2022年
No.3
PubMed Filters applied: from 2022/3/1 - 2022/3/31
1. Cancer Cell. 2022 Mar 14;40(3):289-300.e4. doi: 10.1016/j.ccell.2022.02.002.
Epub 2022 Feb 24.
Intratumoral plasma cells predict outcomes to PD-L1 blockade in non-small cell
lung cancer.
Patil NS(1), Nabet BY(2), Müller S(3), Koeppen H(4), Zou W(5), Giltnane J(4),
Au-Yeung A(6), Srivats S(5), Cheng JH(5), Takahashi C(6), de Almeida PE(7),
Chitre AS(7), Grogan JL(7), Rangell L(4), Jayakar S(4), Peterson M(5), Hsia
AW(5), O'Gorman WE(6), Ballinger M(8), Banchereau R(5), Shames DS(5).
Author information:
(1)Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA,
USA. Electronic address: patil.namrata@gene.com.
(2)Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA,
USA. Electronic address: nabet.barzin@gene.com.
(3)Oncology Bioinformatics, Genentech, Inc., South San Francisco, CA, USA.
(4)Research Pathology, Genentech, Inc., South San Francisco, CA, USA.
(5)Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA,
USA.
(6)OMNI Biomarker Development, Genentech, Inc., South San Francisco, CA, USA.
(7)Cancer Immunology Research, Genentech, Inc., South San Francisco, CA, USA.
(8)Clinical Science, Genentech, Inc., South San Francisco, CA, USA.
Comment in
Cancer Cell. 2022 Mar 14;40(3):240-243.
Inhibitors of the programmed cell death-1 (PD-1/PD-L1) signaling axis are
approved to treat non-small cell lung cancer (NSCLC) patients, based on their
significant overall survival (OS) benefit. Using transcriptomic analysis of 891
NSCLC tumors from patients treated with either the PD-L1 inhibitor atezolizumab
or chemotherapy from two large randomized clinical trials, we find a significant
B cell association with extended OS with PD-L1 blockade, independent of CD8+
T cell signals. We then derive gene signatures corresponding to the dominant B
cell subsets present in NSCLC from single-cell RNA sequencing (RNA-seq) data.
Importantly, we find increased plasma cell signatures to be predictive of OS in
patients treated with atezolizumab, but not chemotherapy. B and plasma cells are
also associated with the presence of tertiary lymphoid structures and organized
lymphoid aggregates. Our results suggest an important contribution of B and
plasma cells to the efficacy of PD-L1 blockade in NSCLC.
Copyright © 2022 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2022.02.002
PMID: 35216676 [Indexed for MEDLINE]
2. N Engl J Med. 2022 Mar 10;386(10):911-922. doi: 10.1056/NEJMoa2104535.
Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children.
Turkova A(1), Wills GH(1), Wobudeya E(1), Chabala C(1), Palmer M(1), Kinikar
A(1), Hissar S(1), Choo L(1), Musoke P(1), Mulenga V(1), Mave V(1), Joseph B(1),
LeBeau K(1), Thomason MJ(1), Mboizi RB(1), Kapasa M(1), van der Zalm MM(1),
Raichur P(1), Bhavani PK(1), McIlleron H(1), Demers AM(1), Aarnoutse R(1),
Love-Koh J(1), Seddon JA(1), Welch SB(1), Graham SM(1), Hesseling AC(1), Gibb
DM(1), Crook AM(1); SHINE Trial Team.
Author information:
(1)From the Medical Research Council Clinical Trials Unit, University College
London (A.T., G.H.W., L.C., K.L., M.J.T., D.M.G., A.M.C.), and the Department of
Infectious Diseases, Imperial College London (J.A.S.), London, the Centre for
Health Economics, University of York, York (J.L.-K.), and the Department of
Paediatrics, Birmingham Chest Clinic and Heartlands Hospital, University
Hospitals Birmingham, Birmingham (S.B.W.) - all in the United Kingdom; Makerere
University-Johns Hopkins University Research Collaboration, Kampala, Uganda
(E.W., P.M., R.B.M.); University Teaching Hospital, Lusaka, Zambia (C.C., V.
Mulenga, M.K.);…
Comment in
N Engl J Med. 2022 Mar 10;386(10):988-989.
BACKGROUND: Two thirds of children with tuberculosis have nonsevere disease,
which may be treatable with a shorter regimen than the current 6-month regimen.
METHODS: We conducted an open-label, treatment-shortening, noninferiority trial
involving children with nonsevere, symptomatic, presumably drug-susceptible,
smear-negative tuberculosis in Uganda, Zambia, South Africa, and India. Children
younger than 16 years of age were randomly assigned to 4 months (16 weeks) or 6
months (24 weeks) of standard first-line antituberculosis treatment with
pediatric fixed-dose combinations as recommended by the World Health
Organization. The primary efficacy outcome was unfavorable status (composite of
treatment failure [extension, change, or restart of treatment or tuberculosis
recurrence], loss to follow-up during treatment, or death) by 72 weeks, with the
exclusion of participants who did not complete 4 months of treatment (modified
intention-to-treat population). A noninferiority margin of 6 percentage points
was used. The primary safety outcome was an adverse event of grade 3 or higher
during treatment and up to 30 days after treatment.
RESULTS: From July 2016 through July 2018, a total of 1204 children underwent
randomization (602 in each group). The median age of the participants was 3.5
years (range, 2 months to 15 years), 52% were male, 11% had human
immunodeficiency virus infection, and 14% had bacteriologically confirmed
tuberculosis. Retention by 72 weeks was 95%, and adherence to the assigned
treatment was 94%. A total of 16 participants (3%) in the 4-month group had a
primary-outcome event, as compared with 18 (3%) in the 6-month group (adjusted
difference, -0.4 percentage points; 95% confidence interval, -2.2 to 1.5). The
noninferiority of 4 months of treatment was consistent across the
intention-to-treat, per-protocol, and key secondary analyses, including when the
analysis was restricted to the 958 participants (80%) independently adjudicated
to have tuberculosis at baseline. A total of 95 participants (8%) had an adverse
event of grade 3 or higher, including 15 adverse drug reactions (11 hepatic
events, all but 2 of which occurred within the first 8 weeks, when the
treatments were the same in the two groups).
CONCLUSIONS: Four months of antituberculosis treatment was noninferior to 6
months of treatment in children with drug-susceptible, nonsevere, smear-negative
tuberculosis. (Funded by the U.K. Medical Research Council and others; SHINE
ISRCTN number, ISRCTN63579542.).
