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1.
Cell Host Microbe ; 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39423813

RESUMO

The optimal vaginal microbiome is a Lactobacillus-dominant community. Apart from Lactobacillus iners, the presence of Lactobacillus species is associated with reduced vaginal inflammation and reduced levels of pro-inflammatory cytokines. Loss of Lactobacillus-dominance is associated with inflammatory conditions, such as bacterial vaginosis (BV). We have identified that Lactobacillus crispatus, a key vaginal bacterial species, produces a family of ß-carboline compounds with anti-inflammatory activity. These compounds suppress nuclear factor κB (NF-κB) and interferon (IFN) signaling downstream of multiple pattern recognition receptors in primary human cells and significantly dampen type I IFN receptor (IFNAR) activation in monocytes. Topical application of an anti-inflammatory ß-carboline compound, perlolyrine, was sufficient to significantly reduce vaginal inflammation in a mouse model of genital herpes infection. These compounds are enriched in cervicovaginal lavage (CVL) of healthy people compared with people with BV. This study identifies a family of compounds by which vaginal lactobacilli mediate host immune homeostasis and highlights a potential therapeutic avenue for vaginal inflammation.

2.
Lancet Microbe ; 5(6): e570-e580, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38734030

RESUMO

BACKGROUND: Bacterial diversity could contribute to the diversity of tuberculosis infection and treatment outcomes observed clinically, but the biological basis of this association is poorly understood. The aim of this study was to identify associations between phenogenomic variation in Mycobacterium tuberculosis and tuberculosis clinical features. METHODS: We developed a high-throughput platform to define phenotype-genotype relationships in M tuberculosis clinical isolates, which we tested on a set of 158 drug-sensitive M tuberculosis strains sampled from a large tuberculosis clinical study in Ho Chi Minh City, Viet Nam. We tagged the strains with unique genetic barcodes in multiplicate, allowing us to pool the strains for in-vitro competitive fitness assays across 16 host-relevant antibiotic and metabolic conditions. Relative fitness was quantified by deep sequencing, enumerating output barcode read counts relative to input normalised values. We performed a genome-wide association study to identify phylogenetically linked and monogenic mutations associated with the in-vitro fitness phenotypes. These genetic determinants were further associated with relevant clinical outcomes (cavitary disease and treatment failure) by calculating odds ratios (ORs) with binomial logistic regressions. We also assessed the population-level transmission of strains associated with cavitary disease and treatment failure using terminal branch length analysis of the phylogenetic data. FINDINGS: M tuberculosis clinical strains had diverse growth characteristics in host-like metabolic and drug conditions. These fitness phenotypes were highly heritable, and we identified monogenic and phylogenetically linked variants associated with the fitness phenotypes. These data enabled us to define two genetic features that were associated with clinical outcomes. First, mutations in Rv1339, a phosphodiesterase, which were associated with slow growth in glycerol, were further associated with treatment failure (OR 5·34, 95% CI 1·21-23·58, p=0·027). Second, we identified a phenotypically distinct slow-growing subclade of lineage 1 strains (L1.1.1.1) that was associated with cavitary disease (OR 2·49, 1·11-5·59, p=0·027) and treatment failure (OR 4·76, 1·53-14·78, p=0·0069), and which had shorter terminal branch lengths on the phylogenetic tree, suggesting increased transmission. INTERPRETATION: Slow growth under various antibiotic and metabolic conditions served as in-vitro intermediate phenotypes underlying the association between M tuberculosis monogenic and phylogenetically linked mutations and outcomes such as cavitary disease, treatment failure, and transmission potential. These data suggest that M tuberculosis growth regulation is an adaptive advantage for bacterial success in human populations, at least in some circumstances. These data further suggest markers for the underlying bacterial processes that contribute to these clinical outcomes. FUNDING: National Health and Medical Research Council/A∗STAR, National Institutes of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, and the Wellcome Trust Fellowship in Public Health and Tropical Medicine.


