Household Contact Study Research Articles

Patients with skin smear positive leprosy in Bangladesh are the main risk factor for leprosy development: 21-year follow-up in the household contact study (COCOA).

BackgroundLeprosy transmission is ongoing; globally and within Bangladesh. Household contacts of leprosy cases are at increased risk of leprosy development. Identification of household contacts at highest risk would optimize this process.MethodsThe temporal pattern of new case presentation amongst household contacts was documented in the COCOA (Contact Cohort Analysis) study. The COCOA study actively examined household contacts of confirmed leprosy index cases identified in 1995, and 2000–2014, to provide evidence for timings of contact examination policies. Data was available on 9527 index cases and 38303 household contacts. 666 household contacts were diagnosed with leprosy throughout the follow-up (maximum follow-up of 21 years). Risk factors for leprosy development within the data analysed, were identified using Cox proportional hazard regression.FindingsThe dominant risk factor for household contacts developing leprosy was having a highly skin smear positive index case in the household. As the grading of initial slit skin smear of the index case increased from negative to high positive (4–6), the hazard of their associated household contacts developing leprosy increases by 3.14 times (p<0.001). Being a blood relative was not a risk factor, no gender differences in susceptibility were found.InterpretationWe found a dominance of a single variable predicting risk for leprosy transmission–skin smear positive index cases. A small number of cases are maintaining transmission in the household setting. Focus should be performing contact examinations on these households and detecting new skin smear positive index cases. Conducting slit-skin smears on new cases is needed for predicting risk; such services need supporting. If skin smear positive cases are sustaining leprosy infection within the household setting, the administration of single-dose rifampicin (SDR) to household contacts as the sole intervention in Bangladesh will not be effective.

Interaction between host genes and Mycobacterium tuberculosis lineage can affect tuberculosis severity: Evidence for coevolution?

Genetic studies of both the human host and Mycobacterium tuberculosis (MTB) demonstrate independent association with tuberculosis (TB) risk. However, neither explains a large portion of disease risk or severity. Based on studies in other infectious diseases and animal models of TB, we hypothesized that the genomes of the two interact to modulate risk of developing active TB or increasing the severity of disease, when present. We examined this hypothesis in our TB household contact study in Kampala, Uganda, in which there were 3 MTB lineages of which L4-Ugandan (L4.6) is the most recent. TB severity, measured using the Bandim TBscore, was modeled as a function of host SNP genotype, MTB lineage, and their interaction, within two independent cohorts of TB cases, N = 113 and 121. No association was found between lineage and severity, but association between multiple polymorphisms in IL12B and TBscore was replicated in two independent cohorts (most significant rs3212227, combined p = 0.0006), supporting previous associations of IL12B with TB susceptibility. We also observed significant interaction between a single nucleotide polymorphism (SNP) in SLC11A1 and the L4-Ugandan lineage in both cohorts (rs17235409, meta p = 0.0002). Interestingly, the presence of the L4-Uganda lineage in the presence of the ancestral human allele associated with more severe disease. These findings demonstrate that IL12B is associated with severity of TB in addition to susceptibility, and that the association between TB severity and human genetics can be due to an interaction between genes in the two species, consistent with host-pathogen coevolution in TB.

A study of household contacts of persons affected by leprosy with a high bacterial index

A study of household contacts of persons affected by leprosy with a high bacterial index

Tuberculosis household accompaniment to improve the contact management cascade: A prospective cohort study.

