PubMed

(tuberculosis[Title/Abstract]) OR (lung cancer[Title/Abstract])

Filters applied: from 2024/8/1 - 2024/8/31

1. Redox Biol. 2024 Aug;74:103209. doi: 10.1016/j.redox.2024.103209. Epub 2024 May 25.

Lactate-induced activation of tumor-associated fibroblasts and IL-8-mediated macrophage recruitment promote lung cancer progression.

Gu X(1), Zhu Y(2), Su J(3), Wang S(4), Su X(5), Ding X(5), Jiang L(6), Fei X(7), Zhang W(8).

Alterations in the tumor microenvironment are closely associated with the metabolic phenotype of tumor cells. Cancer-associated fibroblasts (CAFs) play a pivotal role in tumor growth and metastasis. Existing studies have suggested that lactate produced by tumor cells can activate CAFs, yet the precise underlying mechanisms remain largely unexplored. In this study, we initially identified that lactate derived from lung cancer cells can promote nuclear

translocation of NUSAP1, subsequently leading to the recruitment of the transcriptional complex JUNB-FRA1-FRA2 near the DESMIN promoter and facilitating DESMIN transcriptional activation, thereby promoting CAFs' activation. Moreover, DESMIN-positive CAFs, in turn, secrete IL-8, which recruits TAMs or promotes M2 polarization of macrophages, further contributing to the alterations in the tumor microenvironment and facilitating lung cancer progression. Furthermore, we observed that the use of IL-8 receptor antagonists, SB225002, or Navarixin, significantly reduced TAM infiltration and enhanced the therapeutic efficacy of anti-PD-1 or anti-PD-L1 treatment. This finding indicates that inhibiting IL-8R activity can attenuate the impact of CAFs on the tumor microenvironment, thus restraining the progression of lung cancer.

PMID: 38861833 [Indexed for MEDLINE]

2. J Thorac Oncol. 2024 Aug;19(8):1164-1185. doi: 10.1016/j.jtho.2024.04.006. Epub 2024 Apr 12.

Treatment Response Biomarkers: Working Toward Personalized Radiotherapy for Lung Cancer.

Horne A(1), Harada K(2), Brown KD(3), Chua KLM(4), McDonald F(5), Price G(6), Putora PM(7), Rothwell DG(8), Faivre-Finn C(9).

Owing to major advances in the field of radiation oncology, patients with lung cancer can now receive technically individualized radiotherapy treatments. Nevertheless, in the era of precision oncology, radiotherapy-based treatment

selection needs to be improved as many patients do not benefit or are not offered optimum therapies. Cost-effective robust biomarkers can address this knowledge gap and lead to individuals being offered more bespoke treatments

leading to improved outcome. This narrative review discusses some of the current achievements and challenges in the realization of personalized radiotherapy delivery in patients with lung cancer.

PMID: 38615939 [Indexed for MEDLINE]

3. J Thorac Oncol. 2024 Aug;19(8):1155-1163. doi: 10.1016/j.jtho.2024.05.001.

Screening Low-Risk Individuals for Lung Cancer: The Need May Be Present, but the Evidence of Benefit Is Not.

Silvestri GA(1), Young RP(2), Tanner NT(3), Mazzone P(4).

Worldwide, lung cancer is the most common killer among cancers, advanced disease has worse outcomes, earlier stage detection leads to better outcomes, and high-quality screening has a favorable net benefit. With the mortality reduction recognized from annual low-radiation dose computed tomography by screening those at high risk, there has been consideration that this benefit could translate to those who have never smoked. There have been several large-scale, single-arm, observational trials in Asia in persons with light to no smoking histories, with or without a family history of lung cancer, which have revealed high or higher lung cancer detection rates than previously reported in high-risk persons who currently or formerly smoked. The Early Detection Program for Lung Cancer in Taiwan, of nearly 50,000 persons, revealed that the cancer detection rate for those screened with low-radiation dose computed tomography was more than twofold higher in light- or never-smokers with a family history of lung cancer compared

with high-risk persons with more than 30 or more pack-years exposure and meeting U.S. Preventative Services Task Force criteria for screening. In addition, more than 90% of the cancers detected in those with a family history were in early stage. On the basis of those findings, the researchers concluded that screening first-degree relatives of those with a family history of lung cancer, irrespective of smoking history, would lead to a decrease in lung cancer mortality. We believe that the findings in this cohort and others like it represent substantial overdiagnosis and that the harms associated with screening a population that has a low likelihood of developing lethal cancers have not been thoroughly considered. Here, we provide our perspective and consider the potential benefits and harms of screening populations outside those currently eligible using the U.S. Preventative Services Task Force criteria.

PMID: 39112003 [Indexed for MEDLINE]

4. Semin Cancer Biol. 2024 Aug 29;106-107:43-57. doi: 10.1016/j.semcancer.2024.08.006. Online ahead of print.

Combined targeting of senescent cells and senescent macrophages: A new idea for integrated treatment of lung cancer.

Gu M(1), Liu Y(2), Zheng W(3), Jing Z(4), Li X(5), Guo W(5), Zhao Z(5), Yang X(5), Liu Z(6), Zhu X(7), Gao W(8).

Lung cancer is one of the most common cancers worldwide and a leading cause of cancer-related deaths. Macrophages play a key role in the immune response and the tumour microenvironment. As an important member of the immune system, macrophages have multiple functions, including phagocytosis and clearance of pathogens, modulation of inflammatory responses, and participation in tissue repair and regeneration. In lung cancer, macrophages are considered to be the major cellular component of the tumor-associated inflammatory response and are closely associated with tumorigenesis, progression and metastasis. However, macrophages gradually undergo a senescence process with age and changes in pathological states. Macrophage senescence is an important change in the functional and metabolic state of macrophages and may have a significant impact on lung cancer development. In lung cancer, senescent macrophages interact with other cells in the tumor microenvironment (TME) by secreting senescence-associated secretory phenotype (SASP) factors, which can either promote the proliferation, invasion and metastasis of tumor cells or exert anti-tumor effects through reprogramming or clearance under specific conditions. Therefore, senescent macrophages are considered important potential targets for lung cancer therapy. In this paper, a systematic review of macrophages and their senescence process, and their role in tumors is presented. A variety of inhibitory strategies against senescent macrophages, including enhancing autophagy, inhibiting SASP, reducing DNA damage, and modulating metabolic pathways, were also explored. These strategies are expected to improve lung cancer treatment outcomes by restoring the anti-tumor function of macrophages.