Assuntos
Antituberculosos , Mycobacterium tuberculosis , Tuberculose , Humanos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Vietnã/epidemiologia , Antituberculosos/uso terapêutico , Antituberculosos/farmacologia , Estudo de Associação Genômica Ampla , Resultado do Tratamento , Fenótipo , Filogenia , Mutação , Fenômica , Genótipo , Feminino , Adulto , Masculino
3.
Cancer ; 130(18): 3170-3179, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-38795024

RESUMO

BACKGROUND: Colorectal cancer (CRC) screening is underused, particularly among low-income and minoritized populations, for whom the coronavirus disease 2019 (COVID-19) pandemic has challenged progress in achieving equity. METHODS: A hub-and-spoke model was used. The hub was a nonacademic organization and the spokes were three community health center (CHC) systems overseeing numerous clinic sites. Via a cluster-randomized trial design, nine clinic sites were randomized to intervention and 16 clinic sites were randomized to usual care. Patient-level interventions included invitation letters, mailed fecal immunochemical tests (FITs), and call/text-based reminders. Year 1 intervention impact, which took place during the COVID-19 pandemic, was assessed as the proportion completing screening among individuals not up to date at baseline, which compared intervention and nonintervention clinics accounting for intraclinic cluster variation; confidence intervals (CIs) around differences not including 0 were interpreted as statistically significant. RESULTS: Among 26,736 patients who met eligibility criteria, approximately 58% were female, 55% were Hispanic individuals, and 44% were Spanish speaking. The proportion completing screening was 11.5 percentage points (ppts) (95% CI, 6.1-16.9 ppts) higher in intervention versus usual care clinics. Variation in differences between intervention and usual care clinics was observed by sex (12.6 ppts [95% CI, 7.2-18.0 ppts] for females; 8.8 ppts [95% CI, 4.7-13.9 ppts] for males) and by racial and ethnic group (13.8 ppts [95% CI, 7.0-20.6 ppts] for Hispanic individuals; 13.0 ppts [95% CI, 3.6-22.4 ppts] for Asian individuals; 11.3 ppts [95% CI, 5.8-16.8 ppts] for non-Hispanic White individuals; 6.1 ppts [95% CI, 0.8-10.4 ppts] for Black individuals). CONCLUSIONS: A regional mailed FIT intervention was effective for increasing CRC screening rates across CHC systems serving diverse, low-income populations.


Assuntos
Neoplasias Colorretais , Detecção Precoce de Câncer , Sangue Oculto , Pobreza , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Colorretais/diagnóstico , COVID-19 , Detecção Precoce de Câncer/métodos , Fezes/química , Hispânico ou Latino/estatística & dados numéricos , Acessibilidade aos Serviços de Saúde , Disparidades em Assistência à Saúde
4.
Contemp Clin Trials ; 134: 107353, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37802222

RESUMO

BACKGROUND: Guidelines recommend screening for colorectal cancer (CRC), but participation and abnormal test follow up rates are suboptimal, with disparities by demography. Evidence-based interventions exist to promote screening, but community adoption and implementation are limited. METHODS: The San Diego Accelerating Colorectal Cancer Screening and Follow-up through Implementation Science (ACCSIS) program is an academic-community partnership testing regional implementation of a Hub-and-Spoke model for increasing CRC screening and follow-up. The "hub" is a non-academic, non-profit organization that includes 17 community health center (CHC) systems, serving over 190 rural and urban clinic sites. The "spokes" are 3 CHC systems that oversee 11-28 clinics each, totaling over 60 clinics. Using a cluster-randomized trial design, 9 clinics were randomized to intervention and 16 to usual care. Within intervention clinics, approximately 5000 eligible patients not up-to-date with CRC screening per year were identified for intervention. Interventions include an invitation primer, a mailed fecal immunochemical test with completion instructions, and phone and text-based reminders (hub) and patient navigation protocol to promote colonoscopy completion after abnormal FIT (spoke). Outcomes include: 1) proportion of patients up-to-date with screening after three years in intervention versus non-intervention clinics; 2) proportion of patients with abnormal FIT completing colonoscopy within six months of the abnormal result. Implementation science measures are collected to assess acceptability, intervention and usual care adaptations, and sustainability of the intervention strategies. CONCLUSION: This large-scale, regional cluster randomized trial among CHCs serving diverse populations is anticipated to accelerate progress in CRC prevention in underserved populations. TRIAL REGISTRATION: NCT04941300.