Copyright © 2022 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2104535
PMCID: PMC7612496
PMID: 35263517 [Indexed for MEDLINE]
3. Nat Commun. 2022 Mar 30;13(1):1675. doi: 10.1038/s41467-022-29353-x.
Integrating central nervous system metagenomics and host response for diagnosis
of tuberculosis meningitis and its mimics.
Ramachandran PS(#)(1)(2)(3)(4), Ramesh A(#)(1), Creswell FV(5)(6)(7), Wapniarski
A(1), Narendra R(1), Quinn CM(8), Tran EB(8), Rutakingirwa MK(6), Bangdiwala
AS(9), Kagimu E(6), Kandole KT(6), Zorn KC(4)(10), Tugume L(6), Kasibante J(6),
Ssebambulidde K(6), Okirwoth M(6), Bahr NC(11), Musubire A(6), Skipper CP(6)(9),
Fouassier C(1), Lyden A(12), Serpa P(12), Castaneda G(12), Caldera S(12), Ahyong
V(12), DeRisi JL(4)(10)(12), Langelier C(12)(13), Crawford ED(12), Boulware
DR(9), Meya DB(6)(9), Wilson MR(14)(15)(16).
Author information:
(1)Weill Institute for Neurosciences, Department of Neurology, University of
California, San Francisco, San Francisco, CA, USA.
(2)University of Melbourne, Melbourne, VIC, Australia.
(3)UCSF Center for Tuberculosis, San Francisco, CA, USA.
…
The epidemiology of infectious causes of meningitis in sub-Saharan Africa is not
well understood, and a common cause of meningitis in this region, Mycobacterium
tuberculosis (TB), is notoriously hard to diagnose. Here we show that
integrating cerebrospinal fluid (CSF) metagenomic next-generation sequencing
(mNGS) with a host gene expression-based machine learning classifier (MLC)
enhances diagnostic accuracy for TB meningitis (TBM) and its mimics. 368
HIV-infected Ugandan adults with subacute meningitis were prospectively
enrolled. Total RNA and DNA CSF mNGS libraries were sequenced to identify
meningitis pathogens. In parallel, a CSF host transcriptomic MLC to distinguish
between TBM and other infections was trained and then evaluated in a blinded
fashion on an independent dataset. mNGS identifies an array of infectious TBM
mimics (and co-infections), including emerging, treatable, and
vaccine-preventable pathogens including Wesselsbron virus, Toxoplasma gondii,
Streptococcus pneumoniae, Nocardia brasiliensis, measles virus and
cytomegalovirus. By leveraging the specificity of mNGS and the sensitivity of an
MLC created from CSF host transcriptomes, the combined assay has high
sensitivity (88.9%) and specificity (86.7%) for the detection of TBM and its
many mimics. Furthermore, we achieve comparable combined assay performance at
sequencing depths more amenable to performing diagnostic mNGS in low resource
settings.
© 2022. The Author(s).
DOI: 10.1038/s41467-022-29353-x
PMCID: PMC8967864
PMID: 35354815 [Indexed for MEDLINE]
4. Nat Commun. 2022 Mar 29;13(1):1667. doi: 10.1038/s41467-022-29292-7.
Knowledge graph-based recommendation framework identifies drivers of resistance
in EGFR mutant non-small cell lung cancer.
Gogleva A(1), Polychronopoulos D(2), Pfeifer M(3), Poroshin V(4), Ughetto M(5),
Martin MJ(3), Thorpe H(3), Bornot A(6), Smith PD(3), Sidders B(2), Dry JR(7),
Ahdesmäki M(2), McDermott U(3), Papa E(8), Bulusu KC(9).
Author information:
(1)Biological Insight Knowledge Graph (BIKG), AI Engineering, R&D IT,
AstraZeneca, Cambridge, UK.
(2)Early Computational Oncology, Research and Early Development, Oncology R&D,
AstraZeneca, Cambridge, UK.
(3)Bioscience, Research and Early Development, Oncology R&D, AstraZeneca,
Cambridge, UK.
…
Resistance to EGFR inhibitors (EGFRi) presents a major obstacle in treating
non-small cell lung cancer (NSCLC). One of the most exciting new ways to find
potential resistance markers involves running functional genetic screens, such
as CRISPR, followed by manual triage of significantly enriched genes. This
triage process to identify 'high value' hits resulting from the CRISPR screen
involves manual curation that requires specialized knowledge and can take even
experts several months to comprehensively complete. To find key drivers of
resistance faster we build a recommendation system on top of a heterogeneous
biomedical knowledge graph integrating pre-clinical, clinical, and literature
evidence. The recommender system ranks genes based on trade-offs between diverse
types of evidence linking them to potential mechanisms of EGFRi resistance. This
unbiased approach identifies 57 resistance markers from >3,000 genes, reducing
hit identification time from months to minutes. In addition to reproducing known
resistance markers, our method identifies previously unexplored resistance
mechanisms that we prospectively validate.
© 2022. The Author(s).
DOI: 10.1038/s41467-022-29292-7
PMCID: PMC8964738
PMID: 35351890 [Indexed for MEDLINE]
5. Clin Microbiol Rev. 2022 Mar 21:e0022721. doi: 10.1128/cmr.00227-21. Online
ahead of print.
Tuberculosis Treatment Monitoring and Outcome Measures: New Interest and New
Strategies.
Heyckendorf J(#)(1)(2)(3)(4), Georghiou SB(#)(5), Frahm N(6), Heinrich N(7),
Kontsevaya I(2)(3)(4), Reimann M(2)(3)(4), Holtzman D(5), Imperial M(8), Cirillo
DM(9), Gillespie SH(10), Ruhwald M(5); UNITE4TB Consortium.
Author information:
(1)Department of Medicine I, University Hospital Schleswig-Holstein, Kiel,
Germany.
(2)Division of Clinical Infectious Diseases, Research Center Borstel, Borstel,
Germany.
(3)German Center for Infection Research (DZIF), Braunschweig, Germany.
…
Despite the advent of new diagnostics, drugs and regimens, tuberculosis (TB)
remains a global public health threat. A significant challenge for TB control
efforts has been the monitoring of TB therapy and determination of TB treatment
success. Current recommendations for TB treatment monitoring rely on sputum and
culture conversion, which have low sensitivity and long turnaround times,
present biohazard risk, and are prone to contamination, undermining their
usefulness as clinical treatment monitoring tools and for drug development. We
review the pipeline of molecular technologies and assays that serve as suitable
substitutes for current culture-based readouts for treatment response and
outcome with the potential to change TB therapy monitoring and accelerate drug
development.
DOI: 10.1128/cmr.00227-21
PMID: 35311552
6. Nat Commun. 2022 Mar 10;13(1):1268. doi: 10.1038/s41467-022-28840-5.
Clinical and genomic features of Chinese lung cancer patients with germline
mutations.
