shed light on their function in NSCLC.
DOI: 10.1038/s41467-021-22801-0
PMCID: PMC8100173
PMID: 33953163 [Indexed for MEDLINE]
18. Sci Transl Med. 2021 May 5;13(592):eabg7673. doi: 10.1126/scitranslmed.abg7673.
Exaggerated IL-17A activity in human in vivo recall responses discriminates
active tuberculosis from latent infection and cured disease.
Pollara G(1), Turner CT(2), Rosenheim J(2), Chandran A(2), Bell LCK(2), Khan
A(2), Patel A(2), Peralta LF(3), Folino A(4), Akarca A(2), Venturini C(2), Baker
T(2), Ecker S(2), Ricciardolo FLM(4), Marafioti T(2), Ugarte-Gil C(3)(5), Moore
DAJ(5)(6), Chain BM(2), Tomlinson GS(1), Noursadeghi M(1).
Author information:
(1)University College London, London, UK. g.pollara@ucl.ac.uk.
(2)University College London, London, UK.
(3)School of Medicine, Universidad Peruana Cayetano Heredia, Lima, Peru.
…
Host immune responses at the site of Mycobacterium tuberculosis infection can
mediate pathogenesis of tuberculosis (TB) and onward transmission of infection.
We hypothesized that pathological immune responses would be enriched at the site
of host-pathogen interactions modeled by a standardized tuberculin skin test
(TST) challenge in patients with active TB compared to those without disease,
and interrogated immune responses by genome-wide transcriptional profiling. We
show exaggerated interleukin-17A (IL-17A) and T helper 17 (TH17) responses among
48 individuals with active TB compared to 191 with latent TB infection,
associated with increased neutrophil recruitment and matrix metalloproteinase-1
expression, both involved in TB pathogenesis. Curative antimicrobial treatment
reversed these observed changes. Increased IL-1β and IL-6 responses to
mycobacterial stimulation were evident both in circulating monocytes and in
molecular changes at the site of TST in individuals with active TB, supporting a
model in which monocyte-derived IL-1β and IL-6 promote TH17 differentiation
within tissues. Modulation of these cytokine pathways may provide a rational
strategy for host-directed therapy in active TB.
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American
Association for the Advancement of Science. No claim to original U.S. Government
Works.
DOI: 10.1126/scitranslmed.abg7673
PMCID: PMC7610803
PMID: 33952677 [Indexed for MEDLINE]
19. Cancer Discov. 2021 May 4:candisc.0725.2020. doi: 10.1158/2159-8290.CD-20-0725. Online ahead of print.
Induction of APOBEC3 exacerbates DNA replication stress and chromosomal
instability in early breast and lung cancer evolution.
Venkatesan S(1), Angelova M(1), Puttick C(1), Zhai H(2), Caswell DR(1), Lu
WT(1), Dietzen M(3), Galanos P(4), Evangelou K(5), Bellelli R(6), Lim EL(1),
Watkins TBK(1), Rowan A(7), Teixeira VH(8), Zhao Y(9), Chen H(9), Ngo B(10),
…
Author information:
(1)Cancer Evolution and Genome Instability Laboratory, The Francis Crick
Institute.
(2)UCL Cancer Institute, University College London.
(3)Cancer Genome Evolution Research Group, UCL Cancer Institute.
…
APOBEC3 enzymes are cytosine deaminases implicated in cancer. Precisely when
APOBEC3 expression is induced during cancer development remains to be defined.
Here we show that specific APOBEC3 genes are upregulated in breast DCIS, and in
pre-invasive lung cancer lesions coincident with cellular proliferation. We
observe evidence of APOBEC3-mediated subclonal mutagenesis propagated from
TRACERx pre-invasive to invasive NSCLC lesions. We find that APOBEC3B
exacerbates DNA replication stress and chromosomal instability through
incomplete replication of genomic DNA, manifested by accumulation of mitotic
ultrafine bridges and 53BP1 nuclear bodies in the G1 phase of the cell cycle.
Analysis of TRACERx NSCLC clinical samples and mouse lung cancer models,
revealed APOBEC3B expression driving replication stress and chromosome
missegregation. We propose that APOBEC3 is functionally implicated in the onset
of chromosomal instability and somatic mutational heterogeneity in pre-invasive
disease, providing fuel for selection early in cancer evolution.
Copyright ©2021, American Association for Cancer Research.
DOI: 10.1158/2159-8290.CD-20-0725
PMID: 33947663
20. Mol Syst Biol. 2021 May;17(5):e10280. doi: 10.15252/msb.202110280.
Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis.