PMID: 39214157

5. Lancet Respir Med. 2024 Aug;12(8):633-641. doi: 10.1016/S2213-2600(24)00083-3. Epub 2024 May 8.

Effectiveness of preventive treatment among different age groups and Mycobacterium tuberculosis infection status: a systematic review and individual-participant data meta-analysis of contact tracing studies.

Martinez L(1), Seddon JA(2), Horsburgh CR(3), Lange C(4), Mandalakas AM(5); TB Contact Studies Consortium.

BACKGROUND: Tuberculosis is a preventable disease. However, there is debate regarding which individuals would benefit most from tuberculosis preventive treatment and whether these benefits vary in settings with a high burden and low burden of tuberculosis. We aimed to compare the effectiveness of tuberculosis preventive treatment in exposed individuals of differing ages and Mycobacterium tuberculosis infection status while considering tuberculosis burden of the settings.

METHODS: In this systematic review and individual-participant meta-analysis, we investigated the development of incident tuberculosis in people closely exposed to individuals with tuberculosis. We searched for studies published between Jan 1, 1998, and April 6, 2018, in MEDLINE, Web of Science, BIOSIS, and Embase. We restricted our search to cohort studies; case-control studies and outbreak reports were excluded. Two reviewers evaluated titles, abstracts, and full text articles for eligibility. At each stage, two reviewers discussed discrepancies and re-evaluated articles until a consensus was reached. Individual-participant data and a pre-specified list of variables, including characteristics of the exposed contact, the index patient, and environmental characteristics, were requested from authors of all eligible studies; contacts exposed to a drug-resistant tuberculosis index patient were excluded. The primary study outcome was incident tuberculosis. We estimated adjusted hazard ratios (aHRs) for incident tuberculosis with mixed-effects Cox regression models with a study-level random effect. We estimated the number-needed-to-treat (NNT) to prevent one person developing tuberculosis. Propensity score matching procedures were used in all analyses. This study is registered with PROSPERO (CRD42018087022).

FINDINGS: After screening 25 358 records for eligibility, 439 644 participants from 32 cohort studies were included in the individual-participant data meta-analysis. Participants were followed for 1 396 413 person-years (median of 2·7 years [IQR 1·3-4.4]), during which 2496 people were diagnosed with incident tuberculosis. Overall, effectiveness of preventive treatment was 49% (aHR 0·51 [95% CI 0·44-0·60]). Participants with a positive tuberculin-skin-test (TST) or IFNγ release assay (IGRA) result at baseline benefitted from greater protection, regardless of age (0·09 [0·05-0·17] in children younger than 5 years, 0·20 [0·15-0·28] in individuals aged 5-17 years, and 0·17 [0·13-0·22] in adults aged

18 years and older). The effectiveness of preventive treatment was greater in high-burden (0·31 [0·23-0·40]) versus low-burden (0·58 [0·47-0·72]) settings. The NNT ranged from 9 to 34 depending on age among participants with a positive TST or IGRA in both high-burden and low-burden settings; among all contacts (regardless of TST or IGRA test result), the NNT ranged from 29 to 43 in high-burden settings and 213 to 455 in low-burden settings.

INTERPRETATION: Our findings suggest that a risk-targeted strategy prioritising contacts with evidence of M tuberculosis infection might be indicated in low-burden settings, and a broad approach including all contacts should be considered in high-burden settings. Preventive treatment was similarly effective among contacts of all ages.

PMID: 38734022 [Indexed for MEDLINE]

6. Nature. 2024 Sep;633(8029):417-425. doi: 10.1038/s41586-024-07866-3. Epub 2024 Aug 28.

Tuberculosis in otherwise healthy adults with inherited TNF deficiency.

Arias AA(#)(1)(2)(3), Neehus AL(#)(4)(5), Ogishi M(3), Meynier V(6)(7), Krebs A(8)(9), Lazarov T(8)(9), Lee AM(9)(10), Arango-Franco CA(1)(6)(7), Yang R(3),

Severe defects in human IFNγ immunity predispose individuals to both Bacillus Calmette-Guérin disease and tuberculosis, whereas milder defects predispose only to tuberculosis1. Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant. Neither has any other clinical phenotype and both mount normal clinical and biological inflammatory responses. Their leukocytes, including monocytes and monocyte-derived macrophages (MDMs) do not produce TNF, even after stimulation with IFNγ. Blood leukocyte subset development is normal in these patients. However, an impairment in the respiratory burst was observed in granulocyte-macrophage colony-stimulating factor (GM-CSF)-matured MDMs and alveolar macrophage-like (AML) cells2 from both patients with TNF deficiency, TNF- or TNFR1-deficient induced pluripotent stem (iPS)-cell-derived GM-CSF-matured macrophages, and healthy control MDMs and AML cells differentiated with TNF blockers in vitro, and in lung macrophages treated with TNF blockers ex vivo. The stimulation of TNF-deficient iPS-cell-derived macrophages with TNF rescued the respiratory burst. These findings contrast with

those for patients with inherited complete deficiency of the respiratory burst across all phagocytes, who are prone to multiple infections, including both Bacillus Calmette-Guérin disease and tuberculosis3. Human TNF is required for

respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but is surprisingly redundant otherwise, including for inflammation and immunity to weakly virulent mycobacteria and many other infectious agents.

PMID: 39198650 [Indexed for MEDLINE]

7. Am J Respir Crit Care Med. 2024 Aug 14. doi: 10.1164/rccm.202402-0374SO. Online ahead of print.

Pathogenesis of Post-Tuberculosis Lung Disease: Defining Knowledge Gaps and Research Priorities at the 2(nd) International Post-Tuberculosis Symposium.

Auld SC(1), Barczak AK(2), Bishai W(3), Coussens AK(4), Dewi IMW(5), Mitini-Nkhoma SC(6), Muefong C(7), Naidoo T(8), Pooran A(9), Stek C(10)(11), Steyn AJC(12), Tezera L(13), Walker NF(14).

Post-tuberculosis (TB) lung disease (PTLD) is increasingly recognized as a major contributor to the global burden of chronic lung disease, with recent estimates indicating that over half of TB survivors have impaired lung function after

successful completion of TB treatment. However, the pathologic mechanisms that contribute to PTLD are not well understood, thus limiting the development of therapeutic interventions to improve long-term outcomes after TB. This report summarizes the work of the "Pathogenesis and Risk Factors Committee" for the Second International Post-Tuberculosis Symposium, which took place in Stellenbosch, South Africa in April 2023. The committee first identified six areas with high translational potential: (1) tissue matrix destruction, including the role of matrix metalloproteinase dysregulation and neutrophil activity, (2) fibroblasts and profibrotic activity, (3) granuloma fate and cell death pathways, (4) mycobacterial factors including pathogen burden, (5) animal models, and (6) the impact of key clinical risk factors including HIV, diabetes, smoking, malnutrition, and alcohol. We share here the key findings from a literature review of those areas, highlighting knowledge gaps and areas where further research is needed.