Peng W(1)(2), Li B(3)(4), Li J(5), Chang L(5), Bai J(5), Yi Y(5), Chen R(5),
Zhang Y(5), Chen C(5), Pu X(1), Jiang M(1), Li J(1), Zhong R(1), Xu F(1), Chen
B(1), Xu L(1), Wang N(6), Huan J(5), Dai P(5), Guan Y(5), Yang L(5), Xia X(5),
Yi X(5), Wang J(7), Yu F(8), Wu L(9).
Author information:
(1)The Second Department of Thoracic Oncology, Hunan Cancer Hospital/the
Affiliated Cancer Hospital of Xiangya School of Medicine, Central South
University, 410000, Changsha, China.
(2)The second department of Oncology, Yunnan Cancer Hospital & The Third
Affiliated Hospital of Kunming Medical University & Yunnan Cancer Center,
650000, Kunming, China.
(3)Department of Oncology, Xiangya Hospital, Central South University, 410000,
Changsha, China.
…
The germline mutation landscape in Chinese lung cancer patients has not been
well defined. In this study, sequencing data of 1,021 cancer genes of 1,794
Chinese lung cancer patients was analyzed. A total of 111 pathogenic or likely
pathogenic germline mutations were identified, significantly higher than
non-cancer individuals (111/1794 vs. 84/10,588, p < 2.2e-16). BRCA1/2 germline
mutations are associated with earlier onset age (median 52.5 vs 60 years-old,
p = 0.008). Among 29 cancer disposition genes with germline mutations detected
in Chinese cohort and/or TCGA lung cancer cohort, Only 11 from 29 genes are
identified in both cohorts and BRCA2 mutations are significantly more common in
Chinese cohort (p = 0.015). Chinese patients with germline mutations have
different prevalence of somatic KRAS, MET exon 14 skipping and TP53 mutations
compared to those without. Our findings suggest potential ethnic and etiologic
differences between Western and Asian lung cancer patients.
© 2022. The Author(s).
DOI: 10.1038/s41467-022-28840-5
PMCID: PMC8913621
PMID: 35273153 [Indexed for MEDLINE]
7. J Clin Oncol. 2022 Mar 10:JCO2102010. doi: 10.1200/JCO.21.02010. Online ahead of print.
Artificial Intelligence-Powered Spatial Analysis of Tumor-Infiltrating
Lymphocytes as Complementary Biomarker for Immune Checkpoint Inhibition in
Non-Small-Cell Lung Cancer.
Park S(1), Ock CY(2), Kim H(3), Pereira S(2), Park S(2), Ma M(2), Choi S(4), Kim
S(5), Shin S(2), Aum BJ(2), Paeng K(2), Yoo D(2), Cha H(1), Park S(1), Suh
KJ(6), Jung HA(1), Kim SH(6), Kim YJ(6), Sun JM(1), Chung JH(3), Ahn JS(1), Ahn
MJ(1), Lee JS(6), Park K(1), Song SY(4), Bang YJ(7), Choi YL(4), Mok TS(8), Lee
SH(1)(9).
Author information:
(1)Division of Hematology-Oncology, Department of Medicine, Samsung Medical
Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of
Korea.
(2)Lunit, Seoul, Republic of Korea.
(3)Department of Pathology, Seoul National University Bundang Hospital,
Seongnam, Republic of Korea.
…
PURPOSE: Biomarkers on the basis of tumor-infiltrating lymphocytes (TIL) are
potentially valuable in predicting the effectiveness of immune checkpoint
inhibitors (ICI). However, clinical application remains challenging because of
methodologic limitations and laborious process involved in spatial analysis of
TIL distribution in whole-slide images (WSI).
METHODS: We have developed an artificial intelligence (AI)-powered WSI analyzer
of TIL in the tumor microenvironment that can define three immune phenotypes
(IPs): inflamed, immune-excluded, and immune-desert. These IPs were correlated
with tumor response to ICI and survival in two independent cohorts of patients
with advanced non-small-cell lung cancer (NSCLC).
RESULTS: Inflamed IP correlated with enrichment in local immune cytolytic
activity, higher response rate, and prolonged progression-free survival compared
with patients with immune-excluded or immune-desert phenotypes. At the WSI
level, there was significant positive correlation between tumor proportion score
(TPS) as determined by the AI model and control TPS analyzed by pathologists (P
< .001). Overall, 44.0% of tumors were inflamed, 37.1% were immune-excluded, and
18.9% were immune-desert. Incidence of inflamed IP in patients with programmed
death ligand-1 TPS at < 1%, 1%-49%, and ≥ 50% was 31.7%, 42.5%, and 56.8%,
respectively. Median progression-free survival and overall survival were,
respectively, 4.1 months and 24.8 months with inflamed IP, 2.2 months and 14.0
months with immune-excluded IP, and 2.4 months and 10.6 months with
immune-desert IP.
CONCLUSION: The AI-powered spatial analysis of TIL correlated with tumor
response and progression-free survival of ICI in advanced NSCLC. This is
potentially a supplementary biomarker to TPS as determined by a pathologist.
DOI: 10.1200/JCO.21.02010
PMID: 35271299
8. J Clin Oncol. 2022 Mar 8:JCO2102496. doi: 10.1200/JCO.21.02496. Online ahead of print.
Lung Cancer Diagnosed Through Screening, Lung Nodule, and Neither Program: A
Prospective Observational Study of the Detecting Early Lung Cancer (DELUGE) in
the Mississippi Delta Cohort.
Osarogiagbon RU(1), Liao W(1), Faris NR(1), Meadows-Taylor M(1), Fehnel C(1),
Lane J(1), Williams SC(1), Patel AA(1), Akinbobola OA(1), Pacheco A(1), Epperson
A(1), Luttrell J(1), McCoy D(1), McHugh L(1), Signore R(1), Bishop AM(1), Tonkin
K(1)(2), Optican R(1)(2), Wright J(1)(3), Robbins T(1), Ray MA(4), Smeltzer
MP(4).
Author information:
(1)Multidisciplinary Thoracic Oncology Program, Baptist Cancer Center, Memphis,
TN.
(2)Mid-South Imaging and Therapeutics, Memphis, TN.
(3)Memphis Lung Physicians, Memphis, TN.
(4)Division of Epidemiology, Biostatistics, and Environmental Health, School of
Public Health, University of Memphis, Memphis, TN.
PURPOSE: Lung cancer screening saves lives, but implementation is challenging.
We evaluated two approaches to early lung cancer detection-low-dose computed
tomography screening (LDCT) and program-based management of incidentally
detected lung nodules.
