Wild mouse gut microbiota limits initial tuberculosis infection in BALB/c mice.

Mouse models are critical tools in tuberculosis (TB) research. Recent studies have demonstrated that the wild mouse gut microbiota promotes host fitness and improves disease resistance. Here we examine whether the wild mouse gut microbiota alters the immunopathology of TB in BALB/c mice. Conventional BALB/c mice (LabC) and mice born to germ-free BALB/c mothers reconstituted with the wild mouse gut microbiota (WildR) were used in our studies. WildR mice controlled initial TB infection better than LabC mice. The microbial gut communities of LabC mice and WildR mice had similar richness but significantly different composition prior to infection. TB reduced the gut community richness in both cohorts while differences in community composition remained indicating a general TB-induced dysbiosis. The wild mouse gut microbiota did not alter the typical lung histopathology of TB in the BALB/c model that includes unstructured immune cell infiltrates with infected foamy macrophages invading alveolar spaces. Animals of both cohorts mounted robust T cell responses in lungs and spleen with lower absolute counts of CD4 and CD8 T cells in lungs of WildR mice during acute infection, corresponding with observed differences in pathogen load. In summary, LabC mice and WildR mice showed largely overlapping TB immunopathology and pathogen kinetics, with WildR mice controlling early acute infection better than LabC mice.

Targeting Non-Replicating Mycobacterium tuberculosis and Latent Infection: Alternatives and Perspectives (Mini-Review).

Latent tuberculosis infection (LTBI) represents a major challenge to curing TB disease. Current guidelines for LTBI management include only three older drugs and their combinations-isoniazid and rifamycins (rifampicin and rifapentine). These available control strategies have little impact on latent TB elimination, and new specific therapeutics are urgently needed. In the present mini-review, we highlight some of the alternatives that may potentially be included in LTBI treatment recommendations and a list of early-stage prospective small molecules that act on drug targets specific for Mycobacterium tuberculosis latency.

Reactivation of latent tuberculosis through modulation of resuscitation promoting factors by diabetes.

The evidence of an association between diabetes and latent tuberculosis infection (LTBI) remains limited and inconsistent. Thus, the study aims to delineate the role of diabetes in activation of latent tuberculosis infection. Murine model of latent tuberculosis and diabetes was developed, bacillary load and gene expression of resuscitation promoting factors (rpfA-E) along with histopathological changes in the lungs and spleen were studied. Treatment for LTBI [Rifampicin (RIF) + Isoniazid (INH)] was also given to latently infected mice with or without diabetes for 4 weeks. Diabetes was found to activate latent tuberculosis as the colony forming unit (CFU) counts were observed to be > 104 in lungs and spleen. The gene expression of hspX was downregulated and that of rpfB and rpfD was observed to be upregulated in latently infected mice with diabetes compared to those without diabetes. However, no significant reduction in the CFU counts was observed after 4 weeks of treatment with RIF and INH. Diabetes helps in the progression of LTBI to active disease mainly through altered expression of resuscitation promoting factors rpfB and rpfD, which can serve as important targets to reduce the shared burden of tuberculosis and diabetes.

Defective expansion and function of memory like natural killer cells in HIV+ individuals with latent tuberculosis infection.

PURPOSE: Tuberculosis (TB) is the leading cause of infectious disease related mortality, and only 10% of the infected individuals develop active disease. The likelihood of progression of latent tuberculosis infection (LTBI) to active TB disease is high in HIV infected individuals. Identification of HIV+ individuals at risk would allow treating targeted population, facilitating completion of therapy for LTBI and prevention of TB development. NK cells have an important role in T cell independent immunity against TB, but the exact role of NK cell subsets in LTBI and HIV is not well characterized. METHODS: In this study, we compared the expansion and function of memory like NK cells from HIV-LTBI+ individuals and treatment naïve HIV+LTBI+ patients in response to Mtb antigens ESAT-6 and CFP-10. RESULTS: In freshly isolated PBMCs, percentages of CD3-CD56+ NK cells were similar in HIV+LTBI+ patients and healthy HIV-LTBI+ individuals. However, percentages of CD3-CD56+CD16+ NK cells were higher in healthy HIV-LTBI+ individuals compared to HIV+LTBI+ patients. HIV infection also inhibited the expansion of memory like NK cells, production of IL-32α, IL-15 and IFN-γ in response to Mtb antigens in LTBI+ individuals. CONCLUSION: We studied phenotypic, functional subsets and activation of memory like-NK cells during HIV infection and LTBI. We observed that HIV+LTBI+ patients demonstrated suboptimal NK cell and monocyte interactions in response to Mtb, leading to reduced IL-15, IFN-γ and granzyme B and increased CCL5 production. Our study highlights the effect of HIV and LTBI on modulation of NK cell activity to understand their role in development of interventions to prevent progression to TB in high risk individuals.