BackgroundAppropriate management of people exposed in the home to tuberculosis is essential to prevent morbidity. These household contacts, particularly children, should receive preventive therapy to prevent them from falling ill. However, few people receive preventive therapy worldwide. We sought to determine whether a community-based accompaniment intervention could improve tuberculosis contact management.MethodsWe conducted a prospective cohort study of household contacts of tuberculosis patients who initiated treatment during September 2015-June 2016 in Lima, Peru. Enrolled households received an intervention comprising home visits, transport vouchers, assistance coordinating evaluation procedures, and adherence support during preventive therapy. To evaluate the impact of the intervention, we conducted retrospective chart reviews of all patients initiating treatment during 6-month baseline and intervention periods.ResultsWe enrolled 314 household contacts of 109 index patients. Of these, 283 (90%) completed evaluation, and 4 (1%) were diagnosed with tuberculosis. Preventive therapy was prescribed for 35/38 (92%) contacts 0–19 years old who were eligible under Peruvian guidelines. Preventive therapy was also prescribed for 6/26 (23%) contacts with unknown eligibility due to lack of a tuberculin skin test (TST), and 20/69 (29%) who were ineligible either because of a negative TST result or exposure to a drug-resistant or extrapulmonary case. Of the 61 contacts who were prescribed preventive therapy, 57 (93%) initiated treatment, and 51 (91%) completed treatment. The proportion of contacts who completed evaluation increased from 42% during the baseline period to 71% during the evaluation period (risk ratio [RR] = 1.73, 95% confidence interval [95% CI]: 1.41–2.13). The proportion of contacts who initiated preventive therapy increased from 15% to 40% (RR = 2.45, 95% CI: 1.42–4.22).ConclusionAccompaniment of TB patient households greatly improved the evaluation of household contacts for TB and increased the use of preventive therapy.

Transmission phenotype of Mycobacterium tuberculosis strains is mechanistically linked to induction of distinct pulmonary pathology.

In a study of household contacts (HHC), households were categorized into High (HT) and Low (LT) transmission groups based on the proportion of HHC with a positive tuberculin skin test. The Mycobacterium tuberculosis (Mtb) strains from HT and LT index cases of the households were designated Mtb-HT and Mtb-LT, respectively. We found that C3HeB/FeJ mice infected with Mtb-LT strains exhibited significantly higher bacterial burden compared to Mtb-HT strains and also developed diffused inflammatory lung pathology. In stark contrast, a significant number of mice infected with Mtb-HT strains developed caseating granulomas, a lesion type with high potential to cavitate. None of the Mtb-HT infected animals developed diffused inflammatory lung pathology. A link was observed between increased in vitro replication of Mtb-LT strains and their ability to induce significantly high lipid droplet formation in macrophages. These results support that distinct early interactions of Mtb-HT and Mtb-LT strains with macrophages and subsequent differential trajectories in pathological disease may be the mechanism underlying their transmission potential.

Cough-aerosol cultures of Mycobacterium tuberculosis in the prediction of outcomes after exposure. A household contact study in Brazil

BackgroundMycobacterium tuberculosis cultures of cough-generated aerosols from patients with pulmonary tuberculosis (TB) are a quantitative method to measure infectiousness and to predict secondary outcomes in exposed contacts. However, their reproducibility has not been established.ObjectiveTo evaluate the predictive value of colony-forming units (CFU) of M. tuberculosis in cough aerosols on secondary infection and disease in household contacts in Brazil.MethodsAdult sputum smear+ and culture+ pulmonary TB cases underwent a standard evaluation and were categorized according to aerosol CFU. We evaluated household contacts for infection at baseline and at 8 weeks with TST and IGRA, and secondary disease.ResultsWe enrolled 48 index TB cases; 40% had negative aerosols, 27% low aerosols (<10 CFU) and 33% high aerosols (≥10 CFU). Of their 230 contacts, the proportion with a TST ≥10 mm at 8 weeks was 59%, 65% and 75%, respectively (p = 0.34). Contacts of high aerosol cases had greater IGRA readouts (median 4.6 IU/mL, IQR 0.02–10) when compared to those with low (0.8, 0.2–10) or no aerosol (0.1, 0–3.7; p = 0.08). IGRA readouts in TST converters of high aerosol cases (median 20 IU/mL, IQR 10–24) were larger than those from aerosol-negative (0.13, 0.04–3; p = o.o2). 8/9 (89%) culture+ secondary TB cases occurred in contacts of aerosol+ cases.ConclusionAerosol CFU predicts quantitatively IGRA readouts among household contacts of smear positive TB cases. Our results strengthen the argument of using cough aerosols to guide targeted preventive treatment strategies, a necessary component of current TB elimination projections.

Long-term Stability of Resistance to Latent Mycobacterium tuberculosis Infection in Highly Exposed Tuberculosis Household Contacts in Kampala, Uganda.