Assuntos
Neoplasias Colorretais , Detecção Precoce de Câncer , Humanos , Detecção Precoce de Câncer/métodos , Programas de Rastreamento/métodos , Neoplasias Colorretais/diagnóstico , Instituições de Assistência Ambulatorial , Centros Comunitários de Saúde , Sangue Oculto , Ensaios Clínicos Controlados Aleatórios como Assunto
5.
mBio ; 14(5): e0094623, 2023 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-37682004

RESUMO

IMPORTANCE: This study highlights the impact of specific rifampicin-resistance-conferring mutations on the host immune response to Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Clinical reports have previously suggested that multi-drug-resistant) TB patients exhibit altered peripheral immune responses as compared with their drug-sensitive TB counterparts. The murine model of infection with Mtb strains carrying drug-resistance-conferring mutations recapitulated these findings and allowed us to mechanistically interrogate the pathways responsible for driving the divergent immune responses. Our findings underscore the need for greater investigation into bacterial heterogeneity to better appreciate the diversity in host-pathogen interactions during TB disease.


Assuntos
Interferon Tipo I , Mycobacterium tuberculosis , Tuberculose , Humanos , Animais , Camundongos , Mycobacterium tuberculosis/genética , Rifampina/farmacologia , Interferon Tipo I/genética , Mutação , Antituberculosos/farmacologia , RNA Polimerases Dirigidas por DNA/genética , Testes de Sensibilidade Microbiana , Proteínas de Bactérias/genética
6.
Infect Immun ; 91(10): e0020123, 2023 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-37754680

RESUMO

Hematopoietic stem and progenitor cells (HSPCs) play a vital role in the host response to infection through the rapid and robust production of mature immune cells. These HSPC responses can be influenced, directly and indirectly, by pathogens as well. Infection with Mycobacterium tuberculosis (Mtb) can drive lymphopoiesis through modulation of type I interferon (IFN) signaling. We have previously found that the presence of a drug resistance (DR)-conferring mutation in Mtb drives altered host-pathogen interactions and heightened type I IFN production in vitro. But the impacts of this DR mutation on in vivo host responses to Mtb infection, particularly the hematopoietic compartment, remain unexplored. Using a mouse model, we show that, while drug-sensitive Mtb infection induces expansion of HSPC subsets and a skew toward lymphopoiesis, DR Mtb infection fails to induce an expansion of these subsets and an accumulation of mature granulocytes in the bone marrow. Using single-cell RNA sequencing, we show that the HSCs from DR Mtb-infected mice fail to upregulate pathways related to cytokine signaling across all profiled HSC subsets. Collectively, our studies report a novel finding of a chronic infection that fails to induce a potent hematopoietic response that can be further investigated to understand pathogen-host interaction at the level of hematopoiesis.


Assuntos
Infecções Bacterianas , Mycobacterium tuberculosis , Tuberculose , Humanos , Medula Óssea , Células-Tronco Hematopoéticas , Mycobacterium tuberculosis/fisiologia , Hematopoese/fisiologia , Infecções Bacterianas/metabolismo , Células da Medula Óssea
7.
bioRxiv ; 2023 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-37090677