Reduced neutrophil granular proteins and post-treatment modulation in tuberculous lymphadenitis.

BACKGROUND: Neutrophils are important for host innate immune defense and mediate inflammatory responses. Pulmonary tuberculosis (PTB) is associated with increased neutrophil granular protein (NGP) levels in the circulation. However, the systemic levels of neutrophil granular proteins were not examined in tuberculous lymphadenitis (TBL) disease. METHODS: We measured the systemic levels of NGP (myeloperoxidase [MPO], elastase and proteinase 3 [PRTN3]) in TBL and compared them to latent tuberculosis (LTB) and healthy control (HC) individuals. We also measured the pre-treatment (Pre-T) and post-treatment (Post-T) systemic levels of neutrophil granular proteins in TBL individuals upon anti-tuberculosis treatment (ATT) completion. In addition, we studied the correlation and discriminatory ability of NGPs using receiver operating characteristic (ROC) analysis. RESULTS: Our data suggests that systemic levels of NGPs (MPO, PRTN3, elastase) were significantly reduced in TBL individuals compared to LTB and HC individuals. Similarly, after ATT, the plasma levels of MPO and elastase but not PRTN3 were significantly elevated compared to pre-treatment levels. NGPs (except PRTN3) were positively correlated with absolute neutrophil count of TBL, LTB and HC individuals. Further, NGPs were able to significantly discriminate TBL from LTB and HC individuals. CONCLUSION: Hence, we conclude reduced neutrophil granular protein levels might be associated with disease pathogenesis in TBL.

Mycobacterium tuberculosis-derived circulating cell-free DNA in patients with pulmonary tuberculosis and persons with latent tuberculosis infection.

OBJECTIVES: The timely diagnosis of pulmonary tuberculosis (PTB) is challenging. Although pathogen-derived circulating cell-free DNA (cfDNA) has been detected in humans, the significance of Mycobacterium tuberculosis (MTB)-cfDNA detection in patients with PTB remains unclear. METHODS: This study enrolled patients with PTB and persons with latent tuberculosis infection (LTBI) as the study and control groups, respectively, from 2018 to 2020. We measured interferon-γ levels and calculated blood monocyte-to-lymphocyte ratio (MLR). We conducted plasma cfDNA extraction, quantitative polymerase chain reaction (qPCR), and droplet digital PCR targeting the IS6110 gene of MTB. We calculated the sensitivity and specificity of using MTB-cfDNA to identify PTB and analyzed the factors associated with PTB diagnosis and MTB-cfDNA positivity. RESULTS: We enrolled 24 patients with PTB and 57 LTBI controls. The sensitivity of using MTB-cfDNA to identify PTB was 54.2%(13/24) in total and 46.2%(6/13) in smear-negative cases. Two LTBI controls (3.5%) tested positive for MTB-cfDNA, indicating a specificity of 96.5%(55/57). By using MTB-cfDNA positivity and an MLR ≥0.42 to identify PTB, sensitivity increased to 79.2%(19/24). Among patients with PTB, MTB-specific interferon-γ levels were higher in MTB-cfDNA positive participants than in those who tested negative (7.0 ±2.7 vs 2.7±3.0 IU/mL, p<0.001). MTB-cfDNA levels declined after 2 months of anti-tuberculosis therapy (p<0.001). CONCLUSION: The sensitivity of using MTB-cfDNA to identify PTB in participants was 54.2%, which increased to 79.2% after incorporating an MLR ≥0.42 into the analysis. MTB-cfDNA positivity was associated with MTB-specific immune response, and MTB-cfDNA levels declined after treatment. The clinical value of MTB-cfDNA in PTB management necessitates further investigation.