Resistance to latent Mycobacterium tuberculosis (M.tb) infection, identified by persistently negative tuberculin skin tests (TST) and interferon-gamma release assays (IGRA), after close contact with pulmonary tuberculosis (TB) patients has not been extensively characterized. Stability of this "resistance" beyond 2 years from exposure is unknown. 407 of 657 eligible human immunodeficiency virus (HIV)-negative adults from a TB household contact study with persistently negative TST (PTST-) or with stable latent M.tb infection (LTBI) were retraced 9.5 years (standard deviation = 3.2) later. Asymptomatic retraced contacts underwent 3 IGRAs and follow-up TST, and their M.tb infection status classified as definite/possible/probable. Among PTST- with a definite classification, 82.7% were concordantly TST-/ quantiferon-TB Gold- (QFT-), and 16.3% converted to TST+/QFT+ LTBI. Among original LTBI contacts, 83.6% remained LTBI, and 3.9% reverted their TST and were QFT-. Although TST and QFT concordance was high (κ = 0.78), 1.0% of PTST and 12.5% of original LTBI contacts could not be classified due to discordant TST and QFT results. Epidemiological variables did not differ between retraced PTST- and LTBI contacts. Resistance to LTBI, defined by repeatedly negative TST and IGRA, in adults who have had close contact with pulmonary TB patients living in TB-endemic areas, is a stable outcome of M.tb exposure. Repeated longitudinal measurements with 2 different immune assays and extended follow-up provide enhanced discriminatory power to identify this resister phenotype and avoid misclassification. Resisters may use immune mechanisms to control aerosolized M.tb that differ from those used by persons who develop "classic" LTBI.

Human and Equine Infection with Alphaviruses and Flaviviruses in Panamá during 2010: A Cross-Sectional Study of Household Contacts during an Encephalitis Outbreak.

Members of the genera Alphavirus (family Togaviridae) and Flavivirus (family Flaviridae) are important zoonotic human and equine etiologic agents of neurologic diseases in the New World. In 2010, an outbreak of Madariaga virus (MADV; formerly eastern equine encephalitis virus) and Venezuelan equine encephalitis virus (VEEV) infections was reported in eastern Panamá. We further characterized the epidemiology of the outbreak by studying household contacts of confirmed human cases and of equine cases with neurological disease signs. Serum samples were screened using a hemagglutination inhibition test, and human results were confirmed using plaque reduction neutralization tests. A generalized linear model was used to evaluate the human MADV and VEEV seroprevalence ratios by age (in tercile) and gender. Overall, antibody prevalence for human MADV infection was 19.4%, VEEV 33.3%, and Mayaro virus 1.4%. In comparison with individuals aged 2-20 years, people from older age groups (21-41 and > 41 years) were five times more likely to have antibodies against VEEV, whereas the MADV prevalence ratio was independent of age. The overall seroprevalence of MADV in equids was 26.3%, VEEV 29.4%, West Nile virus (WNV) 2.6%, and St. Louis encephalitis virus (SLEV) was 63.0%. Taken together, our results suggest that multiple arboviruses are circulating in human and equine populations in Panamá. Our findings of a lack of increase in the seroprevalence ratio with age support the hypothesis of recent MADV exposure to people living in the affected region.

Household contact non-attendance of clinical evaluation for tuberculosis: a pilot study in a high burden district in South Africa

BackgroundIn 2012, the World Health Organization launched guidelines for systematically investigating contacts of persons with infectious tuberculosis (TB) in low- and middle-income countries. As such, it is necessary to understand factors that would influence successful scale-up. This study targeted household contacts of newly-diagnosed infectious TB patients in the Mangaung Metropolitan district to explore factors associated with non-attendance of clinical evaluation.MethodIn September–October 2016, a pilot study of household contacts was conducted. At each of the 40 primary health care (PHC) facilities in the district, at least one out of four types of TB index cases were purposefully selected. These included children <5 years, smear-positive cases, HIV co-infected cases, and multidrug-resistant TB (MDR-TB) cases. Trained fieldworkers administered questionnaires and screened contacts for TB symptoms. Those with TB symptoms as well as children <5 years were referred for clinical evaluation at the nearest PHC facility. Contacts’ socio-demographic and clinical characteristics, TB knowledge and perception about TB-related discrimination are described. Logistic regression analysis was used to investigate factors associated with non-attendance of clinical evaluation.ResultsOut of the 259 participants, approximately three in every five (59.5%) were female. The median age was 20 (interquartile range: 8–41) years. While the large majority (87.3%) of adult contacts correctly described TB aetiology, almost three in every five (59.9%) thought that it was hereditary, and almost two-thirds (65.5%) believed that it could be cured by herbal medicine. About one-fifth (22.9%) of contacts believed that TB patients were subjected to discrimination. Two in every five (39.4%) contacts were referred for clinical evaluation of whom more than half (52.9%) did not attend the clinic. Non-attendance was significantly associated with inter alia male gender (AOR: 3.4; CI: 1.11–10.24), prior TB diagnosis (AOR: 5.6; CI: 1.13–27.90) and sharing of a bedroom with the index case (AOR: 3.4: CI: 1.07–10.59).ConclusionThe pilot study identified gaps in household contacts’ knowledge of TB. Further research on important individual, clinical and structural factors that can influence and should be considered in the planning, implementation and scale-up of household contact TB investigation is warranted.