PMID: 39141569

8. J Adv Res. 2024 Aug 24:S2090-1232(24)00372-2. doi: 10.1016/j.jare.2024.08.029. Online ahead of print.

New insights into the function and mechanisms of piRNA PMLCPIR in promoting PM(2.5)-induced lung cancer.

Xu L(1), Ma W(2), Huo X(2), Luo J(2), Li R(2), Zhu X(2), Kong X(2), Zhao K(2), Jin Y(2), Zhang M(3), Li X(3), Wang L(4), Han W(5), Yu D(6).

INTRODUCTION: Extensive studies have established the correlation between long-term PM2.5 exposure and lung cancer, yet the mechanisms underlying this association remain poorly understood. PIWI-interacting RNAs (piRNAs), a novel category of small non-coding RNAs, serve important roles in various diseases. However, their biological function and mechanism in PM2.5-induced lung cancer have not been thoroughly investigated.

OBJECTIVES: We aimed to explore the oncogenic role of piRNA in lung cancer induced by PM2.5 exposure, as well as the underlying mechanisms.

METHODS: We conducted a PM2.5-induced human lung epithelial cell malignant transformation model. Human samples were used to further verify the finding. In vitro proliferation, migration, and invasion assays were performed to study the function of piRNA. RNA-sequencing was used to elucidate the the mechanisms of how piRNA mediates cell functions. PiRNA pull-down and computational docking analysis were conducted to identify proteins that binding to piRNA. In vivo experiments were used to explore whether inhibition of PMLCPIR could have a therapeutic effect on lung cancer.

RESULTS: We identified a new up-regulated piRNA, termed PM2.5-induced lung cancer up-regulation piRNA (PMLCPIR), which promotes the proliferation of PM2.5-transformed cells and lung cancer cells. RNA sequencing revealed ITGB1 as a downstream target of PMLCPIR. Importantly, PMLCPIR binds to nucleolin (NCL) and increases the expression of its target gene, ITGB1, thereby activating PI3K/AKT signaling. The inhibition of PMLCPIR could promote apoptosis in lung cancer cells and enhance their chemosensitivity to anti-tumor drugs.

CONCLUSION: We systematically identified the alterations of piRNA expression profiles in the PM2.5-induced malignant transformation model. Then, PMLCPIR was recognized as a novel oncogenic piRNA in PM2.5-induced lung cancer. Mechanically, PMLCPIR binds to NCL, enhancing ITGB1 expression and activating the ontogenetic PI3K/AKT signaling, potentially contributing to lung cancer progression. This study provides novel insights into the revelation of a new epigenetic regulator in PM2.5-induced lung cancer.

PMID: 39187236

9. J Thorac Oncol. 2024 Aug 2:S1556-0864(24)00747-0. doi: 10.1016/j.jtho.2024.07.022. Online ahead of print.

From the International Association for the Study of Lung Cancer Early Detection and Screening Committee: Terminology Issues in Screening and Early Detection of Lung Cancer-International Association for the Study of Lung Cancer Early Detection and Screening Committee Expert Group Recommendations.

Huber RM(1), Cavic M(2), Balata H(3), Borondy Kitts A(4), Field JK(5), Henschke C(6), Kazerooni EA(7), Kerpel-Fronius A(8), Smith RA(9), Taioli E(10), Ventura L(11), Lam S(12), Yankelevitz D(13), Tammemägi M(14); members of the Diagnostics Working Group, ED & Screening Committee.

INTRODUCTION: To facilitate global implementation of lung cancer (LC) screening and early detection in a quality assured and consistent manner, common terminology is needed. Researchers and clinicians within different specialties

may use the same terms but with different meanings or different terms for the same intended meanings.

METHODS: The Diagnostics Working Group of the International Association for the Study of Lung Cancer Early Detection and Screening Committee has analyzed and discussed relevant terms used on a regular basis and suggests recommendations for consensus definitions of terminology applicable in this setting. We explored how to reach consensus to define relevant and unambiguous terminology for use by health care providers, researchers, patients, screening participants, and family.

RESULTS: Terms and definitions for epidemiologic and health-economical purposes included the following: standardized incidence and mortality rates, LC-specific survival, long-term survival and cure rates, overdiagnosis, overtreatment, and undertreatment. Terms and definitions for defining screening findings included the following: positive, false-positive, negative, false-negative, and indeterminate findings and additional and incidental findings. Terms and definitions for describing parameters in screening programs included the following: opportunistic versus programmatic screening, screening rounds, interval or interim diagnoses, and invasive and minimally invasive procedures. Terms and definitions for shared decision-making included the following: LC screening-possible harms and risks and LC risk and modifiers prior and posterior to a measure.

CONCLUSIONS: A common set of terminology with standard definitions is recommended for describing clinical LC screening programs, the discussion about effectiveness and outcomes, or the clinical setting. The use of the terms should be clearly defined and explained.

PMID: 39098452

10. Lancet Public Health. 2024 Aug;9(8):e564-e572. doi: 10.1016/S2468-2667(24)00151-8.

Risk factors underlying racial and ethnic disparities in tuberculosis diagnosis and treatment outcomes, 2011-19: a multiple mediation analysis of national surveillance data.

Regan M(1), Barham T(2), Li Y(3), Swartwood NA(3), Beeler Asay GR(4), Cohen T(5), Horsburgh CR Jr(6), Khan A(4), Marks SM(4), Myles RL(2), Salomon JA(7), Self JL(4), Winston CA(4), Menzies NA(3).

BACKGROUND: Despite an overall decline in tuberculosis incidence and mortality in the USA in the past two decades, racial and ethnic disparities in tuberculosis outcomes persist. We aimed to examine the extent to which

inequalities in health and neighbourhood-level social vulnerability mediate these disparities.

