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Mycobacterium tuberculosis (Mtb) is responsible for approximately 1.5 million deaths each year. Though 10% of patients develop tuberculosis (TB) after infection, 90% of these infections are latent. Further, mice are nearly uniformly susceptible to Mtb but their M1-polarized macrophages (M1-MΦs) can inhibit Mtb in vitro, suggesting that M1-MΦs may be able to regulate anti-TB immunity. We sought to determine whether human MΦ heterogeneity contributes to TB immunity. Here we show that IFN-γ-programmed M1-MΦs degrade Mtb through increased expression of innate immunity regulatory genes (Inregs). In contrast, IL-4-programmed M2-polarized MΦs (M2-MΦs) are permissive for Mtb proliferation and exhibit reduced Inregs expression. M1-MΦs and M2-MΦs express pro- and anti-inflammatory cytokine-chemokines, respectively, and M1-MΦs show nitric oxide and autophagy-dependent degradation of Mtb, leading to increased antigen presentation to T cells through an ATG-RAB7-cathepsin pathway. Despite Mtb infection, M1-MΦs show increased histone acetylation at the ATG5 promoter and pro-autophagy phenotypes, while increased histone deacetylases lead to decreased autophagy in M2-MΦs. Finally, Mtb-infected neonatal macaques express human Inregs in their lymph nodes and macrophages, suggesting that M1 and M2 phenotypes can mediate immunity to TB in both humans and macaques. We conclude that human MФ subsets show unique patterns of gene expression that enable differential control of TB after infection. These genes could serve as targets for diagnosis and immunotherapy of TB., (© 2022. The Author(s).)

Tuberculosis genotypic clustering is used as a proxy for recent transmission. The association between clustering and recent transmission becomes problematic when the genotyping method lacks specificity in defining a cluster, as well as for clusters with extensive jurisdictional histories and/or common genotypes. We investigated the four largest spoligotype/12 loci MIRU-VNTR-defined clusters in Harris County, Texas from 2006-2012 to determine their historical contribution to tuberculosis morbidity, estimate the contributions from recent and remote transmission, and determine the impact of secondary genotyping on cluster definition. The clusters contained 189, 64, 51 and 38 cases. Each cluster was linked to cluster(s) previously identified by Houston Tuberculosis Initiative; 3 since 1995 and the fourth in 2002. Among cases for which timing of Mycobacterium tuberculosis transmission relative to tuberculosis disease could be ascertained, nearly equal proportions were associated with recent and remote transmission. The extent to which genotyping with an additional 12 MIRU-VNTR loci modified the cluster definition varied from little or no impact for the two smaller clusters to moderate impact for the larger clusters. Tuberculosis control measures to reduce morbidity associated with large clusters must involve strategies to identify and treat individuals who recently acquired infection, as well as persons infected for years., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Tuberculosis (TB) surveillance among the homeless is not supported by the political will necessary for TB elimination. We merged the first stakeholder-accepted enumeration of homeless persons with existing surveillance data to assess TB risk among the homeless in Houston, Texas. The average incidence per 100,000 was 411 among homeless and 9.5 among housed persons. The homeless were more likely than the housed to be US-born, clustered, and in a larger-sized cluster. Multivariate analysis revealed that TB rates among the homeless were driven not by comorbidities but by social determinants. Homeless patients were hospitalized more days than the housed and required more follow-up time. Reporting of TB rates for populations with known health disparities could help reframe TB prevention and better target limited funds.