METHODS: A prospective observational study enrolled patients in the early
detection programs. For context, we compared them with patients managed in a
Multidisciplinary Care Program. We compared clinical stage distribution,
surgical resection rates, 3- and 5-year survival rates, and eligibility for LDCT
screening of patients diagnosed with lung cancer.
RESULTS: From 2015 to May 2021, 22,886 patients were enrolled: 5,659 in LDCT,
15,461 in Lung Nodule, and 1,766 in Multidisciplinary Care. Of 150, 698, and
1,010 patients diagnosed with lung cancer in the respective programs, 61%, 60%,
and 44% were diagnosed at clinical stage I or II, whereas 19%, 20%, and 29% were
stage IV (P = .0005); 47%, 42%, and 32% had curative-intent surgery (P < .0001);
aggregate 3-year overall survival rates were 80% (95% CI, 73 to 88) versus 64%
(60 to 68) versus 49% (46 to 53); 5-year overall survival rates were 76% (67 to
87) versus 60% (56 to 65) versus 44% (40 to 48), respectively. Only 46% of 1,858
patients with lung cancer would have been deemed eligible for LDCT by US
Preventive Services Task Force (USPSTF) 2013 criteria, and 54% by 2021 criteria.
Even if all eligible patients by USPSTF 2021 criteria had been enrolled into
LDCT, the Nodule Program would have detected 20% of the stage I-II lung cancer
in the entire cohort.
CONCLUSION: LDCT and Lung Nodule Programs are complementary, expanding access to
early lung cancer detection and curative treatment to different-risk
populations. Implementing Lung Nodule Programs may alleviate emerging
disparities in access to early lung cancer detection.
DOI: 10.1200/JCO.21.02496
PMID: 35258994
9. Am J Respir Crit Care Med. 2022 Mar 8. doi: 10.1164/rccm.202108-1976OC. Online ahead of print.
Early Bactericidal Activity of Meropenem Plus Clavulanate (+/-Rifampin) For TB:
The COMRADE Randomized, Phase 2 Trial.
De Jager V(1), Gupte N(2), Nunes S(1), Barnes GL(3), van Wijk RC(4), Mostert
J(1), Dorman SE(5), Abulfathi AA(6)(7), Upton CM(8), Faraj A(4), Nuermberger
EL(3), Lamichhane G(3), Svensson EM(9), Simonsson U(10), Diacon AH(11), Dooley
KE(12); and the COMRADE Study Team.
Author information:
(1)TASK Applied Science, TASK Clinical Research Centre, Cape Town, South Africa.
(2)Johns Hopkins School of Medicine, Baltimore, Maryland, United States.
(3)Johns Hopkins University, Medicine, Baltimore, Maryland, United States.
(4)Uppsala University, 8097, Department of Pharmaceutical Biosciences, Uppsala,
Sweden.
(5)Medical University of South Carolina, 2345, Charleston, South Carolina,
United States.
(6)Stellenbosch University, 26697, Department of Medicine, Stellenbosch, South
Africa.
(7)University of Maiduguri, 58988, Department of Clinical Pharmacology and
Therapeutics, Maiduguri, Nigeria.
(8)TASK, Cape Town, South Africa.
(9)Radboudumc, 6034, Pharmacy, Nijmegen, Netherlands.
(10)Uppsala Universitet, 8097, Department of Pharmaceutical Biosciences,
Uppsala, Sweden.
(11)University of Stellenbosch, Internal Medicine, Tygerberg, South Africa.
(12)Johns Hopkins University, Medicine, Baltimore, Maryland, United States;
kdooley1@jhmi.edu.
RATIONALE: Carbapenems are recommended for treatment of drug-resistant
tuberculosis. Optimal dosing remains uncertain.
OBJECTIVE: Evaluate the fourteen-day bactericidal activity of meropenem, at
different doses, with or without rifampin,.
METHODS: Individuals with pulmonary tuberculosis were randomized to one of four
intravenous meropenem-based arms: 2 grams 8 hourly (Arm C), 2 grams 8 hourly
plus rifampin 20 mg/kg once daily (Arm D), 1 gram 8 hourly (Arm E) or 3 grams
once daily (Arm F). All participants received amoxicillin/clavulanate with each
meropenem dose. Serial overnight sputum samples were collected from baseline and
throughout treatment. Median daily fall in colony forming unit (CFU) counts per
mL of sputum (solid culture)(EBACFU0-14) and increase in time to liquid culture
positivity (TTP) were estimated with mixed-effects modelling. Serial blood
samples were collected for pharmacokinetic analysis on Day 13.
MEASUREMENTS AND MAIN RESULTS: Sixty participants enrolled. Median (2.5th-97.5th
percentiles) EBACFU0-14 was 0.22 (0.12-0.33), 0.12 (0.057-0.21), 0.059
(0.033-0.097) and 0.053 (0.035-0.081); TTP increased by 0.34 (0.21-0.75), 0.11
(0.052-0.37), 0.094 (0.034-0.23), and 0.12 (0.04-0.41) (log10h), for Arms C, D,
E, and F, respectively. Meropenem pharmacokinetics were not impacted by rifampin
co-administration. Twelve participants withdrew early, many of whom cited
gastrointestinal adverse events.
CONCLUSIONS: Bactericidal activity was greater with the World Health
Organization recommended total daily dose of 6 grams daily than a lower dose of
3 grams daily. This difference was only detectable with solid culture.
Tolerability of intravenous meropenem, with amoxicillin/clavulanate, though, was
poor at all doses, calling into question the utility of this drug in second-line
regimens. Clinical trial registration available at www.
CLINICALTRIALS: gov, ID: NCT03174184.
DOI: 10.1164/rccm.202108-1976OC
PMID: 35258443
10. Nat Commun. 2022 Mar 7;13(1):1195. doi: 10.1038/s41467-022-28562-8.
Geographically dispersed zoonotic tuberculosis in pre-contact South American
human populations.
Vågene ÅJ(#)(1)(2)(3), Honap TP(#)(4)(5)(6), Harkins KM(7), Rosenberg MS(8)(9),
Giffin K(10)(11), Cárdenas-Arroyo F(12), Leguizamón LP(12), Arnett J(7)(13),
Buikstra JE(7), Herbig A(10)(14)(11), Krause J(15)(16)(17), Stone
AC(18)(19)(20), Bos KI(21)(22)(23).
Author information:
(1)Department of Archaeogenetics, Max Planck Institute for the Science of Human
History, Jena, Germany. ashild.vagene@sund.ku.dk.
(2)Institute for Archaeological Sciences, University of Tübingen, Tübingen,
Germany. ashild.vagene@sund.ku.dk.