RESUMO

Background: Combatting the tuberculosis (TB) epidemic caused by Mycobacterium tuberculosis ( Mtb ) necessitates a better understanding of the factors contributing to patient clinical outcomes and transmission. While host and environmental factors have been evaluated, the impact of Mtb genetic background and phenotypic diversity is underexplored. Previous work has made associations between Mtb genetic lineages and some clinical and epidemiological features, but the bacterial traits underlying these connections are largely unknown. Methods: We developed a high-throughput functional genomics platform for defining genotype-phenotype relationships across a panel of Mtb clinical isolates. These phenotypic fitness profiles function as intermediate traits which can be linked to Mtb genetic variants and associated with clinical and epidemiological outcomes. We applied this approach to a collection of 158 Mtb strains from a study of Mtb transmission in Ho Chi Minh City, Vietnam. Mtb strains were genetically tagged in multiplicate, which allowed us to pool the strains and assess in vitro competitive fitness using deep sequencing across a set of 14 host-relevant antibiotic and metabolic conditions. Phylogenetic and monogenic associations with these intermediate traits were identified and then associated with clinical outcomes. Findings: Mtb clinical strains have a broad range of growth and drug response dynamics that can be clustered by their phylogenetic relationships. We identified novel monogenic associations with Mtb fitness in various metabolic and antibiotic conditions. Among these, we find that mutations in Rv1339 , a phosphodiesterase, which were identified through their association with slow growth in glycerol, are further associated with treatment failure. We also identify a previously uncharacterized subclade of Lineage 1 strains (L1.1.1.1) that is phenotypically distinguished by slow growth under most antibiotic and metabolic stress conditions in vitro . This clade is associated with cavitary disease, treatment failure, and demonstrates increased transmission potential. Interpretation: High-throughput phenogenotyping of Mtb clinical strains enabled bacterial intermediate trait identification that can provide a mechanistic link between Mtb genetic variation and patient clinical outcomes. Mtb strains associated with cavitary disease, treatment failure, and transmission potential display intermediate phenotypes distinguished by slow growth under various antibiotic and metabolic conditions. These data suggest that Mtb growth regulation is an adaptive advantage for host bacterial success in human populations, in at least some circumstances. These data further suggest markers for the underlying bacterial processes that govern these clinical outcomes. Funding: National Institutes of Allergy and Infectious Diseases: P01 AI132130 (SS, SMF); P01 AI143575 (XW, SMF); U19 AI142793 (QL, SMF); 5T32AI132120-03 (SS); 5T32AI132120-04 (SS); 5T32AI049928-17 (SS) Wellcome Trust Fellowship in Public Health and Tropical Medicine: 097124/Z/11/Z (NTTT) National Health and Medical Research Council (NHMRC)/A*STAR joint call: APP1056689 (SJD) The funding sources had no involvement in study methodology, data collection, analysis, and interpretation nor in the writing or submission of the manuscript. Research in context: Evidence before this study: We used different combinations of the words mycobacterium tuberculosis, tuberculosis, clinical strains, intermediate phenotypes, genetic barcoding, phenogenomics, cavitary disease, treatment failure, and transmission to search the PubMed database for all studies published up until January 20 th , 2022. We only considered English language publications, which biases our search. Previous work linking Mtb determinants to clinical or epidemiological data has made associations between bacterial lineage, or less frequently, genetic polymorphisms to in vitro or in vivo models of pathogenesis, transmission, and clinical outcomes such as cavitary disease, treatment failure, delayed culture conversion, and severity. Many of these studies focus on the global pandemic Lineage 2 and Lineage 4 Mtb strains due in part to a deletion in a polyketide synthase implicated in host-pathogen interactions. There are a number of Mtb GWAS studies that have led to novel genetic determinants of in vitro drug resistance and tolerance. Previous Mtb GWAS analyses with clinical outcomes did not experimentally test any predicted phenotypes of the clinical strains. Published laboratory-based studies of Mtb clinical strains involve relatively small numbers of strains, do not identify the genetic basis of relevant phenotypes, or link findings to the corresponding clinical outcomes. There are two recent studies of other pathogens that describe phenogenomic analyses. One study of 331 M. abscessus clinical strains performed one-by-one phenotyping to identify bacterial features associated with clearance of infection and another details a competition experiment utilizing three barcoded Plasmodium falciparum clinical isolates to assay antimalarial fitness and resistance. Added value of this study: We developed a functional genomics platform to perform high-throughput phenotyping of Mtb clinical strains. We then used these phenotypes as intermediate traits to identify novel bacterial genetic features associated with clinical outcomes. We leveraged this platform with a sample of 158 Mtb clinical strains from a cross sectional study of Mtb transmission in Ho Chi Minh City, Vietnam. To enable high-throughput phenotyping of large numbers of Mtb clinical isolates, we applied a DNA barcoding approach that has not been previously utilized for the high-throughput analysis of Mtb clinical strains. This approach allowed us to perform pooled competitive fitness assays, tracking strain fitness using deep sequencing. We measured the replicative fitness of the clinical strains in multiplicate under 14 metabolic and antibiotic stress condition. To our knowledge, this is the largest phenotypic screen of Mtb clinical isolates to date. We performed bacterial GWAS to delineate the Mtb genetic variants associated with each fitness phenotype, identifying monogenic associations with several conditions. We then defined Mtb phenotypic and genetic features associated with clinical outcomes. We find that a subclade of Mtb strains, defined by variants largely involved in fatty acid metabolic pathways, share a universal slow growth phenotype that is associated with cavitary disease, treatment failure and increased transmission potential in Vietnam. We also find that mutations in Rv1339 , a poorly characterized phosphodiesterase, also associate with slow growth in vitro and with treatment failure in patients. Implications of all the available evidence: Phenogenomic profiling demonstrates that Mtb strains exhibit distinct growth characteristics under metabolic and antibiotic stress conditions. These fitness profiles can serve as intermediate traits for GWAS and association with clinical outcomes. Intermediate phenotyping allows us to examine potential processes by which bacterial strain differences contribute to clinical outcomes. Our study identifies clinical strains with slow growth phenotypes under in vitro models of antibiotic and host-like metabolic conditions that are associated with adverse clinical outcomes. It is possible that the bacterial intermediate phenotypes we identified are directly related to the mechanisms of these outcomes, or they may serve as markers for the causal yet unidentified bacterial determinants. Via the intermediate phenotyping, we also discovered a surprising diversity in Mtb responses to the new anti-mycobacterial drugs that target central metabolic processes, which will be important in considering roll-out of these new agents. Our study and others that have identified Mtb determinants of TB clinical and epidemiological phenotypes should inform efforts to improve diagnostics and drug regimen design.