Background: The epidemiology of pediatric tuberculosis (TB) from 1995 to 2000 in Harris County, TX, has been previously reported. This study was conducted to evaluate the continued trends of Mycobacterium tuberculosis clustering and the role of genotyping in pediatric TB., Methods: Data came from the Houston Tuberculosis Initiative, a prospective population-based active surveillance and molecular epidemiology project. The study population consisted of TB patients ≤18 years of age diagnosed in Harris County, TX, from 2000 to 2004. Available Mycobacterium tuberculosis isolates were characterized by insertion sequence 6110 restriction fragment length polymorphism and spoligotyping., Results: One hundred three pediatric TB cases were enrolled in the Houston Tuberculosis Initiative study from 2000 to 2004. Sixty-one (59%) patients had potential source cases. Mycobacterium tuberculosis isolates were available and genotyped for 36 pediatric cases; 27 (75%) were clustered into 22 different genotypes. Of the 20 genotyped patients with a potential source case, 16 (80%) were clustered. Genotypes matched the potential source case in 12 cases. Eleven of the 16 (69%) genotyped patients without a potential source case were clustered., Conclusions: Compared with pediatric cases between 1995 and 2000, there was a significant increase in the number of patients with unknown potential source cases that were clustered within the Houston Tuberculosis Initiative database. Because genotypic clustering is associated with recent transmission, there appears to be a failure in the identification of potential source cases through contact tracing. Reduced funding of public health departments forces more limited TB control activities and therefore could pose a threat to TB control.

To reach the tuberculosis (TB) elimination goals established by the Institute of Medicine (IOM) and the Centers for Disease Control and Prevention (CDC), measures must be taken to speed the currently stagnant TB elimination rate and curtail a future peak in TB incidence. Increases in TB incidence have historically coincided with immigration, poverty, and joblessness; all situations that are currently occurring worldwide. Effective TB elimination strategies will require the geographical elucidation of areas within the U.S. that have endemic TB, and systematic surveillance of the locations and location-based risk factors associated with TB transmission. Surveillance data was used to assess the spatial distribution of cases, the yearly TB incidence by census tract, and the statistical significance of case clustering. The analysis revealed that there are neighborhoods within Houston/Harris County that had a heavy TB burden. The maximum yearly incidence varied from 245/100,000-754/100,000 and was not exclusively dependent of the number of cases reported. Geographically weighted regression identified risk factors associated with the spatial distribution of cases such as: poverty, age, Black race, and foreign birth. Public transportation was also associated with the spatial distribution of cases and census tracts identified as high incidence were found to be irregularly clustered within communities of varied SES., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Previous geospatial analysis of the well-defined Houston Tuberculosis Initiative (HTI) database identified an association between the use of city-bus transportation (inclusive of time onboard) and Tuberculosis (TB) incidence in Houston/Harris County census tracts (paper submitted). This paper is an extension of those findings. Contact investigations on school buses have reported a high rate of positive tuberculin skin tests in the persons traveling with the index case and have shown an association with bus ride duration. In Houston, city bus routes are veins connecting even the most diverse of populations within the metropolitan area. Among HTI participants, TB patients who reported weekly bus use were more likely to have demographic and social risk factors associated with poverty, immune suppression and health disparities. An equal proportion of bus riders and non-bus riders were cultured for Mycobacterium tuberculosis (MTB), yet 75% of bus riders were clustered with a mean cluster size of 50.14, indicating recent transmission, compared to 56% of non-bus riders (OR = 2.4, p < 0.001) with a mean cluster size of 28.9 (p < 0.01). Individual bus routes, including one route servicing the local hospitals, were found to be risk factors for endemic MTB clustered strains and the routes themselves geographically connect the census tracts previously identified as having endemic TB., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Tuberculosis (TB) rates in the United States are disproportionately high for certain ethnic minorities. Using univariate and multivariate analyses, we compared data for 1,318 US-born blacks with 565 US-born non-Hispanic whites who participated in the Houston TB Initiative (1995-2004). All available Mycobacterium tuberculosis isolates underwent susceptibility and genotype testing (insertion sequence 6110 restriction fragment length polymorphism, spoligotyping, and genetic grouping). TB in blacks was associated with younger age, inner city residence, HIV seropositivity, and drug resistance. TB cases clustered in 82% and 77% of blacks and whites, respectively (p = 0.46). Three clusters had >100 patients each, including 1 cluster with a predominance of blacks. Size of TB clusters was unexpectedly large, underscoring the ongoing transmission of TB in Houston, particularly among blacks.