METHODS: We extracted data from the US National Tuberculosis Surveillance System on individuals with tuberculosis during 2011-19. Individuals with multidrug-resistant tuberculosis or missing data on race and ethnicity were excluded. We examined potential disparities in tuberculosis outcomes among US-born and non-US-born individuals and conducted a mediation analysis for groups with a higher risk of treatment incompletion (a summary outcome comprising diagnosis after death, treatment discontinuation, or death during treatment). We used sequential multiple mediation to evaluate eight potential mediators: three comorbid conditions (HIV, end-stage renal disease, and diabetes), homelessness, and four census tract-level measures (poverty, unemployment, insurance coverage, and racialised economic segregation [measured by Index of Concentration at the ExtremesRace-Income]). We estimated the marginal contribution of each mediator using Shapley values.

FINDINGS: During 2011-19, 27 788 US-born individuals and 57 225 non-US-born individuals were diagnosed with active tuberculosis, of whom 27 605 and 56 253 individuals, respectively, met eligibility criteria for our analyses. We did not observe evidence of disparities in tuberculosis outcomes for non-US-born individuals by race and ethnicity. Therefore, subsequent analyses were restricted to US-born individuals. Relative to White individuals, Black and Hispanic individuals had a higher risk of not completing tuberculosis treatment (adjusted relative risk 1·27, 95% CI 1·19-1·35; 1·22, 1·11-1·33, respectively). In multiple mediator analysis, the eight measured mediators explained 67% of the disparity for Black individuals and 65% for Hispanic individuals. The biggest contributors to these disparities for Black individuals and Hispanic individuals were concomitant end-stage renal disease, concomitant HIV, census tract-level racialised economic segregation, and census tract-level poverty.

INTERPRETATION: Our findings underscore the need for initiatives to reduce disparities in tuberculosis outcomes among US-born individuals, particularly in highly racially and economically polarised neighbourhoods. Mitigating the structural and environmental factors that lead to disparities in the prevalence of comorbidities and their case management should be a priority.

FUNDING: US Centers for Disease Control and Prevention National Center for HIV, Viral Hepatitis, STD, and Tuberculosis Prevention Epidemiologic and Economic Modeling Agreement.

PMID: 39095133 [Indexed for MEDLINE]

11. Lancet Public Health. 2024 Aug;9(8):e573-e582. doi: 10.1016/S2468-2667(24)00150-6.

The long-term effects of domestic and international tuberculosis service improvements on tuberculosis trends within the USA: a mathematical modelling study.

Menzies NA(1), Swartwood NA(2), Cohen T(3), Marks SM(4), Maloney SA(5), Chappelle C(6), Miller JW(7), Beeler Asay GR(4), Date AA(5), Horsburgh CR(8), Salomon JA(9).

BACKGROUND: For settings with low tuberculosis incidence, disease elimination is a long-term goal. We investigated pathways to tuberculosis pre-elimination (incidence<1·0 cases per 100 000 people) and elimination (incidence<0·1 cases per 100 000 people) in the USA, where incidence was estimated at 2·9 per 100 000 people in 2023.

METHODS: Using a mathematical modelling framework, we simulated how US tuberculosis incidence could be affected by changes in tuberculosis services in the countries of origin for future migrants to the USA, as well as changes in tuberculosis services inside the USA. To do so, we used a linked set of transmission dynamic models, calibrated to demographic and epidemiological data for each setting. We constructed intervention scenarios representing improvements in tuberculosis services internationally and within the USA, individually and in combination, plus a base-case scenario representing continuation of current services. We simulated health and economic outcomes until 2100, using a Bayesian approach to quantify uncertainty in these outcomes.

FINDINGS: Under the base-case scenario, US tuberculosis incidence was projected to decline to 1·8 cases per 100 000 (95% uncertainty interval [UI] 1·5-2·1) in the total population by 2050. Intervention scenarios produced substantial reductions in tuberculosis incidence, with the combination of all domestic and international interventions projected to achieve pre-elimination by 2033 (95% UI 2031-2037). Compared with the base-case scenario, this combination of interventions could avert 101 000 tuberculosis cases (95% UI 84 000-120 000) and 13 300 tuberculosis deaths (95% UI 10 500-16 300) in the USA from 2025 to 2050. Tuberculosis elimination was not projected before 2100.

INTERPRETATION: Strengthening tuberculosis services domestically, promoting the development of more effective technologies and interventions, and supporting tuberculosis programmes in countries with a high tuberculosis burden are key strategies for accelerating progress towards tuberculosis elimination in the USA.

FUNDING: US Centers for Disease Control and Prevention.

PMID: 39095134 [Indexed for MEDLINE]

12. Am J Respir Crit Care Med. 2024 Aug 1;210(3):343-351. doi: 10.1164/rccm.202311-2004OC.

High-Dose Isoniazid Lacks EARLY Bactericidal Activity against Isoniazid-resistant Tuberculosis Mediated by katG Mutations: A Randomized Phase II Clinical Trial.

Gausi K(1), Ignatius EH(2), De Jager V(3), Upton C(3), Kim S(4), McKhann A(5), Moran L(6), Wiesner L(1), von Groote-Bidlingmaier F(3), Marzinek P(7), Vanker N(6), Yvetot J(8), Pierre S(9), Rosenkranz SL(4), Swindells S(8), Diacon AH(6), Nuermberger EL(2), Denti P(1), Dooley KE(10).

Rationale: Observational studies suggest that high-dose isoniazid may be efficacious in treating multidrug-resistant tuberculosis. However, its activity against Mycobacterium tuberculosis (M.tb) with katG mutations (which typically

confer high-level resistance) is not established. Objectives: To characterize the early bactericidal activity (EBA) of high-dose isoniazid in patients with tuberculosis caused by katG-mutated M.tb. Methods: A5312 was a phase IIA

randomized, open-label trial. Participants with tuberculosis caused by katG-mutated M.tb were randomized to receive 15 or 20 mg/kg isoniazid daily for 7 days. Daily sputum samples were collected for quantitative culture. Intensive pharmacokinetic sampling was performed on Day 6. Data were pooled across all A5312 participants for analysis (drug-sensitive, inhA-mutated, and katG-mutated M.tb). EBA was determined using nonlinear mixed-effects modeling. Measurements and Main Results: Of 80 treated participants, 21 had katG-mutated M.tb. Isoniazid pharmacokinetics were best described by a two-compartment model with an effect of NAT2 acetylator phenotype on clearance. Model-derived maximum concentration and area under the concentration-time curve in the 15 and 20 mg/kg groups were 15.0 and 22.1 mg/L and 57.6 and 76.8 mg ⋅ h/L, respectively. Isoniazid bacterial kill was described using an effect compartment and a sigmoidal maximum efficacy relationship. Isoniazid potency against katG-mutated M.tb was approximately 10-fold lower than in inhA-mutated M.tb. The highest dose of 20 mg/kg did not demonstrate measurable EBA, except against a subset of slow NAT2 acetylators (who experienced the highest concentrations). There were no grade 3 or higher drug-related adverse events. Conclusions: This study found negligible bactericidal activity of high-dose isoniazid (15-20 mg/kg) in the majority of participants with tuberculosis caused by katG-mutated M.tb. Clinical trial registered with www.clinicaltrials.gov (NCT01936831).