(3)Section for Evolutionary Genomics, GLOBE Institute, University of Copenhagen,
Copenhagen, Denmark. ashild.vagene@sund.ku.dk.
…
Previous ancient DNA research has shown that Mycobacterium pinnipedii, which
today causes tuberculosis (TB) primarily in pinnipeds, infected human
populations living in the coastal areas of Peru prior to European colonization.
Skeletal evidence indicates the presence of TB in several pre-colonial South and
North American populations with minimal access to marine resources- a scenario
incompatible with TB transmission directly from infected pinnipeds or their
tissues. In this study, we investigate the causative agent of TB in ten
pre-colonial, non-coastal individuals from South America. We reconstruct M.
pinnipedii genomes (10- to 15-fold mean coverage) from three contemporaneous
individuals from inland Peru and Colombia, demonstrating the widespread
dissemination of M. pinnipedii beyond the coast, either through human-to-human
and/or animal-mediated routes. Overall, our study suggests that TB transmission
in the pre-colonial era Americas involved a more complex transmission pathway
than simple pinniped-to-human transfer.
© 2022. The Author(s).
DOI: 10.1038/s41467-022-28562-8
PMCID: PMC8901693
PMID: 35256608 [Indexed for MEDLINE]
11. Lancet Infect Dis. 2022 Mar 3:S1473-3099(21)00808-2. doi:
10.1016/S1473-3099(21)00808-2. Online ahead of print.
25 years of surveillance of drug-resistant tuberculosis: achievements,
challenges, and way forward.
Dean AS(1), Tosas Auguet O(2), Glaziou P(2), Zignol M(2), Ismail N(2), Kasaeva
T(2), Floyd K(2).
Author information:
(1)Global TB Programme, World Health Organization, Geneva, Switzerland.
Electronic address: deanan@who.int.
(2)Global TB Programme, World Health Organization, Geneva, Switzerland.
Tuberculosis is second only to COVID-19 as a cause of death from a single
infectious agent. In 2020, almost 10 million people were estimated to have
developed tuberculosis and it caused 1·5 million deaths. Around a quarter of
deaths caused by antimicrobial resistance are due to rifampicin-resistant
tuberculosis. Antimicrobial resistance surveillance systems for many bacterial
pathogens are still in the early stages of implementation in many countries, and
do not yet allow for the estimation of disease burden at the national level. In
this Personal View, we present the achievements, challenges, and way forward for
the oldest and largest global antimicrobial resistance surveillance system.
Hosted by WHO since 1994, the Global Project on Anti-Tuberculosis Drug
Resistance Surveillance has served as a platform for the evaluation of the
trends in anti-tuberculosis drug resistance for over 25 years at country,
regional, and global levels. With an estimated 465 000 incident cases of
multidrug-resistant and rifampicin-resistant tuberculosis in 2019,
drug-resistant tuberculosis remains a public health crisis. The COVID-19
pandemic has reversed years of progress in providing essential tuberculosis
services and reducing disease burden. The number of people diagnosed with
drug-resistant tuberculosis has dropped by 22% since before the pandemic, and
the number of patients provided with treatment for drug-resistant tuberculosis
has dropped by 15%. Now more than ever, closing gaps in the detection of
drug-resistant tuberculosis requires investment in research and development of
new diagnostic tools and their rollout, expansion of sample transport systems,
and the implementation of data connectivity solutions.
Copyright © 2022 World Health Organization. Published by Elsevier Ltd. All
rights reserved. Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/S1473-3099(21)00808-2
PMCID: PMC8893725
PMID: 35248168
12. J Clin Invest. 2022 Mar 15;132(6):e155851. doi: 10.1172/JCI155851.
High-dose rifampin improves bactericidal activity without increased
intracerebral inflammation in animal models of tuberculous meningitis.
Ruiz-Bedoya CA(1)(2)(3), Mota F(1)(2)(3), Tucker EW(1)(2)(4), Mahmud
FJ(1)(2)(3), Reyes-Mantilla MI(5), Erice C(1)(2)(4), Bahr M(1)(2)(3), Flavahan
K(1)(2)(3), de Jesus P(1)(2)(3), Kim J(1)(2)(4), Foss CA(6), Peloquin CA(7),
Hammoud DA(8), Ordonez AA(1)(2)(3), Pardo CA(5)(9), Jain SK(1)(2)(3)(6).
Author information:
(1)Center for Infection and Inflammation Imaging Research.
(2)Center for Tuberculosis Research.
(3)Department of Pediatrics.
…
Tuberculous meningitis (TB meningitis) is the most severe form of tuberculosis
(TB), requiring 12 months of multidrug treatment for cure, and is associated
with high morbidity and mortality. High-dose rifampin (35 mg/kg/d) is safe and
improves the bactericidal activity of the standard-dose (10 mg/kg/d)
rifampin-containing TB regimen in pulmonary TB. However, there are conflicting
clinical data regarding its benefit for TB meningitis, where outcomes may also
be associated with intracerebral inflammation. We conducted cross-species
studies in mice and rabbits, demonstrating that an intensified high-dose
rifampin-containing regimen has significantly improved bactericidal activity for
TB meningitis over the first-line, standard-dose rifampin regimen, without an
increase in intracerebral inflammation. Positron emission tomography in live
animals demonstrated spatially compartmentalized, lesion-specific pathology,
with postmortem analyses showing discordant brain tissue and cerebrospinal fluid
rifampin levels and inflammatory markers. Longitudinal multimodal imaging in the
same cohort of animals during TB treatment as well as imaging studies in two
cohorts of TB patients demonstrated that spatiotemporal changes in localized
blood-brain barrier disruption in TB meningitis are an important driver of
rifampin brain exposure. These data provide unique insights into the mechanisms
underlying high-dose rifampin in TB meningitis with important implications for
developing new antibiotic treatments for infections.
DOI: 10.1172/JCI155851
PMCID: PMC8920328
PMID: 35085105 [Indexed for MEDLINE]
13. J Clin Oncol. 2022 Mar 1;40(7):719-728. doi: 10.1200/JCO.21.01455. Epub 2022 Jan 24.
Combination of Trastuzumab, Pertuzumab, and Docetaxel in Patients With Advanced
Non-Small-Cell Lung Cancer Harboring HER2 Mutations: Results From the IFCT-1703
R2D2 Trial.
Mazieres J(1), Lafitte C(2), Ricordel C(3), Greillier L(4), Negre E(5), Zalcman
G(6), Domblides C(7), Madelaine J(8), Bennouna J(9), Mascaux C(10), Moro-Sibilot
D(11), Pinquie F(12), Cortot AB(13), Otto J(14), Cadranel J(15), Langlais A(16),
Morin F(17), Westeel V(18), Besse B(19).