8.
J Natl Cancer Inst ; 113(8): 962-968, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-32780851

RESUMO

The 2019 novel coronavirus disease (COVID-19) pandemic has dramatically impacted numerous health and economic fronts. Because of the stay-at-home mandate and practice of physical distancing, nearly all preventive care measures have been halted, including colorectal cancer (CRC) screening. The health consequences of this temporary suspension are of great concern, particularly for underserved populations, who experience substantial CRC-related disparities. In this commentary, we describe challenges and opportunities to deliver COVID-19-adapted CRC screening to medically underserved populations receiving care in community health centers (CHC). This perspective is based on key informant interviews with CHC medical directors, teleconference discussions, and strategic planning assessments. To address the unprecedented challenges created by the COVID-19 pandemic, we identify 2 broad calls to action: invest in CHCs now and support equitable and adaptable telehealth solutions now and in the future. We also recommend 4 CRC-specific calls to action: establish COVID-19-adapted best practices to implement mailed fecal immunochemical test programs, implement grassroots advocacy to identify community gastroenterologists who commit to performing colonoscopies for CHC patients, assess cancer prevention priorities among individuals in underserved communities, and assess regional CRC screening and follow-up barriers and solutions. The COVID-19 pandemic may further exacerbate existing CRC screening disparities in underserved individuals. This will likely lead to delayed diagnosis, a shift to later-stage disease, and increased CRC deaths. To prevent this from happening, we call for timely action and a commitment to address the current extraordinary CRC screening challenges for vulnerable populations.


Assuntos
COVID-19/diagnóstico , Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer , Pandemias , COVID-19/complicações , COVID-19/epidemiologia , COVID-19/virologia , Colonoscopia , Neoplasias Colorretais/complicações , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/virologia , Programas de Rastreamento , Área Carente de Assistência Médica , Sangue Oculto , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/patogenicidade , Telemedicina/tendências
9.
Prof Case Manag ; 26(1): 11-18, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33214506