Interferon-gamma release assay levels and risk of progression to active tuberculosis: a systematic review and dose-response meta-regression analysis.

BACKGROUND: Identifying and treating individuals with high risk of progression from latent tuberculosis infection to active tuberculosis (TB) disease is critical for eliminating the disease. We aimed to conduct a systematic review and meta-regression analysis to quantify the dose-response relationship between interferon-gamma release assay (IGRA) levels and the risk of progression to active TB. METHODS: We searched PubMed and Embase from 1 January 2001 to 10 May 2020 for longitudinal studies that reported the risk of progression from latent to active TB as a function of baseline IGRA values. We used a novel Bayesian meta-regression method to pool effect sizes from included studies and generate a continuous dose-response risk curve. Our modeling framework enabled us to incorporate random effects across studies, and include data with different IGRA ranges across studies. The quality of included studies were assessed using the Newcastle-Ottawa scale (NOS). RESULTS: We included 34 studies representing 581,956 person-years of follow-up with a total of 788 incident cases of TB in the meta-regression analysis. Higher levels of interferon-gamma were associated with increased risk of progression to active tuberculosis. In the dose-response curve, the risk increased sharply between interferon-gamma levels 0 and 5 IU/ml, after which the risk continued to increase moderately but at a slower pace until reaching about 15 IU/ml where the risk levels off. Compared to 0 IU/ml, the relative risk of progression to active TB among those with interferon-gamma levels of 0.35, 1, 5, 10, 15, and 20 IU/ml were: 1.64 (1.28-2.08), 2.90 (2.02-3.88), 11.38 (6.64-16.38), 19.00 (13.08-26.90), 21.82 (14.65-32.57), and 22.31 (15.43-33.00), respectively. The dose-response relationship remains consistent when limiting the analysis to studies that scored highest in the NOS. CONCLUSION: The current practice of dichotomizing IGRA test results simplifies the TB infection disease continuum. Evaluating IGRA test results over a continuous scale could enable the identification of individuals at greatest risk of progression to active TB.

The Pathology of Lymphocytes, Histiocytes, and Immune Mechanisms in Mycobacterium tuberculosis Granulomas.

Granuloma formation is the pathologic hallmark of tuberculosis (TB). Few studies have detailed the exact production of cytokines in human granulomatous inflammation and little is known about accessory molecule expressions in tuberculous granulomas. We aimed to identify some of the components of the immune response in granulomas in HIV-positive and -negative lymph nodes. We investigated the immunohistochemical profiles of CD4+, CD8+, CD68+, Th-17, Forkhead box P3 (FOXP3) cells, accessory molecule expression (human leukocyte antigen [HLA] classes I and II), and selected cytokines (interleukins 2, 4, and 6 and interferon-γ) of various cells, in granulomas within lymph nodes from 10 HIV-negative (-) and 10 HIV-positive (+) cases. CD4+ lymphocyte numbers were retained in HIV- granulomas, whereas CD4+:CD8 + cell were reversed in HIV+ TB granulomas. CD68 stained all histiocytes. Granulomas from the HIV+ group demonstrated a significant increase in FOXP3 cells. Interleukin-2 cytoplasmic expression was similar in both groups. Interferon-gamma (IFN-γ) expression was moderately increased, IL-6 was statistically increased and IL-4 expression was marginally lower in cells from HIV- than HIV+ TB granulomas. Greater numbers of cells expressed IFN-γ and IL-6 than IL-2 and IL-4 in HIV- TB granulomas. This study highlights the varied cytokine production in HIV-positive and -negative TB granulomas and indicates the need to identify localized tissue factors that play a role in mounting an adequate immune response required to halt infection. Although TB mono-infection causes variation in cell marker expression and cytokines in granulomas, alterations in TB and HIV coinfection are greater, pointing toward evolution of microorganism synergism.

The knowns and unknowns of latent Mycobacterium tuberculosis infection.