Author information:
(1)Pneumology, CHU Toulouse-Hôpital Larrey, Université Paul Sabatier, Toulouse,
France.
(2)Pneumology, Hôpital Cardio-Vasculaire & Pneumologique Louis Pradel, Bron,
France.
(3)Pneumology, CHU Rennes-Hôpital Pontchaillou, Rennes, France.
…
Comment in
J Clin Oncol. 2022 Mar 1;40(7):693-697.
PURPOSE: HER2 exon 20 insertions and point mutations are oncogenic drivers found
in 1%-2% of patients with non-small-cell lung cancer (NSCLC). No targeted
therapy is approved for this subset of patients. We prospectively evaluated the
effectiveness of the combination of two antibodies against human epidermal
growth factor 2 (HER2 [HER2] trastuzumab and pertuzumab with docetaxel;
trastuzumab and pertuzumab) and docetaxel.
METHODS: The IFCT 1703-R2D2 trial is a multicenter, nonrandomized phase II
study. Patients with HER2-mutated, advanced NSCLC who progressed after ≥ 1
platinum-based treatment were enrolled. Patients received pertuzumab at a
loading dose of 840 mg and 420 mg thereafter; trastuzumab at an 8 mg/kg loading
dose and 6 mg/kg thereafter; and docetaxel at a dose of 75 mg/m2 every 3 weeks.
The primary outcome was the objective response rate (ORR). Other end points
included the duration of response, progression-free survival, and safety
(NCT03845270).
RESULTS: Forty-five patients were enrolled and treated. The median age was 64.5
years (range, 31-84 years), 35% were smokers, 72% were females, 15% had an
Eastern Cooperative Oncology Group performance status of 2, and 30% had brain
metastases. The objective response rate was 29% (n = 13), and 58% had stable
disease (n = 26). The median progression-free survival was 6.8 months (95% CI,
4.0 to 8.5). The median duration of response in patients with a confirmed
response (n = 13) was 11 months (95% CI, 2.9 to 14.9). Grade 3/4
treatment-related adverse events were observed in 64% of the patients. No
patient discontinued treatment because of toxicity. The most frequent grade ≥ 3
treatment-related adverse events were neutropenia (33%), diarrhea (13%), and
anemia (9%).
CONCLUSION: Triple therapy with trastuzumab, pertuzumab, and docetaxel is
feasible and effective for HER2-mutated pretreated advanced NSCLC. These results
highlight the effectiveness of the HER2 antibody-based strategy, which should be
considered for these patients.
DOI: 10.1200/JCO.21.01455
PMID: 35073148 [Indexed for MEDLINE]
14. J Exp Med. 2022 Mar 7;219(3):e20211777. doi: 10.1084/jem.20211777. Epub 2022 Jan 21.
Single-cell immune profiling reveals functional diversity of T cells in
tuberculous pleural effusion.
Cai Y(#)(1), Wang Y(#)(1), Shi C(#)(1), Dai Y(1), Li F(1), Xu Y(2), Zhang P(3),
Kong F(4), Deng G(3), Wen Z(5), Zhou Q(6), Kang BC(6), Singhal A(7), Yang Q(3),
Feng CG(1)(8), Chen X(1).
Author information:
(1)Guangdong Key Laboratory of Regional Immunity and Diseases, Department of
Pathogen Biology, Shenzhen University School of Medicine, Shenzhen, China.
(2)Department of Clinical Laboratory, Shenzhen Baoan hospital, Shenzhen, China.
(3)Guangdong Key Lab for Diagnosis & Treatment of Emerging Infectious Diseases,
Shenzhen Third People's Hospital, Shenzhen, China.
(4)Harbin Thoracic Hospital, Harbin, China.
(5)Shenzhen University and Yuebei Second People's Hospital Joint Lab, Yuebei
Second People's Hospital, Shaoguan, China.
(6)Analytical Biosciences Limited, Beijing, China.
(7)Infectious Diseases Labs, Agency for Science, Technology and Research,
Singapore.
(8)Immunology and Host Defense Group, School of Medical Sciences, Faculty of
Medicine and Health, the University of Sydney, Sydney, New South Wales,
Australia.
(#)Contributed equally
Orchestration of an effective T lymphocyte response at infection sites is
critical for protection against Mycobacterium tuberculosis (Mtb) infection.
However, the local T cell immunity landscape in human tuberculosis is poorly
defined. Tuberculous pleural effusion (TPE), caused by Mtb, is characterized by
an influx of leukocytes to the pleural space, providing a platform suitable for
delineating complex tissue responses to Mtb infection. Using single-cell
transcriptomics and T cell receptor sequencing, we analyzed mononuclear cell
populations in paired pleural fluid and peripheral blood of TPE patients. While
all major cell clusters were present in both tissues, their relative proportions
varied significantly by anatomic location. Lineage tracking analysis revealed
subsets of CD8 and CD4 T cell populations with distinct effector functions
specifically expanded at pleural sites. Granzyme K-expressing CD8 T cells were
preferentially enriched and clonally expanded in pleural fluid from TPE,
suggesting that they are involved in the pathogenesis of the disease. The
findings collectively reveal the landscape of local T cell immunity in
tuberculosis.
© 2022 Cai et al.
DOI: 10.1084/jem.20211777
PMCID: PMC8789099
PMID: 35061012 [Indexed for MEDLINE]
15. J Clin Oncol. 2022 Mar 10;40(8):876-883. doi: 10.1200/JCO.21.01460. Epub 2022
Jan 7.
Blood-Based Biomarker Panel for Personalized Lung Cancer Risk Assessment.
Fahrmann JF(1), Marsh T(2), Irajizad E(1)(3), Patel N(1), Murage E(1), Vykoukal
J(1), Dennison JB(1), Do KA(3), Ostrin E(4), Spitz MR(5), Lam S(6), Shete S(7),
Meza R(8), Tammemägi MC(9)(10), Feng Z(2), Hanash SM(1).
Author information:
(1)Department of Clinical Cancer Prevention, The University of Texas MD Anderson
Cancer Center, Houston, TX.
(2)Biostatistics Program, Fred Hutchinson Cancer Research Center, Seattle, WA.
(3)Department of Biostatistics, The University of Texas MD Anderson Cancer
Center, Houston, TX.
…
PURPOSE: To investigate whether a panel of circulating protein biomarkers would
improve risk assessment for lung cancer screening in combination with a risk
model on the basis of participant characteristics.