RESUMO

PURPOSE/OBJECTIVES: During the global pandemic of Covid-19, the hospital setting transitional care management was challenged by the complexities of the rapidly changing health care environment, requiring the implementation of an innovative approach to hospital discharge planning. The purpose of this article is to review the experiences of an integrated urban health system, exploring the strategic tactics to ensure effective communication between team members, patient and family engagement in discharge planning, establishing and maintaining trust, connecting patients to appropriate next level of care services, and providing transitional care management support. PRIMARY PRACTICE SETTINGS: The Covid-19 pandemic response stimulated the rapid transformation of the acute care management model amidst the tremendous challenge of meeting the discharge planning needs of the hospitalized population in one large, urban, integrated health care system. FINDINGS/CONCLUSIONS: Patients transitioning to the community setting following discharge are vulnerable and at risk for adverse sequelae, and transitional care management that does not end when the patient leaves the hospital setting is integral to promoting positive patient outcomes (Naylor, Aiken, Kurtzman, Olds, & Hirschman, 2011). The care management approach during the pandemic in one health care system precipitously shifted to an entirely virtual, remote model, and the team continued to provide transitional care support for hospitalized patients to avoid the common pitfalls that are associated with unfavorable outcomes. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: The insights gleaned from one health system's experiences during the pandemic are transferable to other facets of care management in routine circumstances, with emphasis on the avoidance of the common care management snares that lead to less than optimal patient outcomes. The development and implementation of multifaceted interventions, with the goals of supporting health-promoting behavior changes and self-care capacity for at risk populations, are relevant in the current health care environment.


Assuntos
COVID-19/terapia , Pandemias , COVID-19/epidemiologia , COVID-19/virologia , Cuidados Críticos , Humanos , Alta do Paciente , SARS-CoV-2/isolamento & purificação , Cuidado Transicional
10.
Trends Microbiol ; 28(10): 832-850, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32409147

RESUMO

Over a quarter of the world's population is infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Approximately 3.4% of new and 18% of recurrent cases of TB are multidrug-resistant (MDR) or rifampicin-resistant. Recent evidence has shown that certain drug-resistant strains of Mtb modulate host metabolic reprogramming, and therefore immune responses, during infection. However, it remains unclear how widespread these mechanisms are among circulating MDR Mtb strains and what impact drug-resistance-conferring mutations have on immunometabolism during TB. While few studies have directly addressed metabolic reprogramming in the context of drug-resistant Mtb infection, previous literature examining how drug-resistance mutations alter Mtb physiology and differences in the immune response to drug-resistant Mtb provides significant insights into how drug-resistant strains of Mtb differentially impact immunometabolism.


Assuntos
Mycobacterium tuberculosis/metabolismo , Tuberculose/imunologia , Tuberculose/microbiologia , Animais , Antituberculosos/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Humanos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Rifampina/farmacologia
12.
Nature ; 570(7762): 528-532, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31168092

RESUMO

Tuberculosis is the leading cause of death by an infectious disease worldwide1. However, the involvement of innate lymphoid cells (ILCs) in immune responses to infection with Mycobacterium tuberculosis (Mtb) is unknown. Here we show that circulating subsets of ILCs are depleted from the blood of participants with pulmonary tuberculosis and restored upon treatment. Tuberculosis increased accumulation of ILC subsets in the human lung, coinciding with a robust transcriptional response to infection, including a role in orchestrating the recruitment of immune subsets. Using mouse models, we show that group 3 ILCs (ILC3s) accumulated rapidly in Mtb-infected lungs and coincided with the accumulation of alveolar macrophages. Notably, mice that lacked ILC3s exhibited a reduction in the accumulation of early alveolar macrophages and decreased Mtb control. We show that the C-X-C motif chemokine receptor 5 (CXCR5)-C-X-C motif chemokine ligand 13 (CXCL13) axis is involved in Mtb control, as infection upregulates CXCR5 on circulating ILC3s and increases plasma levels of its ligand, CXCL13, in humans. Moreover, interleukin-23-dependent expansion of ILC3s in mice and production of interleukin-17 and interleukin-22 were found to be critical inducers of lung CXCL13, early innate immunity and the formation of protective lymphoid follicles within granulomas. Thus, we demonstrate an early protective role for ILC3s in immunity to Mtb infection.


Assuntos
Imunidade Inata/imunologia , Linfócitos/classificação , Linfócitos/imunologia , Macrófagos Alveolares/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Animais , Quimiocina CXCL13/imunologia , Feminino , Granuloma/imunologia , Granuloma/patologia , Humanos , Interleucina-17/imunologia , Interleucinas/imunologia , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Linfócitos/metabolismo , Macrófagos Alveolares/metabolismo , Masculino , Camundongos , Receptores CXCR5/imunologia , Transcriptoma/genética , Tuberculose Pulmonar/genética , Interleucina 22
14.
Nat Microbiol ; 3(10): 1099-1108, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30224802