Humans have been infected with Mycobacterium tuberculosis (Mtb) for thousands of years. While tuberculosis (TB), one of the deadliest infectious diseases, is caused by uncontrolled Mtb infection, over 90% of presumed infected individuals remain asymptomatic and contain Mtb in a latent TB infection (LTBI) without ever developing disease, and some may clear the infection. A small number of heavily Mtb-exposed individuals appear to resist developing traditional LTBI. Because Mtb has mechanisms for intracellular survival and immune evasion, successful control involves all of the arms of the immune system. Here, we focus on immune responses to Mtb in humans and nonhuman primates and discuss new concepts and outline major knowledge gaps in our understanding of LTBI, ranging from the earliest events of exposure and infection to success or failure of Mtb control.

Blood M2a monocyte polarization and increased formyl peptide receptor 1 expression are associated with progression from latent tuberculosis infection to active pulmonary tuberculosis disease.

OBJECTIVES: This study aims to explore the role of M2a polarization and formyl peptide receptor (FPR) regulation in the reactivation of Mycobacterium tuberculosis (Mtb) infection. METHODS: M1/M2a monocyte percentage and FPR1/2/3 protein expression of blood immune cells were measured in 38 patients with sputum culture (+) active pulmonary TB disease, 18 subjects with latent TB infection (LTBI), and 28 noninfected healthy subjects (NIHS) using flow cytometry method. RESULTS: M1 percentage was decreased in active TB versus either NIHS or LTBI group, while M2a percentage and M2a/M1 percentage ratio were increased. FPR1 expression on M1/M2a, FPR2 expression on M1, and FPR3 expression of M1 were all decreased in active TB versus LTBI group, while FPR1 over FPR2 expression ratio on NK T cell was increased in active TB versus either NIHS or LTBI group. In 11 patients with active TB disease, M1 percentage became normal again after anti-TB treatment. In vitro Mtb-specific antigen stimulation of monocytic THP-1 cells resulted in M2a polarization in association with increased FPR2 expression on M2a. CONCLUSIONS: Increased M2a and decreased M1 phenotypes of blood monocyte may serve as a marker for active TB disease, while decreased FPR1 on blood monocyte may indicate LTBI status.

A reaction-diffusion model to understand granulomas formation inside secondary lobule during tuberculosis infection.

Mycobacterium tuberculosis (Mtb) is the causative agent for tuberculosis, the most extended infectious disease around the world. When Mtb enters inside the pulmonary alveolus it is rapidly phagocytosed by the alveolar macrophage. Although this controls the majority of inhaled microorganisms, in this case, Mtb survives inside the macrophage and multiplies. A posterior chemokine and cytokine cascade generated by the irruption of monocytes, neutrophils and posteriorly, by T-cells, does not necessarily stop the growth of the granuloma. Interestingly, the encapsulation process built by fibroblasts is able to surround the lesion and stop its growing. The success of this last process determines if the host enters in an asymptomatic latent state or continues into a life-threatening and infective active tuberculosis disease (TB). Understanding such dichotomic process is challenging, and computational modeling can bring new ideas. Thus, we have modeled the different stages of the infection, first in a single alveolus (a sac with a radius of 0.15 millimeters) and, second, inside a secondary lobule (a compartment of the lungs of around 3 cm3). We have employed stochastic reaction-diffusion equations to model the interactions among the cells and the diffusive transport to neighboring alveolus. The whole set of equations have successfully described the encapsulation process and determine that the size of the lesions depends on its position on the secondary lobule. We conclude that size and shape of the secondary lobule are the relevant variables to control the lesions, and, therefore, to avoid the evolution towards TB development. As lesions appear near to interlobular connective tissue they are easily controlled and their growth is drastically stopped, in this sense secondary lobules with a more flattened shape could control better the lesion.

Antiretroviral therapy does not reduce tuberculosis reactivation in a tuberculosis-HIV coinfection model.