METHODS: A blinded validation study was performed using prostate lung colorectal
ovarian (PLCO) Cancer Screening Trial data and biospecimens to evaluate the
performance of a four-marker protein panel (4MP) consisting of the precursor
form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and
cytokeratin-19 fragment in combination with a lung cancer risk prediction model
(PLCOm2012) compared with current US Preventive Services Task Force (USPSTF)
screening criteria. The 4MP was assayed in 1,299 sera collected preceding lung
cancer diagnosis and 8,709 noncase sera.
RESULTS: The 4MP alone yielded an area under the receiver operating
characteristic curve of 0.79 (95% CI, 0.77 to 0.82) for case sera collected
within 1-year preceding diagnosis and 0.74 (95% CI, 0.72 to 0.76) among the
entire specimen set. The combined 4MP + PLCOm2012 model yielded an area under
the receiver operating characteristic curve of 0.85 (95% CI, 0.82 to 0.88) for
case sera collected within 1 year preceding diagnosis. The benefit of the 4MP in
the combined model resulted from improvement in sensitivity at high specificity.
Compared with the USPSTF2021 criteria, the combined 4MP + PLCOm2012 model
exhibited statistically significant improvements in sensitivity and specificity.
Among PLCO participants with ≥ 10 smoking pack-years, the 4MP + PLCOm2012 model
would have identified for annual screening 9.2% more lung cancer cases and would
have reduced referral by 13.7% among noncases compared with USPSTF2021 criteria.
CONCLUSION: A blood-based biomarker panel in combination with PLCOm2012
significantly improves lung cancer risk assessment for lung cancer screening.
DOI: 10.1200/JCO.21.01460
PMCID: PMC8906454
PMID: 34995129 [Indexed for MEDLINE]
16. Am J Respir Crit Care Med. 2022 Mar 1;205(5):570-579. doi:
10.1164/rccm.202012-4541OC.
Efficacy of Long-Acting Bedaquiline Regimens in a Mouse Model of Tuberculosis
Preventive Therapy.
Kaushik A(1), Ammerman NC(1), Tasneen R(1), Lachau-Durand S(2), Andries K(2),
Nuermberger E(1).
Author information:
(1)Center for Tuberculosis Research, Johns Hopkins University School of
Medicine, Baltimore, Maryland; and.
(2)Janssen R&D, Beerse, Belgium.
Comment in
Am J Respir Crit Care Med. 2022 Mar 1;205(5):493-494.
Rationale: Completion of preventive therapy is a major bottleneck in global
tuberculosis control. Long-acting injectable drug formulations would shorten
therapy administration and may thereby improve completion rates. Recently, a
long-acting formulation of bedaquiline demonstrated antituberculosis activity
for up to 12 weeks after injection in a validated mouse model of preventive
therapy. Objectives: The objectives of this study were to 1) determine the total
duration of activity after an injection of long-acting bedaquiline and 2)
evaluate the activity of regimens comprised of long-acting bedaquiline plus
short (2-4 wk) oral companion courses of bedaquiline, with or without
rifapentine, using the validated mouse model of tuberculosis preventive therapy.
Methods: After the establishment of a stable Mycobacterium tuberculosis lung
infection in bacillus Calmette-Guérin (BCG)-immunized BALB/c mice, treatment was
initiated with 1 of 12 randomly assigned regimens. In addition to positive and
negative controls, six regimens included one or two injections of long-acting
bedaquiline (alone or with oral bedaquiline with or without rifapentine), and
four comparator regimens consisted of oral agents only. Lung bacterial burden
was measured monthly for up to 28 weeks. Measurements and Main Results: One
injection of long-acting bedaquiline at 160 mg/kg exerted antituberculosis
activity for 12 weeks. Compared with the positive control (daily
isoniazid-rifapentine for 4 wk), six regimens had equivalent bactericidal
activity (including two all-oral comparator regimens), and two regimens had
superior sterilizing activity: one injection with 2 weeks of oral bedaquiline
and high-dose rifapentine; and two injections with 4 weeks of oral bedaquiline.
Conclusions: Long-acting injectable bedaquiline has significant potential for
shortening tuberculosis preventive therapy.
DOI: 10.1164/rccm.202012-4541OC
PMID: 34939891 [Indexed for MEDLINE]
17. J Clin Oncol. 2022 Mar 1;40(7):710-718. doi: 10.1200/JCO.21.01323. Epub 2021 Nov 29.
Poziotinib in Non-Small-Cell Lung Cancer Harboring HER2 Exon 20 Insertion
Mutations After Prior Therapies: ZENITH20-2 Trial.
Le X(1), Cornelissen R(2), Garassino M(3), Clarke JM(4), Tchekmedyian N(5),
Goldman JW(6), Leu SY(7), Bhat G(7), Lebel F(7), Heymach JV(1), Socinski MA(8).
Author information:
(1)Department of Thoracic Head and Neck Medical Oncology, MD Anderson Cancer
Center, Houston, TX.
(2)Medical Oncology, Erasmus University Medical Center, Rotterdam, the
Netherlands.
(3)Medical Thoracic Oncology, Istituto Nazionale dei Tumori di Milano-Fondazione
IRCCS, Milan, Italy.
…
Comment in
J Clin Oncol. 2022 Mar 1;40(7):693-697.
PURPOSE: Insertion mutations in Erb-b2 receptor tyrosine kinase 2 gene (ERBB2 or
HER2) exon 20 occur in 2%-5% of non-small-cell lung cancers (NSCLCs) and
function as an oncogenic driver. Poziotinib, a tyrosine kinase inhibitor, was
evaluated in previously treated patients with NSCLC with HER2 exon 20
insertions.
METHODS: ZENITH20, a multicenter, multicohort, open-label phase II study,
evaluated poziotinib in patients with advanced or metastatic NSCLC. In cohort 2,
patients received poziotinib (16 mg) once daily. The primary end point was
objective response rate evaluated by independent review committee (RECIST v1.1);
secondary outcome measures were disease control rate, duration of response,
progression-free survival, and safety and tolerability. Quality of life was
assessed.
RESULTS: Between October 2017 and March 2021, 90 patients with a median of two
prior lines of therapy (range, 1-6) were treated. With a median follow-up of 9.0
months, objective response rate was 27.8% (95% CI, 18.9 to 38.2); 25 of 90
patients achieved a partial response. Disease control rate was 70.0% (95% CI,
59.4 to 79.2). Most patients (74%) had tumor reduction (median reduction 22%).
Median progression-free survival was 5.5 months (95% CI, 3.9 to 5.8); median
duration of response was 5.1 months (95% CI, 4.2 to 5.5). Clinical benefit was
seen regardless of lines and types of prior therapy, presence of central nervous
system metastasis, and types of HER2 mutations. Grade 3 or higher
treatment-related adverse events included rash (48.9%), diarrhea (25.6%), and
stomatitis (24.4%). Most patients had poziotinib dose reductions (76.7%), with
median relative dose intensity of 71.5%. Permanent treatment discontinuation
because of treatment-related adverse events occurred in 13.3% of patients.