RESUMO

Tuberculosis is a significant global health threat, with one-third of the world's population infected with its causative agent Mycobacterium tuberculosis (Mtb). The emergence of multidrug-resistant (MDR) Mtb that is resistant to the frontline anti-tubercular drugs rifampicin and isoniazid forces treatment with toxic second-line drugs. Currently, ~4% of new and ~21% of previously treated tuberculosis cases are either rifampicin-drug-resistant or MDR Mtb infections1. The specific molecular host-pathogen interactions mediating the rapid worldwide spread of MDR Mtb strains remain poorly understood. W-Beijing Mtb strains are highly prevalent throughout the world and associated with increased drug resistance2. In the early 1990s, closely related MDR W-Beijing Mtb strains (W strains) were identified in large institutional outbreaks in New York City and caused high mortality rates3. The production of interleukin-1ß (IL-1ß) by macrophages coincides with the shift towards aerobic glycolysis, a metabolic process that mediates protection against drug-susceptible Mtb4. Here, using a collection of MDR W-Mtb strains, we demonstrate that the overexpression of Mtb cell wall lipids, phthiocerol dimycocerosates, bypasses the interleukin 1 receptor, type I (IL-1R1) signalling pathway, instead driving the induction of interferon-ß (IFN-ß) to reprogram macrophage metabolism. Importantly, Mtb carrying a drug resistance-conferring single nucleotide polymorphism in rpoB (H445Y)5 can modulate host macrophage metabolic reprogramming. These findings transform our mechanistic understanding of how emerging MDR Mtb strains may acquire drug resistance single nucleotide polymorphisms, thereby altering Mtb surface lipid expression and modulating host macrophage metabolic reprogramming.


Assuntos
Proteínas de Bactérias/genética , Parede Celular/química , RNA Polimerases Dirigidas por DNA/genética , Farmacorresistência Bacteriana Múltipla/genética , Interações Hospedeiro-Patógeno , Macrófagos/metabolismo , Mycobacterium tuberculosis/genética , Tuberculose/imunologia , Animais , Antituberculosos/farmacologia , Parede Celular/genética , Células Cultivadas , Feminino , Expressão Gênica , Interferon beta/metabolismo , Interleucina-1/metabolismo , Lipídeos/genética , Macrófagos/microbiologia , Masculino , Camundongos , Mycobacterium tuberculosis/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-1/metabolismo , Rifampina/farmacologia , Transdução de Sinais
15.
Mucosal Immunol ; 11(6): 1727-1742, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30115997

RESUMO

C-C motif chemokine receptor 2 (CCR2) is a major chemokine axis that recruits myeloid cells including monocytes and macrophages. Thus far, CCR2-/- mice have not been found to be susceptible to infection with Mycobacterium tuberculosis (Mtb). Here, using a prototype W-Beijing family lineage 2 Mtb strain, HN878, we show that CCR2-/- mice exhibit increased susceptibility to tuberculosis (TB). Following exposure to Mtb HN878, alveolar macrophages (AMs) are amongst the earliest cells infected. We show that AMs accumulate early in the airways following infection and express CCR2. During disease progression, CCR2-expressing AMs exit the airways and localize within the TB granulomas. RNA-sequencing of sorted airway and non-airway AMs from infected mice show distinct gene expression profiles, suggesting that upon exit from airways and localization within granulomas, AMs become classically activated. The absence of CCR2+ cells specifically at the time of AM egress from the airways resulted in enhanced susceptibility to Mtb infection. Furthermore, infection with an Mtb HN878 mutant lacking phenolic glycolipid (PGL) expression still resulted in increased susceptibility in CCR2-/- mice. Together, these data show a novel role for CCR2 in protective immunity against clinically relevant Mtb infections.