Existing blood transcriptional classifiers accurately discriminate active tuberculosis from latent infection in individuals from south India

Several studies have identified blood transcriptomic signatures that can distinguish active from latent Tuberculosis (TB). The purpose of this study was to assess how well these existing gene profiles classify TB disease in a South Indian population. RNA sequencing was performed on whole blood PAXgene samples collected from 28 TB patients and 16 latently TB infected (LTBI) subjects enrolled as part of an ongoing household contact study. Differential gene expression and clustering analyses were performed and compared with explicit predictive testing of TB and LTBI individuals based on established gene signatures. We observed strong predictive performance of TB disease states based on expression of known gene sets (ROC AUC 0.9007–0.9879). Together, our findings indicate that previously reported classifiers generated from different ethnic populations can accurately discriminate active TB from LTBI in South Indian patients. Future work should focus on converting existing gene signatures into a universal TB gene signature for diagnosis, monitoring TB treatment, and evaluating new drug regimens.

Household tuberculosis contact investigation in a tuberculosis-prevalent country: Are the tuberculin skin test and interferon-gamma release assay enough in elderly contacts?

The high background rates of positive results on the tuberculin skin test (TST) and interferon-gamma release assay (IGRA) sometimes confuse the investigation of tuberculosis (TB) contact in TB-prevalent countries, particularly in elderly contacts. The aim was to investigate the predictive value of TST and IGRA for diagnosing latent TB infection (LTBI) in elderly household contacts in South Korea.In this retrospective study, TST and IGRA results of household contacts of suspected pulmonary TB patients were reviewed according to the index patient's final diagnosis (TB group: culture-confirmed pulmonary TB, non-TB group: pulmonary disease other than TB).A total of 249 contacts were included in the analysis (188 in the TB group and 61 in the non-TB group). In the TB group, TST and IGRA were positive in 42.6% and 45.7% of contacts, respectively. In the non-TB group, TST and IGRA were positive in 32.8% and 23.0% of contacts, respectively. TST did not show any differences between the TB and non-TB groups for any age group, whereas IGRA showed differences between the 2 groups for those ages 18 to 39 and 40 to 59 years. However, there were no significant differences between the groups for the ≥60 years old group.In elderly contacts, neither TST nor IGRA showed clear discrimination of positivity between the groups. Further studies are needed to predict which elderly contacts are at risk for progression to active TB as well as to accurately detect recent Mycobacterium tuberculosis infection in this vulnerable population.

Case-control study of household contacts to examine immunological protection from Bordetella pertussis transmission - study protocol.

There is mounting evidence that the recent resurgence of pertussis in many countries is in part related to the acellular vaccine, which has been administered in Canada since 1997. This vaccine elicits a different cell-mediated immune response than the previously used whole-cell vaccine, and its effectiveness wanes over time. The aim of this study is to understand the immunological, demographic and clinical factors that mediate protection from pertussis on exposure. This is a household case-control study protocol. Following notification of an index case in a household, a study team will conduct a home visit to collect data and biological specimens. The study team will return to the household 8 weeks from the onset of illness in the index case. The Th1, Th2 and Th17 responses, cytokine expression, IgG subclass, blood cell counts and presence of Bordetella pertussis will be determined. We will use laboratory and statistical analyses to determine immunological differences between contacts who are infected with B. pertussis and contacts who remain healthy, and to determine which clinical and demographic covariates are associated with a reduced risk of infection. The results of this study will be essential for understanding the immune response required for protection from infection with B. pertussis and will contribute to our understanding of the shortcomings of the current vaccine.