CONCLUSION: Poziotinib demonstrates antitumor activity in previously treated
patients with HER2 exon 20 insertion NSCLC.
DOI: 10.1200/JCO.21.01323
PMCID: PMC8887939
PMID: 34843401 [Indexed for MEDLINE]
18. J Clin Oncol. 2022 Mar 1;40(7):702-709. doi: 10.1200/JCO.21.01113. Epub 2021 Sep 22.
Poziotinib for Patients With HER2 Exon 20 Mutant Non-Small-Cell Lung Cancer:
Results From a Phase II Trial.
Elamin YY(1), Robichaux JP(1), Carter BW(2), Altan M(1), Gibbons DL(1), Fossella
FV(1), Lam VK(1)(3), Patel AB(4), Negrao MV(1), Le X(1), Mott FE(1), Zhang J(1),
Feng L(5), Blumenschein G Jr(1), Tsao AS(1), Heymach JV(1).
Author information:
(1)Department of Thoracic/Head and Neck Medical Oncology, The University of
Texas MD Anderson Cancer Center, Houston, TX.
(2)Department of Thoracic Imaging, The University of Texas MD Anderson Cancer
Center, Houston, TX.
(3)Department of Medicine, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore,
MD.
(4)Department of Dermatology, The University of Texas MD Anderson Cancer Center,
Houston, TX.
(5)Department of Biostatistics, The University of Texas MD Anderson Cancer
Center, Houston, TX.
Comment in
J Clin Oncol. 2022 Mar 1;40(7):693-697.
PURPOSE: Targeted therapies against non-small-cell lung cancer (NSCLC) harboring
HER2 mutations remain an unmet need. In this study, we assessed the efficacy and
safety of poziotinib in patients with HER2 exon 20 mutant advanced NSCLC in a
single-arm, open-label, phase II study.
PATIENTS AND METHODS: Patients with advanced HER2 exon 20 mutant NSCLC were
enrolled to receive poziotinib at a dose of 16 mg/d for 28-day cycles. The
primary end point was objective response rate per RECIST version 1.1.
Confirmatory scans were performed at least 28 days from initial radiologic
response.
RESULTS: Thirty patients received poziotinib treatment. At baseline, 90% of
patients received prior platinum-based chemotherapy and 53% had two lines or
more prior systemic therapies. As of data cutoff on March 1, 2021, the confirmed
objective response rate was 27% (95% CI, 12 to 46). Responses were observed
across HER2 exon 20 mutation subtypes. The median duration of response was 5.0
months (95% CI, 4.0 to not estimable). The median progression-free survival was
5.5 months (95% CI, 4.0 to 7.0). The median overall survival was 15 months (95%
CI, 9.0 to not estimable). The most common grade 3 treatment-related adverse
events were skin rash (47%) and diarrhea (20%). There was one possible
treatment-related death because of pneumonitis.
CONCLUSION: Poziotinib showed promising antitumor activity in patients with HER2
exon 20 mutant NSCLC including patients who had previously received
platinum-based chemotherapy.
DOI: 10.1200/JCO.21.01113
PMCID: PMC8887948
PMID: 34550757 [Indexed for MEDLINE]
19. Autophagy. 2022 Mar;18(3):576-594. doi: 10.1080/15548627.2021.1938912. Epub 2021 Jul 7.
M. tuberculosis PknG manipulates host autophagy flux to promote pathogen
intracellular survival.
Ge P(1)(2), Lei Z(1)(2), Yu Y(1)(2), Lu Z(1)(2), Qiang L(1)(2), Chai Q(1), Zhang
Y(1), Zhao D(1)(2), Li B(1), Pang Y(3), Liu CH(1)(2), Wang J(1).
Author information:
(1)CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of
Microbiology, Center for Biosafety Mega-Science, Chinese Academy of Sciences,
Beijing, China.
(2)Savaid Medical School, University of Chinese Academy of Sciences, Beijing,
China.
(3)Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest
Hospital, Capital Medical University, Beijing, China.
The eukaryotic-type protein kinase G (PknG), one of the eleven eukaryotic type
serine-threonine protein kinase (STPK) in Mycobacterium tuberculosis (Mtb), is
involved in mycobacterial survival within macrophages, presumably by suppressing
phagosome and autophagosome maturation, which makes PknG an attractive drug
target. However, the exact mechanism by which PknG inhibits pathogen clearance
during mycobacterial infection remains largely unknown. Here, we show that PknG
promotes macroautophagy/autophagy induction but inhibits autophagosome
maturation, causing an overall effect of blocked autophagy flux and enhanced
pathogen intracellular survival. PknG prevents the activation of AKT (AKT
serine/threonine kinase) via competitively binding to its pleckstrin homology
(PH) domain, leading to autophagy induction. Remarkably, PknG could also inhibit
autophagosome maturation to block autophagy flux via targeting host small GTPase
RAB14. Specifically, PknG directly interacts with RAB14 to block RAB14-GTP
hydrolysis. Furthermore, PknG phosphorylates TBC1D4/AS160 (TBC1 domain family
member 4) to suppress its GTPase-activating protein (GAP) activity toward RAB14.
In macrophages and in vivo, PknG promotes Mtb intracellular survival through
blocking autophagy flux, which is dependent on RAB14. Taken together, our data
unveil a dual-functional bacterial effector that tightly regulates host
autophagy flux to benefit pathogen intracellular survival.Abbreviations: AKT:
AKT serine/threonine kinase; ATG5: autophagy related 5; BMDMs: bone
marrow-derived macrophages; DTT: dithiothreitol; FBS: fetal calf serum; GAP:
GTPase-activating protein; MOI: multiplicity of infection; Mtb: Mycobacterium
tuberculosis; MTOR: mechanistic target of rapamycin kinase; OADC: oleic
acid-albumin-dextrose-catalase; PC, phosphatidylcholine; PH: pleckstrin
homology; PI3K: phosphoinositide 3-kinase; PknG: protein kinase G;
PtdIns(3,4,5)P3: phosphatidylinositol(3,4,5)-trisphosphate; SQSTM1: sequestosome
1; STPK: serine-threonine protein kinase; TB: tuberculosis; TBC1D4: TBC1 domain
family member 4; TPR: tetratricopeptide repeat; ULK1: unc-51 like autophagy
activating kinase 1; WT: wild-type.
DOI: 10.1080/15548627.2021.1938912
PMCID: PMC9037497
PMID: 34092182 [Indexed for MEDLINE]