Tuberculosis (TB) is the leading cause of death worldwide due to an infectious agent. Data have accumulated over decades suggesting that variability in human susceptibility to TB disease has a genetic component. Toll-like receptors (TLRs) play a critical role in initiating the innate immune response to many pathogens in mouse models, but little is known about their role in human infections. Human TLRs have been reported to recognize mycobacterial antigens and initiate an immune response. We tested the hypothesis that amino acid-altering polymorphisms in five TLRs were associated with susceptibility to TB disease using a population-based case-control study with 1,312 adult TB patients and controls. Full-coding region sequencing of the five TLR genes in all 1,312 subjects yielded a data set in excess of 16 Mb. Rare nonsynonymous polymorphisms in TLR6-TLR1-TLR10 were significantly overrepresented among African-American TB cases compared with ethnically-matched control subjects. Common nonsynonymous polymorphisms in TLR6-TLR1-TLR10 also were significantly associated with TB disease in certain ethnic groups. Among African Americans, homozygotes for the common-variant haplotype TLR1-248S, TLR1-602I, and TLR6-249S had a significantly increased TB disease risk. A transmission/disequilibrium test on an independent sample found that the TLR1-248S variant was preferentially transmitted to diseased children, thereby confirming disease association. These results are consistent with recent reports implicating TLR1 variants, including TLR1-602, in significantly altered innate immune responses. Also consistent with disease association, rare TLR6 variants were defective in their ability to mediate NF-kappaB signal transduction in transfected human cells. Taken together, the data suggest that variant TLRs contribute to human susceptibility to TB disease. Extensive full-exon resequencing was critical for revealing new information about the role of TLRs in human-pathogen interactions and the genetic basis of innate immune function.

Screening for latent tuberculosis infection (LTBI) with Mantoux tuberculin skin test (TST) has many limitations, including false-positive results due to exposure to Mycobacterium other than tuberculosis (TB) and BCG vaccination. A total of 474 adult inmates in a county jail were screened for LTBI using TST and a new ESAT-6/CFP-10 peptide-based whole-blood gamma interferon (IFN-gamma) assay. LTBI prevalence was 9.0 and 5.4% as determined by TST and IFN-gamma assay, respectively. Overall, agreement between test results was 90% (kappa = 0.25). Positive TST results were significantly associated with increased age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.01 to 1.08), African-American ethnicity (OR, 4.97; 95% CI, 1.58 to 15.68), foreign birth (OR, 20.20; 95% CI, 4.21 to 97.02) and prior incarceration (OR, 6.19; 95% CI, 1.48 to 25.95). Positive IFN-gamma assay results were significantly associated with African-American ethnicity (OR, 5.58; 95% CI, 1.16 to 26.74). Factors associated with statistically significant discordance between TST and IFN-gamma assay results were African-American ethnicity (OR, 0.29; 95% CI, 0.11 to 0.77), foreign birth (OR, 0.23; 95% CI, 0.07-0.80), and prior incarceration (OR, 0.06; 95% CI, 0.01-0.50). Among subjects born in the United States, African-American ethnicity was the only variable significantly associated with positive test results for both TST (OR, 4.26; 95% CI, 1.38 to 13.16) and IFN-gamma assay (OR, 5.74; 95% CI, 1.19 to 27.75) and remained associated with statistically significant discordance between TST and IFN-gamma assay results. The reactivity of the new IFN-gamma assay is unaffected by prior BCG vaccination or serial TSTs but may be diminished in African-Americans. Future longitudinal studies are needed to assess the sensitivity and specificity of this new assay in detecting LTBI.

Objective: To investigate the transmission dynamics of pediatric tuberculosis (TB) by analyzing the clinical characteristics with the molecular profiles of Mycobacterium tuberculosis isolates during a 5-year period., Methods: A retrospective review of a prospective population-based active surveillance and molecular epidemiology project was conducted in private and public pediatric clinics within Houston and Harris County, Texas. The study population consisted of patients who had pediatric TB diagnosed from October 1, 1995, through September 30, 2000. Cases and potential source cases (PSC) were interviewed using a standardized questionnaire. Available Mycobacterium tuberculosis isolates from cases and PSCs were characterized and compared by IS6110 restriction fragment length polymorphism, spoligotyping, and genetic group assignment. Clinical characteristics were described, and molecular characterizations were compared. Data were analyzed by using EpiInfo 6.02b and SAS 8.2., Results: A total of 220 (92%) of 238 pediatric TB cases were included. Epidemiologic and clinical findings were consistent with previous studies. Molecular profiles from 3 cases did not match the profile of PSC. Four previously unknown PSCs were identified using molecular techniques. Fifty-one (71.8%) of 71 isolates matched at least 1 other Houston Tuberculosis Initiative TB database isolate and were grouped into 33 molecular clusters. Cases were more likely to be clustered when the patients were younger than 5 years, identified a source case, or were US born., Conclusions: Traditional contact tracing may not always be accurate, and molecular characterization can lead to identification of previously unrecognized source cases. Recent transmission plays a significant role in the transmission of TB to children as evident by the high degree of clustering found in our study population.