An eQTL variant of ZXDC is associated with IFN-\u03b3 production following Mycobacterium tuberculosis antigen-specific stimulation

There is a large inter-individual variability in the response to Mycobacterium tuberculosis infection. In previous linkage analyses, we identified a major locus on chromosome region 8q controlling IFN-γ production after stimulation with live BCG (Bacillus Calmette-Guérin), and a second locus on chromosome region 3q affecting IFN-γ production triggered by the 6-kDa early secretory antigen target (ESAT-6), taking into account the IFN-γ production induced by BCG (IFNγ-ESAT6BCG). High-density genotyping and imputation identified ~100,000 variants within each linkage region, which we tested for association with the corresponding IFN-γ phenotype in families from a tuberculosis household contact study in France. Significant associations were replicated in a South African familial sample. The most convincing association observed was that between the IFNγ-ESAT6BCG phenotype and rs9828868 on chromosome 3q (p = 9.8 × 10−6 in the French sample). This variant made a significant contribution to the linkage signal (p < 0.001), and a trend towards the same association was observed in the South African sample. This variant was reported to be an eQTL of the ZXDC gene, biologically linked to monocyte IL-12 production through CCL2/MCP1. The identification of rs9828868 as a genetic driver of IFNγ production in response to mycobacterial antigens provides new insights into human anti-tuberculosis immunity.

Incident Mycobacterium tuberculosis infection in household contacts of infectious tuberculosis patients in Brazil

BackgroundIn household contact investigations of tuberculosis (TB), a second tuberculin skin test (TST) obtained several weeks after a first negative result consistently identifies individuals that undergo TST conversion. It remains unclear whether this delay in M. tuberculosis infection is related to differences in the infectious exposure, TST boosting, partial host resistance, or some other factor.MethodsWe conducted a household contact study Vitória, Brazil. Between 2008 and 2013, we identified culture-positive pulmonary TB patients and evaluated their household contacts with both a TST and interferon gamma release assay (IGRA), and identified TST converters at 8–12 weeks post study enrollment. Contacts were classified as TST-positive (≥10 mm) at baseline, TST converters, or persistently TST-negative. We compared TST converters to TST-positive and to TST-negative contacts separately, using generalized estimating equations.ResultsWe enrolled 160 index patients and 838 contacts; 523 (62.4%) were TST+, 62 (7.4%) TST converters, and 253 (30.2%) TST−. TST converters were frequently IGRA− at 8–12 weeks. In adjusted analyses, characteristics distinguishing TST converters from TST+ contacts (no contact with another TB patient and residence ownership) were different than those differentiating them from TST− contacts (stronger cough in index patient and contact BCG scar).ConclusionsThe individual risk and timing of M. tuberculosis infection within households is variable and dependent on index patient, contact and environmental factors within the household, and the surrounding community. Our findings suggest a threshold effect in the risk of infection in humans.

Multifunctional cytokine and T cell memory phenotype profiles differ in active versus cured tuberculosis.

Abstract Tuberculosis, one of the most prevalent and deadliest infectious diseases worldwide, requires long-term multidrug treatment regimens for curing active clinical disease. However, a diagnostic method for identifying successful cure from TB disease following anti-TB chemotherapy remains elusive. The overall goal of this study was to assess differential patterns of cytokine production and memory T cell phenotypes to distinguish between active TB subjects and remotely cured TB individuals. Using peripheral blood mononuclear cells from subjects enrolled in a TB household contact study established in Vitória, Brazil, cells were stimulated ex vivo with TB antigens and evaluated using multi-parametric flow cytometry. Total cytokine and multifunctional cytokine analyses revealed an increase in the proportion of IL-17 producing CD4+ T cells in active TB subjects, while cured TB subjects showed a clear dominance of cells producing IFNγ and IL-2 or TNFα. Comparison of memory phenotypes revealed differences between proportions of several CD4+ T cell memory subsets, with an effector memory dominance in cured TB compared to an increased stem cell memory representation in active TB. Increased expression of exhaustion marker PD-1 in advanced stages of memory cell differentiation suggested its possible use as a surrogate indicator of memory subset fluxes, with possible application as a biomarker for distinguishing differences between cured TB and active TB individuals.