While the advent of combination antiretroviral therapy (ART) has significantly improved survival, tuberculosis (TB) remains the leading cause of death in the HIV-infected population. We used Mycobacterium tuberculosis/simian immunodeficiency virus-coinfected (M. tuberculosis/SIV-coinfected) macaques to model M. tuberculosis/HIV coinfection and study the impact of ART on TB reactivation due to HIV infection. Although ART significantly reduced viral loads and increased CD4+ T cell counts in blood and bronchoalveolar lavage (BAL) samples, it did not reduce the relative risk of SIV-induced TB reactivation in ART-treated macaques in the early phase of treatment. CD4+ T cells were poorly restored specifically in the lung interstitium, despite their significant restoration in the alveolar compartment of the lung as well as in the periphery. IDO1 induction in myeloid cells in the inducible bronchus-associated lymphoid tissue (iBALT) likely contributed to dysregulated T cell homing and impaired lung immunity. Thus, although ART was indispensable for controlling viral replication, restoring CD4+ T cells, and preventing opportunistic infection, it appeared inadequate in reversing the clinical signs of TB reactivation during the relatively short duration of ART administered in this study. This finding warrants the modeling of concurrent treatment of TB and HIV to potentially reduce the risk of reactivation of TB due to HIV to inform treatment strategies in patients with M. tuberculosis/HIV coinfection.

Pulmonary Mycobacterium tuberculosis control associates with CXCR3- and CCR6-expressing antigen-specific Th1 and Th17 cell recruitment.

Mycobacterium tuberculosis-specific (M. tuberculosis-specific) T cell responses associated with immune control during asymptomatic latent tuberculosis infection (LTBI) remain poorly understood. Using a nonhuman primate aerosol model, we studied the kinetics, phenotypes, and functions of M. tuberculosis antigen-specific T cells in peripheral and lung compartments of M. tuberculosis-infected asymptomatic rhesus macaques by longitudinally sampling blood and bronchoalveolar lavage, for up to 24 weeks postinfection. We found substantially higher frequencies of M. tuberculosis-specific effector and memory CD4+ and CD8+ T cells producing IFN-γ in the airways compared with peripheral blood, and these frequencies were maintained throughout the study period. Moreover, M. tuberculosis-specific IL-17+ and IL-17+IFN-γ+ double-positive T cells were present in the airways but were largely absent in the periphery, suggesting that balanced mucosal Th1/Th17 responses are associated with LTBI. The majority of M. tuberculosis-specific CD4+ T cells that homed to the airways expressed the chemokine receptor CXCR3 and coexpressed CCR6. Notably, CXCR3+CD4+ cells were found in granulomatous and nongranulomatous regions of the lung and inversely correlated with M. tuberculosis burden. Our findings provide insights into antigen-specific T cell responses associated with asymptomatic M. tuberculosis infection that are relevant for developing better strategies to control TB.

Tryptophan catabolism reflects disease activity in human tuberculosis.

There is limited understanding of the role of host metabolism in the pathophysiology of human tuberculosis (TB). Using high-resolution metabolomics with an unbiased approach to metabolic pathway analysis, we discovered that the tryptophan pathway is highly regulated throughout the spectrum of TB infection and disease. This regulation is characterized by increased catabolism of tryptophan to kynurenine, which was evident not only in active TB disease but also in latent TB infection (LTBI). Further, we found that tryptophan catabolism is reversed with effective treatment of both active TB disease and LTBI in a manner commensurate with bacterial clearance. Persons with active TB and LTBI also exhibited increased expression of indoleamine 2,3-dioxygenase-1 (IDO-1), suggesting IDO-1 mediates observed increases in tryptophan catabolism. Together, these data indicate IDO-1-mediated tryptophan catabolism is highly preserved in the human response to Mycobacterium tuberculosis and could be a target for biomarker development as well as host-directed therapies.

Chronic Immune Activation in TB/HIV Co-infection.

HIV co-infection is the most critical risk factor for the reactivation of latent tuberculosis (TB) infection (LTBI). While CD4+ T cell depletion has been considered the major cause of HIV-induced reactivation of LTBI, recent work in macaques co-infected with Mycobacterium tuberculosis (Mtb)/simian immunodeficiency virus (SIV) suggests that cytopathic effects of SIV resulting in chronic immune activation and dysregulation of T cell homeostasis correlate with reactivation of LTBI. This review builds on compelling data that the reactivation of LTBI during HIV co-infection is likely to be driven by the events of HIV replication and therefore highlights the need to have optimum translational interventions directed at reactivation due to co-infection.