PMID: 38564365 [Indexed for MEDLINE]

13. Clin Infect Dis. 2024 Aug 28:ciae388. doi: 10.1093/cid/ciae388. Online ahead of print.

Effectiveness and Safety of Varying Doses of Linezolid With Bedaquiline and Pretomanid in Treatment of Drug-Resistant Pulmonary Tuberculosis: Open-Label, Randomized Clinical Trial.

Padmapriyadarsini C(1), Oswal VS(2), Jain CD(3), Mariappan MV(1), Singla N(4), Kumar S(5), Daniel BD(1), Dave JD(6), Vadgama P(7), Ramraj B(1), Kant S(8),

BACKGROUND: Treatment of drug-resistant tuberculosis with bedaquiline-pretomanid-linezolid regimen has demonstrated good treatment efficacy. Given linezolid's toxicity profile, prudence suggests reconsidering its dose and duration. We determined the effectiveness and safety of structured dose reduction of linezolid with bedaquiline and pretomanid in adults with pre-extensively drug-resistant (pre-XDR) or treatment-intolerant/nonresponsive multidrug-resistant (MDRTI/NR) pulmonary tuberculosis.

METHOD: Adults with pre-XDR or MDRTI/NR pulmonary tuberculosis were enrolled in a multicenter, parallel-group, randomized clinical trial in India. Patients were randomized to 26 weeks of bedaquiline, pretomanid, and daily linezolid, at 600 mg for 26 weeks (arm 1); 600 mg for 9 weeks followed by 300 mg for 17 weeks (arm 2); or 600 mg for 13 weeks followed by 300 mg for 13 weeks (arm 3). Study end points included sustained cure, bacteriological failure, toxicity, and death.

RESULTS: Of 403 patients enrolled, 255 (63%) were<30 years old, 273 (68%) had prior tuberculosis episodes, and 238 (59%) were malnourished. At the end of treatment, after excluding those with negative baseline cultures, cure was seen in 120 (93%), 117 (94%), and 115 (93%) in arms 1, 2, and 3 respectively. Myelosuppression seen in 85 patients each in arms 1 and 2 and 77 patients in arm 3, not significantly different. Peripheral neuropathy was noticed in 66 patients (30, 17, and 19 in arms 1, 2, and 3) at 10-26 weeks (P = .02). The linezolid dose was reduced because of toxicity in 13, 2, and 4 patients in arms 1, 2, and 3, respectively.

CONCLUSIONS: In adults with pre-XDR or MDRTI/NR pulmonary tuberculosis, structured linezolid dose reduction to 300 mg/d is as effective as the standard 600-mg dose but with fewer cases of peripheral neuropathy when given with bedaquiline and pretomanid.

CLINICAL TRIALS REGISTRATION: Clinical Trial Registry of India (CTRI/2021/03/032189).

PMID: 39194339

14. Bone Res. 2024 Aug 27;12(1):47. doi: 10.1038/s41413-024-00350-8.

The HOXC10/NOD1/ERK axis drives osteolytic bone metastasis of pan-KRAS-mutant lung cancer.

Li K(#)(1)(2)(3), Yang B(#)(4), Du Y(#)(4), Ding Y(4), Shen S(4)(5), Sun Z(1), Liu Y(4), Wang Y(4), Cao S(4), Ren W(4), Wang X(4), Li M(4), Zhang Y(4), Wu J(6), Zheng W(7)(8)(9), Yan W(10), Li L(11)(12)(13).

While KRAS mutation is the leading cause of low survival rates in lung cancer bone metastasis patients, effective treatments are still lacking. Here, we identified homeobox C10 (HOXC10) as a lynchpin in pan-KRAS-mutant lung cancer bone metastasis. Through RNA-seq approach and patient tissue studies, we demonstrated that HOXC10 expression was dramatically increased. Genetic depletion of HOXC10 preferentially impeded cell proliferation and migration in vitro. The bioluminescence imaging and micro-CT results demonstrated that inhibition of HOXC10 significantly reduced bone metastasis of KRAS-mutant lung cancer in vivo. Mechanistically, the transcription factor HOXC10 activated NOD1/ERK signaling pathway to reprogram epithelial-mesenchymal transition (EMT) and bone microenvironment by activating the NOD1 promoter. Strikingly, inhibition of HOXC10 in combination with STAT3 inhibitor was effective against KRAS-mutant lung cancer bone metastasis by triggering ferroptosis. Taken together, these findings reveal that HOXC10 effectively alleviates pan-KRAS-mutant lung cancer with bone metastasis in the NOD1/ERK axis-dependent manner, and support further development of an effective combinatorial strategy for this kind of disease.

PMID: 39191757 [Indexed for MEDLINE]

15. Lancet Glob Health. 2024 Oct;12(10):e1629-e1637. doi: 10.1016/S2214-109X(24)00284-5. Epub 2024 Aug 16.

Projected health and economic effects of a pan-tuberculosis treatment regimen: a modelling study.

Ryckman TS(1), McQuaid CF(2), Cohen T(3), Menzies NA(4), Kendall EA(5).

BACKGROUND: A pan-tuberculosis regimen that could be initiated without knowledge of drug susceptibility has been proposed as an objective of tuberculosis regimen development. We modelled the health and economic benefits of such a regimen and analysed which of its features contribute most to impact and savings.

METHODS: We constructed a mathematical model of tuberculosis treatment parameterised with data from the published literature specific to three countries with a high tuberculosis burden (India, the Philippines, and South

Africa). Our model simulated cohorts of newly diagnosed tuberculosis patients, including drug susceptibility testing if performed, regimen assignment, discontinuation, adherence, costs, and resulting outcomes of durable cure (microbiological cure without relapse), need for retreatment, or death. We compared a pan-tuberculosis regimen meeting the WHO 2023 target regimen profile against the standard of care of separate rifampicin-susceptible and rifampicin-resistant regimens. We estimated incremental cures; averted deaths, secondary cases, and costs; and prices below which a pan-tuberculosis regimen would be cost saving. We also assessed scenarios intended to describe which

mechanisms of benefit from a pan-tuberculosis regimen (including improved characteristics compared with the current rifampicin-susceptible and rifampicin-resistant regimens and improved regimen assignment and retention in

care for patients with rifampicin-resistant tuberculosis) would be most impactful. Results are presented as a range of means across countries with the most extreme 95% uncertainty intervals (UIs) from the three UI ranges.