Borah K(1), Mendum TA(1), Hawkins ND(2), Ward JL(2), Beale MH(2), Larrouy-Maumus
G(3), Bhatt A(4), Moulin M(5)(6), Haertlein M(5)(6), Strohmeier G(7)(8), Pichler
H(7)(8)(9), Forsyth VT(5)(6)(10), Noack S(11), Goulding CW(12), McFadden J(1),
Beste DJV(1).
Author information:
(1)Department of Microbial and Cellular Sciences, Faculty of Health and Medical
Sciences, University of Surrey, Guildford, UK.
(2)Department of Computational and Analytical Sciences, Rothamsted Research,
Harpenden, UK.
(3)MRC Centre for Molecular Bacteriology and Infection, Department of Life
Sciences, Faculty of Natural Sciences, Imperial College London, London, UK.
…
The co-catabolism of multiple host-derived carbon substrates is required by
Mycobacterium tuberculosis (Mtb) to successfully sustain a tuberculosis
infection. However, the metabolic plasticity of this pathogen and the complexity
of the metabolic networks present a major obstacle in identifying those nodes
most amenable to therapeutic interventions. It is therefore critical that we
define the metabolic phenotypes of Mtb in different conditions. We applied
metabolic flux analysis using stable isotopes and lipid fingerprinting to
investigate the metabolic network of Mtb growing slowly in our steady-state
chemostat system. We demonstrate that Mtb efficiently co-metabolises either
cholesterol or glycerol, in combination with two-carbon generating substrates
without any compartmentalisation of metabolism. We discovered that partitioning
of flux between the TCA cycle and the glyoxylate shunt combined with a
reversible methyl citrate cycle is the critical metabolic nodes which underlie
the nutritional flexibility of Mtb. These findings provide novel insights into
the metabolic architecture that affords adaptability of bacteria to divergent
carbon substrates and expand our fundamental knowledge about the methyl citrate
cycle and the glyoxylate shunt.
© 2021 The Authors. Published under the terms of the CC BY 4.0 license.
DOI: 10.15252/msb.202110280
PMCID: PMC8094261
PMID: 33943004
21. J Clin Invest. 2021 May 17;131(10):e142014. doi: 10.1172/JCI142014.
Tissue-resident-like CD4+ T cells secreting IL-17 control Mycobacterium
tuberculosis in the human lung.
Ogongo P(1)(2)(3), Tezera LB(4)(5)(6), Ardain A(1)(2), Nhamoyebonde S(1)(2),
Ramsuran D(1), Singh A(1), Ng'oepe A(1), Karim F(1), Naidoo T(1), Khan K(1),
Dullabh KJ(7), Fehlings M(8), Lee BH(8), Nardin A(8), Lindestam Arlehamn CS(9),
Sette A(9)(10), Behar SM(11), Steyn AJ(1)(12)(13), Madansein R(7), Kløverpris
HN(1)(6)(14), Elkington PT(4)(5), Leslie A(1)(2)(6).
Author information:
(1)Africa Health Research Institute, Durban, South Africa.
(2)School of Laboratory Medicine and Medical Sciences, University of
KwaZulu-Natal, Durban, South Africa.
(3)Institute of Primate Research, National Museums of Kenya, Nairobi, Kenya.
…
T cell immunity is essential for the control of tuberculosis (TB), an important
disease of the lung, and is generally studied in humans using peripheral blood
cells. Mounting evidence, however, indicates that tissue-resident memory T cells
(Trms) are superior at controlling many pathogens, including Mycobacterium
tuberculosis (M. tuberculosis), and can be quite different from those in
circulation. Using freshly resected lung tissue, from individuals with active or
previous TB, we identified distinct CD4+ and CD8+ Trm-like clusters within
TB-diseased lung tissue that were functional and enriched for IL-17-producing
cells. M. tuberculosis-specific CD4+ T cells producing TNF-α, IL-2, and IL-17
were highly expanded in the lung compared with matched blood samples, in which
IL-17+ cells were largely absent. Strikingly, the frequency of M.
tuberculosis-specific lung T cells making IL-17, but not other cytokines,
inversely correlated with the plasma IL-1β levels, suggesting a potential link
with disease severity. Using a human granuloma model, we showed the addition of
either exogenous IL-17 or IL-2 enhanced immune control of M. tuberculosis and
was associated with increased NO production. Taken together, these data support
an important role for M. tuberculosis-specific Trm-like, IL-17-producing cells
in the immune control of M. tuberculosis in the human lung.