Impact of Latent Tuberculosis Infection on Neurocognitive Functioning and Inflammation in HIV-Infected and Uninfected South Indians.

BACKGROUND: HIV-associated neurocognitive disorder persists in some people living with HIV despite optimal antiretroviral therapy. Latent tuberculosis infection (LTBI) may cause systemic inflammation and immune activation that may impair brain function. We assessed cognition and biomarkers of inflammation in both HIV+ and HIV- South Indians with and without LTBI. METHODS: Adults (≥18 years old) with and without HIV infection were screened for LTBI by interferon-gamma release assays, completed comprehensive neurocognitive assessments, and underwent measurement of serum inflammatory biomarker levels. RESULTS: The participants (n = 119) were HIV+/LTBI+ (n = 15), HIV+/LTBI- (n = 50), HIV-/LTBI+ (n = 26), and HIV-/LTBI- (n = 28). HIV+ participants, regardless of LTBI status, had more impaired global deficit scores than HIV- participants (odds ratio = 3.42, P = 0.028, adjusted for sex and education differences). Neither global deficit scores nor impairment rates differed in the LTBI+ group compared with the LTBI- group (P = 0.79 and P = 0.41, respectively). The mean log10 interleukin (IL)-6 and monocyte chemoattractant protein-1 values were significantly higher and high sensitivity C-reactive protein lower in the LTBI+ group than the LTBI- group (P = 0.044, 0.023, and 0.03, respectively, adjusting for HIV status and sex). CONCLUSIONS: In this cross-sectional study of South Indians, HIV infection, but not LTBI, was associated with increased neurocognitive impairment. Proinflammatory biomarkers (IL-6 and monocyte chemoattractant protein-1, but not tumor necrosis factor-α) were elevated in the LTBI+ groups compared with the LTBI- groups. Biomarkers of immune activation (interferon-γ, macrophage inflammatory protein-1ß, IL-2, interferon gamma inducible protein-10, RANTES, and IL-22) did not differ between these groups. Larger longitudinal studies should be conducted to confirm our findings that the effect of LTBI on systemic inflammation or neurocognitive impairment is likely small.

Anti-PD-1 immunotherapy leads to tuberculosis reactivation via dysregulation of TNF-α.

Previously, we developed a 3-dimensional cell culture model of human tuberculosis (TB) and demonstrated its potential to interrogate the host-pathogen interaction (Tezera et al., 2017a). Here, we use the model to investigate mechanisms whereby immune checkpoint therapy for cancer paradoxically activates TB infection. In patients, PD-1 is expressed in Mycobacterium tuberculosis (Mtb)-infected lung tissue but is absent in areas of immunopathology. In the microsphere model, PD-1 ligands are up-regulated by infection, and the PD-1/PD-L1 axis is further induced by hypoxia. Inhibition of PD-1 signalling increases Mtb growth, and augments cytokine secretion. TNF-α is responsible for accelerated Mtb growth, and TNF-α neutralisation reverses augmented Mtb growth caused by anti-PD-1 treatment. In human TB, pulmonary TNF-α immunoreactivity is increased and circulating PD-1 expression negatively correlates with sputum TNF-α concentrations. Together, our findings demonstrate that PD-1 regulates the immune response in TB, and inhibition of PD-1 accelerates Mtb growth via excessive TNF-α secretion.

Trends in diagnostic methods and treatment of latent tuberculosis infection in a tertiary care center from 2000 to 2017.