FINDINGS: Compared with the standard of care, a pan-tuberculosis regimen could increase the proportion of patients durably cured after an initial treatment attempt from 69-71% (95% UI 57-80) to 75-76% (68-83), preventing 30-32% of the deaths (20-43) and 17-20% of the transmission (9-29) that occur after initial tuberculosis diagnosis. Considering savings to the health system and patients during and after the initial treatment attempt, the regimen could reduce non-drug costs by 32-42% (22-49) and would be cost saving at prices below US$170-340 (130-510). A rifamycin-containing regimen that otherwise met pan-tuberculosis targets yielded only slightly less impact, indicating that most

of the benefits from a pan-tuberculosis regimen resulted from its improvements upon the rifampicin-susceptible standard of care. Eliminating non-adherence and treatment discontinuation, for example via a long-acting injectable regimen, increased health impact and savings.

INTERPRETATION: In countries with a high tuberculosis burden, a shorter, highly efficacious, safe, and tolerable regimen to treat all tuberculosis could yield substantial health improvements and savings.

PMID: 39159654 [Indexed for MEDLINE]

16. J Infect. 2024 Aug;89(2):106200. doi: 10.1016/j.jinf.2024.106200. Epub 2024 Jun 18.

Elderly patients with tuberculosis in a low-incidence country - Clinical characteristics, inflammation and outcome.

van Arkel C(1), Storms I(2), Kurver L(3), Smeenk F(4), Wielders P(4), Hoefsloot W(5), Carpaij N(5), Boeree MJ(5), van Crevel R(3), van Laarhoven A(3), Magis-Escurra C(5).

BACKGROUND: Susceptibility to respiratory infections increases with age. Diagnosing and treating tuberculosis in the elderly comes with the challenges of fewer specific symptoms and possibly more side effects of treatment. Much is unknown when it comes to tuberculosis in the elderly, especially in relation to inflammation, which may impact mortality. We, therefore, investigated a clinical cohort of elderly tuberculosis patients.

METHODS: Patients aged ≥65 years, admitted to our tuberculosis reference center between 2005 and 2021, were retrospectively included in our cohort. Sociodemographic data, clinical characteristics, laboratory results, including

inflammatory markers at baseline (monocyte, neutrophil, lymphocyte count, and CRP levels), and treatment outcomes were collected. They were compared to the National Dutch TB Registry and analyzed using descriptive statistics. Survival analysis was performed using univariate Cox regression analysis and a log-rank test. Results were visualized in Kaplan-Meier curves.

RESULTS: 104 elderly tuberculosis patients, mostly European, with a mean age of 75 years, were included. None were HIV-infected. Miliary tuberculosis cases were overrepresented (14 %) compared to the National Dutch TB Registry (5 % in elderly, 2 % adults). Fever occurred in 77 % (57/74), and the duration of fever decreased with age. Innate immune markers, including monocyte/lymphocyte-ratio, moderately correlated with CRP. Overall mortality was 15 %, and highest (33 %) in patients with CRP levels >100 mg/mL.

CONCLUSION: In elderly tuberculosis patients in a low-incidence setting, mortality rates are higher in comparison to younger patients. The overrepresentation of miliary tuberculosis may suggest waning immunity, with a

subset of patients exhibiting strong inflammation associated with increased mortality.

PMID: 38901573 [Indexed for MEDLINE]

17. Acta Pharm Sin B. 2024 Aug;14(8):3605-3623. doi: 10.1016/j.apsb.2024.03.018. Epub 2024 Mar 16.

Discovery of first-in-class DOT1L inhibitors against the R231Q gain-of-function mutation in the catalytic domain with therapeutic potential of lung cancer.

Tan Z(1), Guo N(2), Cao Z(1), Liu S(1), Zhang J(2), Ma D(1), Zhang J(1), Lv W(2), Jiang N(1), Zang L(2), Wang L(2), Zhai X(1).

Recent research certified that DOT1L and its mutations represented by R231Q were potential targets for the treatment of lung cancer. Herein, a series of adenosine-containing derivatives were identified with DOT1LR231Q inhibition through antiproliferation assay and Western blot analysis in the H460R231Q cell. The most promising compound 37 significantly reduced DOT1LR231Q mediated H3K79 methylation and effectively inhibited the proliferation, self-renewal, migration, and invasion of lung cancer cell lines at low micromolar concentrations. The cell permeability and cellular target engagement of 37 were verified by both CETSA and DARTS assays. In the H460R231Q OE cell-derived xenograft (CDX) model, 37 displayed pronounced tumor growth inhibition after intraperitoneal administration at 20 mg/kg dose for 3 weeks (TGI = 54.38%), without obvious toxicities. A pharmacokinetic study revealed that 37 possessed tolerable properties (t 1/2 = 1.93 ± 0.91 h, F = 97.2%) after intraperitoneal administration in rats. Mechanism study confirmed that 37 suppressed malignant phenotypes of lung cancer carrying R231Q gain-of-function mutation via the MAPK/ERK signaling pathway. Moreover, analysis of the binding modes between molecules and DOT1LWT/R231Q proteins put forward the "Induced-fit" allosteric model in favor to the discovery of potent DOT1L candidates.

PMCID: PMC11365375

18. Int J Surg. 2024 Aug 1;110(8):4767-4774. doi: 10.1097/JS9.0000000000001531.

Breastfeeding may reduce the effects of maternal smoking on lung cancer mortality in adult offspring: a prospective cohort study.

Yin H(1), Wang Y(2), Wang S(1), Zhang S(1), Ling X(2), Han T(3), Sun C(3), Ma J(2), Wei W(4)(3), Zhu J(5), Wang X(2).

BACKGROUND: Although previous research has indicated a correlation between smoking and the mortality rate in patients with lung cancer, the impact of early life factors on this relationship remains unclear and requires further

investigation. This study aimed to investigate the hypothesis that breastfeeding reduces the risk of lung cancer-related death.