Relatively little is known about the human genetics of susceptibility to common diseases caused by bacterial pathogens. Tuberculosis, caused by Mycobacterium tuberculosis, is a major cause of morbidity and mortality worldwide. So far, genetic studies of tuberculosis susceptibility have largely been focused on adult patients despite the fact that tuberculosis is highly prevalent among children. To study the host genetic component of pediatric tuberculosis susceptibility, we enrolled 184 ethnically diverse families from the Greater Houston area with at least one child affected by pediatric tuberculosis disease. Using a family-based control design, we found allelic variants of the natural resistance-associated macrophage protein gene 1 (NRAMP1) (alias SLC11A1) significantly associated with tuberculosis disease in this pediatric patient population [P = 0.01; odds ratio = 1.75 (95% confidence interval, 1.10-2.77)]. The association of NRAMP1 with pediatric tuberculosis disease was significantly heterogeneous (P = 0.01) between simplex [P <0.0008; odds ratio = 3.13 (1.54-6.25)] and multiplex families (P = 1), suggesting an interplay between mechanisms of genetic control and exposure intensities. In striking contrast to previous studies in the adult population, we observed that the common alleles of NRAMP1 polymorphisms were risk factors for pediatric tuberculosis disease. To explain the different direction of allelic association between adult and pediatric disease, we hypothesize that NRAMP1 influences the speed of progression from infection to tuberculosis disease.

Molecular profiling of Mycobacterium tuberculosis isolates has improved recognition of tuberculosis case clusters, but the determinants of cluster size are unknown. We hypothesized that longer duration of symptoms prior to initiation of tuberculosis therapy would be associated with increased cluster size. All patients with tuberculosis in Harris County, Texas, identified between 10/1/95 and 12/31/97 through a prospective population-based project were interviewed, had their medical records reviewed, and had M. tuberculosis isolates molecularly characterized. There were 506 symptomatic, evaluable patients in 74 clusters, ranging in size from 2 patients (32 clusters) to 61 patients (1 cluster). The median duration of symptoms was 46 days (range, 1-471 days). There was no association between the log-transformed duration of symptoms and cluster size in univariate or multivariate analysis. In multivariate analysis, age and HIV coinfection were inversely related to cluster size, but only weakly. The size of molecularly defined clusters of tuberculosis was not related to the duration of symptoms of most patients who belonged to clusters.

Interleukin (IL)-8 is involved in the pathogenesis of human tuberculosis (TB). However, the contribution of polymorphisms of the IL-8 gene and its receptor genes CXCR-1 and CXCR-2 to human TB susceptibility remains untested. In a case-control study, white subjects with TB disease were more likely to be homozygous for the IL-8 -251A allele, compared with control subjects (odds ratio [OR], 3.41; 95% confidence interval [CI], 1.52-7.64). African Americans with TB also showed an increased odds of being homozygous for this allele (OR, 3.46; 95% CI, 1.48-8.08). To exclude population artifacts in the case-control study, a separate analysis that used a transmission-disequilibrium test with 76 informative families confirmed that the IL-8 -251A allele was preferentially transmitted to TB-infected children (P=.02). CXCR-1 and CXCR-2 did not demonstrate significant associations with TB susceptibility. These data suggest that IL-8 is important in the genetic control of human TB susceptibility.