Transcriptional networks are associated with resistance to Mycobacterium tuberculosis infection.

RationaleUnderstanding mechanisms of resistance to M. tuberculosis (M.tb) infection in humans could identify novel therapeutic strategies as it has for other infectious diseases, such as HIV.ObjectivesTo compare the early transcriptional response of M.tb-infected monocytes between Ugandan household contacts of tuberculosis patients who demonstrate clinical resistance to M.tb infection (cases) and matched controls with latent tuberculosis infection.MethodsCases (n = 10) and controls (n = 18) were selected from a long-term household contact study in which cases did not convert their tuberculin skin test (TST) or develop tuberculosis over two years of follow up. We obtained genome-wide transcriptional profiles of M.tb-infected peripheral blood monocytes and used Gene Set Enrichment Analysis and interaction networks to identify cellular processes associated with resistance to clinical M.tb infection.Measurements and main resultsWe discovered gene sets associated with histone deacetylases that were differentially expressed when comparing resistant and susceptible subjects. We used small molecule inhibitors to demonstrate that histone deacetylase function is important for the pro-inflammatory response to in-vitro M.tb infection in human monocytes.ConclusionsMonocytes from individuals who appear to resist clinical M.tb infection differentially activate pathways controlled by histone deacetylase in response to in-vitro M.tb infection when compared to those who are susceptible and develop latent tuberculosis. These data identify a potential cellular mechanism underlying the clinical phenomenon of resistance to M.tb infection despite known exposure to an infectious contact.

Asymptomatic infection and unrecognised Ebola virus disease in Ebola-affected households in Sierra Leone: a cross-sectional study using a new non-invasive assay for antibodies to Ebola virus

The frequency of asymptomatic infection with Ebola virus is unclear: previous estimates vary and there is no standard test. Asymptomatic infection with Ebola virus could contribute to population immunity, reducing spread. If people with asymptomatic infection are infectious it could explain re-emergences of Ebola virus disease (EVD) without known contact. We validated a new oral fluid anti-glycoprotein IgG capture assay among survivors from Kerry Town Ebola Treatment Centre and controls from communities unaffected by EVD in Sierra Leone. We then assessed the seroprevalence of antibodies to Ebola virus in a cross-sectional study of household contacts of the survivors. All household members were interviewed. Two reactive tests were required for a positive result, with a third test to resolve any discrepancies. The assay had a specificity of 100% (95% CI 98·9-100; 339 of 339 controls tested negative) and sensitivity of 95·9% (89·8-98·9; 93 of 97 PCR-confirmed survivors tested positive). Of household contacts not diagnosed with EVD, 47·6% (229 of 481) had high level exposure (direct contact with a corpse, body fluids, or a case with diarrhoea, vomiting, or bleeding). Among the contacts, 12·0% (95% CI 6·1-20·4; 11 of 92) with symptoms at the time other household members had EVD, and 2·6% (1·2-4·7; 10 of 388) with no symptoms tested positive. Among asymptomatic contacts, seropositivity was weakly correlated with exposure level. This new highly specific and sensitive assay showed asymptomatic infection with Ebola virus was uncommon despite high exposure. The low prevalence suggests asymptomatic infection contributes little to herd immunity in Ebola, and even if infectious, would account for few transmissions. Wellcome Trust ERAES Programme, Save the Children.

Epidemiologically characterized high and low transmission isolates of Mycobacterium tuberculosis induce distinct infection outcomes in mice

Abstract In a study of household contacts of infectious TB cases (HHC) conducted by us in Brazil, “index” cases were categorized into High (HT) and Low (LT) transmission groups based on the proportion of household contacts with a positive tuberculin skin test. In this study we wanted to determine whether Mycobacterium tuberculosis (Mtb) isolates with different transmission phenotypes diverged in their interaction with the host immune system. Initial in vitro analysis of 15 isolates from each group revealed significantly higher levels of TNF produced by macrophages infected with HT isolates. Two each of the HT and LT isolates were further characterized in vivo in the C3HeB/FeJ mice which develop lesions characteristic of human TB. Through the course of these infections, both the LT isolates exhibited a significantly higher bacterial burden and enhanced cellular recruitment to the lungs. Mice infected with the LT isolates exhibited early pulmonary inflammation that rapidly progressed to widespread consolidation of the granulomatous lesions. In contrast, mice infected with the two HT isolates formed organized cellular aggregates that contained abundant lymphocytes and foamy macrophages. Interestingly, pathological progression of the cellular aggregates into caseous fibrotic lesions, with abundant extracellular bacilli, was observed with one of the HT isolates. Furthermore, elevated levels of the pro-inflammatory cytokines IL-1β, IL-6 and IL-17 were found in the lungs of mice infected with the LT isolates. These results suggest that distinct interactions between microbe and host immunity might lead to differential trajectory in intracellular growth pattern and lung pathology that underlie differences in transmission potential.