METHODS: The authors conducted a prospective cohort study involving 501 859 participants recruited from the United Kingdom Biobank to explore the potential association between breastfeeding and the risk of lung cancer mortality using a Cox proportional hazards model. Subsequently, the polygenic risk score for lung cancer was calculated to detect interactions between genes and the environment.

RESULTS: Over a median follow-up duration of 11.8 years, encompassing a total of 501 859 participants, breastfeeding was found to reduce the risk of lung cancer-related death and the impact of maternal smoking on lung cancer mortality in adult offspring. This association remained consistent after stratification. Furthermore, the influence of maternal smoking and breastfeeding on the risk of lung cancer mortality was significant at a high genetic risk level.

CONCLUSION: Breastfeeding can reduce the risk of lung cancer-related death and the impact of maternal smoking on lung cancer mortality in adult offspring. This correlation has the potential to reduce the probability of lung-cancer-related deaths in subsequent generations.

PMCID: PMC11326021

19. Adv Sci (Weinh). 2024 Aug 20:e2400176. doi: 10.1002/advs.202400176. Online ahead of print.

CRISPR Screening and Comparative LC-MS Analysis Identify Genes Mediating Efficacy of Delamanid and Pretomanid against Mycobacterium tuberculosis.

Yan MY(1), Li H(2), Qu YM(1), Li SS(1), Zheng D(1), Guo XP(1), Wu Z(3), Lu J(4), Pang Y(5), Li W(3), Yang J(1), Zhan L(2), Sun YC(1).

Tuberculosis (TB), the leading cause of death from bacterial infections worldwide, results from infection with Mycobacterium tuberculosis (Mtb). The antitubercular agents delamanid (DLM) and pretomanid (PMD) are nitroimidazole prodrugs that require activation by an enzyme intrinsic to Mtb; however, the mechanism(s) of action and the associated metabolic pathways are largely unclear. Profiling of the chemical-genetic interactions of PMD and DLM in Mtb using combined CRISPR screening reveals that the mutation of rv2073c increases susceptibility of Mtb to these nitroimidazole drugs both in vitro and in infected mice, whereas mutation of rv0078 increases drug resistance. Further assays show that Rv2073c might confer intrinsic resistance to DLM/PMD by interfering with inhibition of the drug target, decaprenylphophoryl-2-keto-b-D-erythro-pentose reductase (DprE2), by active nicotinamide adenine dinucleotide (NAD) adducts. Characterization of the metabolic pathways of DLM/PMD in Mtb using a combination of chemical genetics and comparative liquid chromatography-mass spectrometry (LC-MS) analysis of DLM/PMD metabolites reveals that Rv0077c, which is negatively regulated by Rv0078, mediates drug resistance by metabolizing activated DLM/PMD. These results might guide development of new nitroimidazole prodrugs and new regimens for TB treatment.

PMID: 39162029

20. J Infect. 2024 Aug;89(2):106198. doi: 10.1016/j.jinf.2024.106198. Epub 2024 Jun 19.

Prevalence of tuberculosis infection among contacts of drug-resistant tuberculosis patients: A systematic review and meta-analysis.

Akalu TY(1), Clements ACA(2), Gebreyohannes EA(3), Gilmour B(4), Alene KA(4).

INTRODUCTION: Contact investigations with drug-susceptible tuberculosis (DS-TB) patients have demonstrated a high prevalence of tuberculosis infection (TBI). However, the prevalence of TBI among individuals in close contact with drug-resistant tuberculosis (DR-TB) patients is poorly understood. This systematic review and meta-analysis aimed to determine the prevalence of TBI among household and non-household contacts of DR-TB patients.

METHOD AND ANALYSIS: We searched five databases (Medline, Embase, Scopus, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL)) from inception to 2 June 2023. All studies that reported the prevalence of TBI among DR-TB contacts were included in the study. A random-effects meta-analysis was conducted to estimate the pooled prevalence of TBI with a 95% confidence interval (CI). Sub-group analyses were conducted using study characteristics as covariates.

RESULTS: Thirty studies involving 7659 study participants from 19 countries were included. The pooled prevalence of TBI among DR-TB contacts was 36.52% (95% CI: 30.27-42.77). The sub-group analysis showed considerable heterogeneity in the estimates, with the highest prevalence reported in Southeast Asia (80.74%; 95%

CI: 74.09-87.39), household contacts (38.60%; 95% CI: 30.07-47.14), lower-middle-income countries (LMICs) (54.72; 95% CI: 35.90, 73.55), children (43.27%; 95% CI: 25.50, 61.04), and studies conducted between 2004 and 2012 (45.10; 95% CI: 32.44, 57.76).

CONCLUSION: The prevalence of TBI among DR-TB contacts was high, with substantial regional variations. Further research is needed to determine the drug susceptibility status of TBI in DR-TB contacts.

PMID: 38906264 [Indexed for MEDLINE]

21. Angew Chem Int Ed Engl. 2024 Sep 23;63(39):e202408473. doi: 10.1002/anie.202408473. Epub 2024 Aug 21.

N-Phenyl-2-Pyridone-Derived Endoperoxide Suppressing both Lung Cancer and Idiopathic Pulmonary Fibrosis Progression by Three-Pronged Action.

Wang L(1), Wu H(1), Liu Z(1), Sun R(1), Li Y(1), Si Y(1), Nie Y(1), Qiao Y(1), Qian X(1), Zhang S(1), Li G(1), Sun W(1), Pan Y(1), Akkaya EU(1).

We report an endoperoxide compound (E5) which can deliver three therapeutic components by a thermal cycloreversion, namely, singlet oxygen, triplet oxygen and 3-methyl-N-phenyl-2-pyridone (P5), thus targeting multiple mechanisms for treating non-small cell lung cancer and idiopathic pulmonary fibrosis. In aqueous environment, E5 undergoes clean reaction to afford three therapeutic components with a half-life of 8.3 hours without the generation of other by-products, which not only achieves good cytotoxicity toward lung cancer cells and decreases the levels of hypoxia-inducible factor 1α (HIF-1α) protein, but also inhibits the transforming growth factor β1 (TGF-β1) induced fibrosis in vitro. In vivo experiments also demonstrated the efficacy of E5 in inhibiting tumor growth and relieving idiopathic pulmonary fibrosis, while exhibiting good biocompatibility. Many lines of evidence reveal the therapeutic efficacy of singlet oxygen and 3-methyl-N-phenyl-2-pyridone for these two lung diseases, and triplet oxygen could downregulate HIF-1α and relieve tumor hypoxia which is a critical issue in photodynamic therapy (PDT). Unlike other combination therapies, in which multiple therapeutic agents are given in independent formulations, our work demonstrates single molecule endoperoxide prodrugs could be developed as new platforms for treatment of cancers and related diseases.