Assuntos
Granuloma/imunologia , Macrófagos/imunologia , Mycobacterium tuberculosis/fisiologia , Receptores CCR2/metabolismo , Tuberculose/imunologia , Animais , Movimento Celular , Quimiocina CCL2/metabolismo , Predisposição Genética para Doença , Humanos , Pulmão/patologia , Ativação de Macrófagos/genética , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium tuberculosis/patogenicidade , Receptores CCR2/genética , Transcriptoma , Virulência
16.
G3 (Bethesda) ; 8(3): 815-822, 2018 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-29305388

RESUMO

Received wisdom in the field of fungal biology holds that the process of editing a genome by transformation and homologous recombination is inherently mutagenic. However, that belief is based on circumstantial evidence. We provide the first direct measurement of the effects of transformation on a fungal genome by sequencing the genomes of 29 transformants and 30 untransformed controls with high coverage. Contrary to the received wisdom, our results show that transformation of DNA segments flanked by long targeting sequences, followed by homologous recombination and selection for a drug marker, is extremely safe. If a transformation deletes a gene, that may create selective pressure for a few compensatory mutations, but even when we deleted a gene, we found fewer than two point mutations per deletion strain, on average. We also tested these strains for changes in gene expression and found only a few genes that were consistently differentially expressed between the wild type and strains modified by genomic insertion of a drug resistance marker. As part of our report, we provide the assembled genome sequence of the commonly used laboratory strain Cryptococcus neoformans var. grubii strain KN99α.


Assuntos
Cryptococcus neoformans/genética , Transformação Genética , Variações do Número de Cópias de DNA , Deleção de Genes , Regulação Fúngica da Expressão Gênica , Genoma Fúngico , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Mutagênese Insercional , Fenótipo , Genética Reversa , Análise de Sequência de DNA , Deleção de Sequência
17.
Nat Immunol ; 18(2): 132-141, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28092376

RESUMO

Inflammation is emerging as a critical mechanism underlying neurological disorders of various etiologies, yet its role in altering brain function as a consequence of neuroinfectious disease remains unclear. Although acute alterations in mental status due to inflammation are a hallmark of central nervous system (CNS) infections with neurotropic pathogens, post-infectious neurologic dysfunction has traditionally been attributed to irreversible damage caused by the pathogens themselves. More recently, studies indicate that pathogen eradication within the CNS may require immune responses that interfere with neural cell function and communication without affecting their survival. In this Review we explore inflammatory processes underlying neurological impairments caused by CNS infection and discuss their potential links to established mechanisms of psychiatric and neurodegenerative diseases.


Assuntos
Encéfalo/imunologia , Sistema Nervoso Central/imunologia , Doenças do Sistema Nervoso/imunologia , Neuroimunomodulação , Viroses/imunologia , Animais , Encéfalo/virologia , Sistema Nervoso Central/virologia , Humanos , Imunidade , Inflamação Neurogênica , Carga Viral/imunologia
18.
Environ Manage ; 53(3): 583-93, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24385066

RESUMO

Few published studies present data on relationships between fish mercury and surface or pore water sulfate concentrations, particularly on an ecosystem-wide basis. Resource managers can use these relationships to identify the sulfate conditions that contain fish with health-concerning total mercury (THg) levels and to evaluate the role of sulfate in methyl-mercury (MeHg) production. In this study, we derived relationships between THg in three fish trophic levels (mosquitofish, sunfish, and age-1 largemouth bass) and surface water sulfate from 1998 to 2009 for multiple stations across the Everglades Protection Area (EPA). Results show the relationship between sulfate and fish THg in each fish type is nonlinear and largely skewed, similar to the relationship between MeHg production and sulfate concentration in peatland sediment pore water identified by other researchers. Peak fish THg levels occurred in ~1 to 12 mg/L sulfate conditions. There was significant variability in the fish THg data, and there were several instances of high-fish THg levels in high-sulfate conditions (>30 mg/L). Health-concerning fish THg levels were present in all surface water sulfate conditions; however, most of these levels occurred in 1-20 mg/L sulfate. The data in this study, including recent studies, show consistent and identifiable areas of high- and low-fish THg across the spectrum of surface water sulfate concentration, therefore, applying an ecosystem-wide sulfur strategy may be an effective management approach as it would significantly reduce MeHg risk in the EPA.


Assuntos
Conservação dos Recursos Naturais/estatística & dados numéricos , Ecossistema , Peixes/metabolismo , Contaminação de Alimentos , Água Doce/química , Mercúrio/análise , Sulfatos/análise , Poluentes Químicos da Água/análise , Animais , Monitoramento Ambiental/estatística & dados numéricos , Florida
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