The role of histone deacetylases in the innate immune response to Mycobacterium tuberculosis infection

Abstract Most of household contacts of pulmonary TB cases, develop latent Mtb infection (LTBI). In a large TB household contact study in Uganda, we found that 9.1% of contacts remained persistently TST negative in 2 years of follow up. We hypothesized that resistance to Mtb infection is mediated by monocytes. We compared genome-wide mRNA profiles of Mtb-infected monocytes from those who are resistant or susceptible to Mtb infection. Using Gene Set Enrichment Analysis, we recently identified a butyrate stimulated gene set that distinguished these two groups. Butyrate inhibits histone deacetylases (HDAC), a gene family that regulates transcription as well as innate immune responses to microbes. We found that treatment of peripheral blood monocytes with class I HDAC inhibitors, depsipeptide and sodium butyrate, led to reduced IL6 and TNF secretion after Mtb infection compared to untreated cells. In contrast, IL1beta levels were increased. Together, these data indicate that class I HDAC inhibitors modulate proinflammatory cytokines after Mtb infection. Future studies will examine how HDAC inhibitors regulate inflammasome-dependent IL-1beta and IL6 secretion differently. HDACs likely regulate multiple pathways that modulate Mtb pathogenesis and mediate clinical to Mtb infection. HDACs are plausible candidate human Mtb resistance genes and promising targets for host-directed therapeutics.

What is the effect of antiretroviral treatment on the infectiousness of patients with smear-positive tuberculosis in rural Malawi?

BackgroundSeveral studies have found a lower risk of Mycobacterium tuberculosis infection among household contacts of HIV-positive patients with pulmonary tuberculosis than among patients with HIV-negative pulmonary tuberculosis, suggesting reduced transmission. Our hypothesis is that this association is reversed by antiretroviral therapy (ART). We examined the effect of ART on the prevalence of M tuberculosis infection among child contacts of adults with smear-positive tuberculosis. MethodsA cross-sectional household contact study of smear-positive tuberculosis index cases was conducted in Karonga, Malawi, between Jan 1, 2013, and Dec 31, 2014. Prevalence of tuberculin skin test (TST) positivity was compared between household contacts aged 11 years of index cases (HIV-negative, HIV-positive not on ART, and HIV-positive on ART [HIV status at diagnosis of tuberculosis]). A positive TST was defined as ≥10 mm induration. Data were analysed with a random-effects logistic regression model to account for clustering. FindingsThere were 376 child contacts (148 index cases), of whom 330 (88%) had a TST reading. The proportion of contacts of index cases with the highest mycobacillary burden, with smear-positivity as a proxy, was similar: HIV-negative (78%, 149/191) and HIV-positive index cases on ART (71%, 50/70), compared with HIV-positive index cases not on ART (57%, 39/69). The odds of a positive TST were 60% lower in contacts of HIV-positive patients not on ART (adjusted odds ratio 0·4, 95% CI 0·1–1·0; p=0·04) and 70% lower in contacts of HIV-positive patients on ART (0·3, 0·1–0·8; p=0·02) than in HIV-negative index cases, adjusted for degree of contact and age of index case. The reduction in odds of TST positivity among contacts of HIV-positive patients on ART remained after additionally adjusting for degree of smear-positivity. InterpretationContrary to expectation, we found a reduced prevalence of M tuberculosis infection among contacts of HIV-positive patients with tuberculosis on ART, after adjusting for degree of smear-positivity. This finding is suggestive of decreased transmission from these index cases. This reduction in transmission might be due to earlier diagnosis of tuberculosis in patients who are already engaged in care. FundingWellcome Trust.