Screening for latent tuberculosis infection (LTBI) is indicated before immunosuppressive therapies but is complicated by lack of a gold standard and limited by, e.g., immunosuppression. This study aimed to investigate a series of patients diagnosed with LTBI during screening before immunosuppressive therapy, describing how the use of diagnostic tests and treatment evolved over time. This retrospective cohort study included all individuals diagnosed with LTBI during screening before intended immunosuppressive therapy in a tertiary care hospital between January 2000 and December 2017. Evidence for LTBI, including history, tuberculin skin test (TST), QuantiFERON (QFT) result and suggestive lesions on chest radiography (CXR), and CT scan if available, was analyzed. The study included 295 individuals with LTBI, with median follow-up of 3.8 years (IQR 1.7-7.4 years). During screening, TST, QFT, and CXR were positive in 80.8%, 53.4%, and 22.7%, respectively. Chest CT revealed lesions associated with past tuberculosis infection in around 70%, significantly more frequent than CXR. In patients diagnosed with LTBI, we observed that the use of TST declined over time whereas the use of QFT increased, and that isoniazid was replaced with rifampicin as preferential treatment. Preventive treatment was started in 82.3%, of whom 88.6% completed treatment. During follow-up, no individuals developed active tuberculosis. The diagnosis of LTBI was based on history, TST, QFT, and/or CXR in nearly every possible combination, but mostly on TST and QFT. The most striking trends were the decreased use of TST, increased use of QFT, and the replacement of isoniazid with rifampicin for treatment.

Helminth Coinfection Alters Monocyte Activation, Polarization, and Function in Latent Mycobacterium tuberculosis Infection.

Helminth infections are known to influence T and B cell responses in latent tuberculosis infection (LTBI). Whether helminth infections also modulate monocyte responses in helminth-LTBI coinfection has not been fully explored. To this end, we examined the activation, polarization, and function of human monocytes isolated from individuals with LTBI with (n = 25) or without (n = 25) coincident Strongyloides stercoralis infection (S. stercoralis-positive and S. stercoralis-negative respectively). Our data reveal that the presence of S. stercoralis infection is associated with lower frequencies of monocytes expressing CD54, CD80, CD86 at baseline (absence of stimulation) and in response to mycobacterial-Ag stimulation than monocytes from S. stercoralis-negative individuals. In contrast, S. stercoralis infection was associated with higher frequencies of M2-like monocytes, as determined by expression of CD206 and CD163. Monocytes from S. stercoralis-positive individuals had a reduced capacity to phagocytose or exhibit respiratory burst activity following mycobacterial-Ag or LPS stimulation and were less capable of expression of IL-1ß, TNF-α, IL-6, and IL-12 at baseline and/or following Ag stimulation compared with those without S. stercoralis infection. In addition, definitive treatment of S. stercoralis infection resulted in a significant reversal of the altered monocyte function 6 mo after anthelmintic therapy. Finally, T cells from S. stercoralis-positive individuals exhibited significantly lower activation at baseline or following mycobacterial-Ag stimulation. Therefore, our data highlight the induction of dampened monocyte activation, enhanced M2 polarization, and impaired monocyte function in helminth-LTBI coinfection. Our data also reveal a different mechanism by which helminth infection modulates immune function in LTBI.

Identifying latent tuberculosis in high-risk populations: systematic review and meta-analysis of test accuracy.

BACKGROUND: The relative accuracy of interferon-gamma release assays (IGRAs) and the tuberculin skin test (TST) in identifying latent tuberculosis infection (LTBI) is uncertain.OBJECTIVE: To perform a systematic review and meta-analysis to compare the sensitivity and specificity of IGRAs and TST for the prediction of progression to clinical tuberculosis (TB).METHODS: We searched electronic databases (e.g., MEDLINE and EMBASE) from December 2009 to September 2018 for prospective studies that followed up individuals who had undergone testing with commercial IGRAs and/or TST but had not received treatment based on the test result. The sensitivity and specificity estimates were pooled using a Bayesian bivariate random-effects model.RESULTS: Twenty-five studies, mostly with moderate to high risk of bias and a mean follow-up time ranging from 1 to 5 years were included. TST (10-15 mm) tended to have lower sensitivity and higher specificity than QuantiFERON® Gold In-Tube, T-SPOT®.TB and TST (5 mm). The evidence did not indicate that any test outperformed the others due to wide and overlapping 95% credible intervals.CONCLUSION: The evidence following individuals who had undergone testing for LTBI and had progressed to clinical TB is sparse. We did not find that IGRAs were superior to TST or vice versa; however, as our findings are based on a small number of studies with methodological limitations and great uncertainty around the pooled estimates, the results should be interpreted with caution.