DOI: 10.1172/JCI142014
PMCID: PMC8121523
PMID: 33848273
22. Immunol Rev. 2021 May;301(1):122-144. doi: 10.1111/imr.12965. Epub 2021 Mar 12.
BCG-induced protection against Mycobacterium tuberculosis infection: Evidence,
mechanisms, and implications for next-generation vaccines.
Foster M(1), Hill PC(2), Setiabudiawan TP(3), Koeken VACM(3)(4), Alisjahbana
B(5), van Crevel R(3).
Author information:
(1)Department of Microbiology and Immunology, University of Otago, Dunedin, New
Zealand.
(2)Centre for International Health, University of Otago, Dunedin, New Zealand.
(3)Department of Internal Medicine and Radboud Center for Infectious Diseases
(RCI), Radboud University Medical Center, Nijmegen, The Netherlands.
(4)Department of Computational Biology for Individualised Infection Medicine,
Centre for Individualised Infection Medicine (CiiM) & TWINCORE, Joint Ventures
between The Helmholtz-Centre for Infection Research (HZI) and The Hannover
Medical School (MHH), Hannover, Germany.
(5)Tuberculosis Working Group, Faculty of Medicine, Universitas Padjadjaran,
Bandung, Indonesia.
The tuberculosis (TB) vaccine Bacillus Calmette-Guérin (BCG) was introduced 100
years ago, but as it provides insufficient protection against TB disease,
especially in adults, new vaccines are being developed and evaluated. The
discovery that BCG protects humans from becoming infected with Mycobacterium
tuberculosis (Mtb) and not just from progressing to TB disease provides
justification for considering Mtb infection as an endpoint in vaccine trials.
Such trials would require fewer participants than those with disease as an
endpoint. In this review, we first define Mtb infection and disease phenotypes
that can be used for mechanistic studies and/or endpoints for vaccine trials.
Secondly, we review the evidence for BCG-induced protection against Mtb
infection from observational and BCG re-vaccination studies, and discuss
limitations and variation of this protection. Thirdly, we review possible
underlying mechanisms for BCG efficacy against Mtb infection, including
alternative T cell responses, antibody-mediated protection, and innate immune
mechanisms, with a specific focus on BCG-induced trained immunity, which
involves epigenetic and metabolic reprogramming of innate immune cells. Finally,
we discuss the implications for further studies of BCG efficacy against Mtb
infection, including for mechanistic research, and their relevance to the design
and evaluation of new TB vaccines.
© 2021 The Authors. Immunological Reviews published by John Wiley & Sons Ltd.
DOI: 10.1111/imr.12965
PMCID: PMC8252066
PMID: 33709421
23. Immunol Rev. 2021 May;301(1):84-97. doi: 10.1111/imr.12952. Epub 2021 Feb 8.
Not too fat to fight: The emerging role of macrophage fatty acid metabolism in
immunity to Mycobacterium tuberculosis.
Laval T(1)(2), Chaumont L(1), Demangel C(1).
Author information:
(1)Immunobiology of Infection Unit, Institut Pasteur, INSERM U1221, Paris,
France.
(2)Université de Paris, Sorbonne Paris Cité, Paris, France.
While the existence of a special relationship between Mycobacterium tuberculosis
(Mtb) and host lipids has long been known, it remains a challenging enigma. It
was clearly established that Mtb requires host fatty acids (FAs) and cholesterol
to produce energy, build its distinctive lipid-rich cell wall, and produce lipid
virulence factors. It was also observed that in infected hosts, Mtb constantly
resides in a FA-rich environment that the pathogen contributes to generate by
inducing a lipid-laden "foamy" phenotype in host macrophages. These observations
and the proximity between lipid droplets and phagosomes containing bacteria
within infected macrophages gave rise to the hypothesis that Mtb reprograms host
cell lipid metabolism to ensure a continuous supply of essential nutrients and
its long-term persistence in vivo. However, recent studies question this
principle by indicating that in Mtb-infected macrophages, lipid droplet
formation prevents bacterial acquisition of host FAs while supporting the
production of FA-derived protective lipid mediators. Further, in vivo
investigations reveal discrete macrophage phenotypes linking the FA metabolisms
of host cell and intracellular pathogen. Notably, FA storage within lipid
droplets characterizes both macrophages controlling Mtb infection and dormant
intracellular Mtb. In this review, we integrate findings from immunological and
microbiological studies illustrating the new concept that cytoplasmic
accumulation of FAs is a metabolic adaptation of macrophages to Mtb infection,
which potentiates their antimycobacterial responses and forces the intracellular
pathogen to shift into fat-saving, survival mode.
© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
DOI: 10.1111/imr.12952
PMID: 33559209