Background: Tuberculosis (TB) of the central nervous system (CNSTB) is associated with higher mortality rates than other forms of TB. Epidemiologic associations with and prognostic indicators of CNSTB have not been assessed in a large US population-based study.Methods: Between 1995 and 2004 and using a population-based active surveillance study, we compared patients with CNSTB to patients with TB affecting sites other than CNS (non-CNSTB) with respect to sociodemographic, clinical and Mycobacterium tuberculosis genotype variables. Risk factors associated with mortality at 180 days were compared between the 2 groups.Results: We enrolled 92 patients with CNSTB and 3570 with non-CNSTB. HIV co-infection was present in 31 (33.7%) of the CNSTB cases. In a Cox proportion hazard model, we found that CNSTB patients who died within 180 days were more likely to be older (HR 1.06, 95% CI 1.02-1.10), have a positive MTB culture from a CNS source (HR 5.11, 95% CI 1.06-24.62) and have hydrocephalus (HR 10.62, 95% CI 3.28-34.36) than patients who survived CNSTB. HIV co-infection association with mortality was not statistically significant (HR 1.74, 95% CI 0.35-8.62).Conclusions: In our cohort, hydrocephalus was the most important predictor of mortality post-CNSTB diagnosis. [ABSTRACT FROM AUTHOR]

Background: Alcohol mediates detrimental alterations in the immune response to Mycobacterium tuberculosis. The association between quantity and frequency of alcohol use and the prevalence of cavitary disease in tuberculosis (TB) has not been analyzed. To investigate the relationship of alcohol use and the prevalence of cavitary disease in a 6-year population-based data set of individuals with TB. Methods: We assessed quantity and frequency of alcohol use (daily alcohol use, years of alcohol use, and lifetime alcohol use) with a standardized questionnaire. The study group consisted of 1,250 patients analyzed for cavitary disease (HIV sero-negative subjects that were 18 years or older). Significant covariates for cavitary disease were entered into multiple logistic regression models. Results: Although daily alcohol use, years of alcohol use, and alcohol use 30 days or 6 months before symptom onset were significant predictors of cavitary disease in univariate analysis, no independent associations were found between alcohol use and cavitary disease in the multivariate analysis. Only diabetes mellitus was independently associated with cavitary disease at any level or frequency of alcohol use. Conclusion: Alcohol use is not independently associated with increased prevalence of cavitary disease in adult patients with TB. [ABSTRACT FROM AUTHOR]

Summary: Objectives: To analyse the traditional and molecular epidemiology of drug-resistant tuberculosis (DRTB) in Houston and Harris County, Texas in the setting of decreasing disease incidence. Methods: Case–control study of 193 patients with DRTB and 1977 patients with drug-susceptible TB (DSTB) identified from a population-based surveillance, 1995–2001. Results: In a multivariate logistic regression, the following risk factors were found to be predictors of having DRTB (P≤0.05): human immunodeficiency virus (HIV) seropositivity, Hispanic ethnicity, Asian ethnicity, history of past TB; whereas being foreign born, having a history of past TB, and younger age were predictors of MDRTB. There were 15 patients who acquired drug resistance while on therapy, and they were significantly more likely than controls to be HIV-seropositive, be of Asian ethnicity, have smear-positive pulmonary disease and present with pleural effusion on chest radiograph. No difference in 6-month mortality between DRTB and DSTB cases was found. During the study period, the incidence of DRTB remained constant. Conclusions: In Houston, there is a steady, low-level, incidence of DRTB which disproportionately affects specific subpopulations, with no evidence of increased mortality at 6 months. [Copyright &y& Elsevier]

The article discusses on the retrospective analysis conducted on hundreds of index cases in Houston, Texas that investigate the correlation between the number of negative acid-fast bacilli (AFB) smear results and the infectivity of pulmonary tuberculosis. The study found out that all cases had only negative AFB smear in two categories at the time of infectious period. It emphasizes that the smear category of the case index case was not independently associated with transmission.

In order to investigate the role of MBL gene polymorphisms in susceptibility to tuberculosis (TB) we genotyped 487 TB cases and 232 controls. Among African-American individuals, the frequency of B allele was lower among controls than cases ( p <0.01), but we found no differences between cases and controls of white and Hispanic ethnicity. [ABSTRACT FROM AUTHOR]