PMID: 38979839 [Indexed for MEDLINE]

22. Bioact Mater. 2024 May 11;38:384-398. doi: 10.1016/j.bioactmat.2024.04.035. eCollection 2024 Aug.

Biomimetic hydrogels with mesoscale collagen architecture for patient-derived tumor organoids culture.

Wang J(1), Sui Z(1), Huang W(2)(3), Yu Z(1), Guo L(1)(3).

Patient-derived tumor organoids (PDTOs) shows great potential as a preclinical model. However, the current methods for establishing PDTOs primarily focus on modulating local properties, such as sub-micrometer topographies. Nevertheless, they neglect to capture the global millimeter or intermediate mesoscale architecture that have been demonstrated to influence tumor response to therapeutic treatment and tumor progression. In this study, we present a rapid technique for generating collagen bundles with an average length of 90 ± 27 μm and a mean diameter of 5 ± 1.5 μm from tumor tissue debris that underwent mechanical agitation following enzymatic digestion. The collagen bundles were subsequently utilized for the fabrication of biomimetic hydrogels, incorporating microbial transglutaminase (mTG) crosslinked gelatin. These biomimetic hydrogels, referred to as MC-gel, were specifically designed for patient-derived tumor organoids. The lung cancer organoids cultured in MC-gel exhibited larger diameters and higher cell viability compared to those cultured in gels lacking the mesoscale collagen bundle; moreover, their irregular morphology more closely resembled that observed in vivo. The MC-gel-based lung cancer organoids

effectively replicated the histology and mutational landscapes observed in the original donor patient's tumor tissue. Additionally, these lung cancer organoids showed a remarkable similarity in their gene expression and drug response across different matrices. This recently developed model holds great potential for investigating the occurrence, progression, metastasis, and management of tumors, thereby offering opportunities for personalized medicine and customized treatment options.

PMCID: PMC11101944

23. J Clin Oncol. 2024 Aug 1:JCO2400048. doi: 10.1200/JCO.24.00048. Online ahead of print.

Randomized Controlled Trial of a Nurse-Led Brief Behavioral Intervention for Dyspnea in Patients With Advanced Lung Cancer.

Greer JA(1)(2), Post KE(1)(2), Chabria R(1), Aribindi S(1), Brennan N(1), Eche-Ugwu IJ(2)(3), Halpenny B(3), Fox E(3), Lo S(1)(2), Waldman LP(4), Pintro K(1), Rabideau DJ(1)(2), Pirl WF(2)(3), Cooley ME(2)(3), Temel JS(1)(2).

PURPOSE: In patients with lung cancer, dyspnea is one of the most prevalent and disabling symptoms, for which effective treatments are lacking. We examined the efficacy of a nurse-led brief behavioral intervention to improve dyspnea in patients with advanced lung cancer.

METHODS: Patients with advanced lung cancer reporting at least moderate breathlessness (n = 247) were enrolled in a randomized trial of a nurse-led two-session intervention (focused on breathing techniques, postural positions,

and fan therapy) versus usual care. At baseline and weeks 8 (primary end point), 16, and 24, participants completed measures of dyspnea (Modified Medical Research Council Dyspnea Scale [mMRCDS]; Cancer Dyspnoea Scale [CDS]), quality of life (Functional Assessment of Cancer Therapy-Lung [FACT-L]), psychological symptoms (Hospital Anxiety and Depression Scale), and activity level (Godin-Shephard Leisure Time Physical Activity Questionnaire). To examine intervention effects, we conducted analysis of covariance and longitudinal mixed effects models.

RESULTS: The sample (Agemean = 66.15 years; 55.9% female) primarily included patients with advanced non-small cell lung cancer (85.4%). Compared with usual care, the intervention improved the primary outcome of patient-reported dyspnea on the mMRCDS (difference = -0.33 [95% CI, -0.61 to -0.05]) but not the CDS total score at 8 weeks. Intervention patients also reported less dyspnea on the CDS sense of discomfort subscale (difference = -0.59 [95% CI, -1.16 to -0.01]) and better functional well-being per the FACT-L (difference = 1.39 [95% CI, 0.18

to 2.59]) versus the control group. Study groups did not differ in overall quality of life, psychological symptoms, or activity level at 8 weeks or longitudinally over 24 weeks.

CONCLUSION: For patients with advanced lung cancer, a scalable behavioral intervention alleviated the intractable symptom of dyspnea. Further research is needed on ways to enhance intervention effects over the long-term and across

additional outcomes.

PMID: 39088766

24. Nat Microbiol. 2024 Aug;9(8):2113-2127. doi: 10.1038/s41564-024-01758-y. Epub 2024 Aug 1.

Differential rates of Mycobacterium tuberculosis transmission associate with host-pathogen sympatry.

Gröschel MI(#)(1)(2)(3), Pérez-Llanos FJ(#)(4)(5)(6), Diel R(7)(8), Vargas R Jr(9), Escuyer V(10), Musser K(10), Trieu L(11), Meissner JS(11), Knorr J(11), Klinkenberg D(12), Kouw P(13), Homolka S(14), Samek W(15)(16), Mathema B(17), van Soolingen D(12), Niemann S(#)(4)(18), Ahuja SD(11), Farhat MR(#)(19)(20).

Several human-adapted Mycobacterium tuberculosis complex (Mtbc) lineages exhibit a restricted geographical distribution globally. These lineages are hypothesized to transmit more effectively among sympatric hosts, that is, those that share the same geographical area, though this is yet to be confirmed while controlling for exposure, social networks and disease risk after exposure. Using pathogen genomic and contact tracing data from 2,279 tuberculosis cases linked to 12,749 contacts from three low-incidence cities, we show that geographically restricted Mtbc lineages were less transmissible than lineages that have a widespread global distribution. Allopatric host-pathogen exposure, in which the restricted pathogen and host are from non-overlapping areas, had a 38% decrease in the odds of infection among contacts compared with sympatric exposures. We measure tenfold lower uptake of geographically restricted lineage 6 strains compared with widespread lineage 4 strains in allopatric macrophage infections. We conclude that Mtbc strain-human long-term coexistence has resulted in differential transmissibility of Mtbc lineages and that this differs by human population.

PMID: 39090390 [Indexed for MEDLINE]