Helminth Infections and Diabetes: Mechanisms Accounting for Risk Amelioration.

The global prevalence of type 2 diabetes is increasing rapidly, with an anticipated 600 million cases by 2035. While infectious diseases such as helminth infections have decreased due to improved sanitation and health care, recent research suggests a link between helminth infections and type 2 diabetes mellitus (T2D), with helminths such as Schistosoma, Nippostrongylus, Strongyloides, and Heligmosomoides potentially mitigating or slowing down T2D progression in human and animal models. Helminth infections enhance host immunity by promoting interactions between innate and adaptive immune systems. In T2D, type 1 immune responses are suppressed and type 2 responses are augmented, expanding regulatory T cells and innate immune cells, particularly type 2 immune cells and macrophages. This article reviews recent research shedding light on the favorable effects of helminth infections on T2D. The potential defense mechanisms identified include heightened insulin sensitivity and reduced inflammation. The synthesis of findings from studies investigating parasitic helminths and their derivatives underscores promising avenues for defense against T2D.

Unique cellular immune signatures of multisystem inflammatory syndrome in children.

The clinical presentation of MIS-C overlaps with other infectious/non-infectious diseases such as acute COVID-19, Kawasaki disease, acute dengue, enteric fever, and systemic lupus erythematosus. We examined the ex-vivo cellular parameters with the aim of distinguishing MIS-C from other syndromes with overlapping clinical presentations. MIS-C children differed from children with non-MIS-C conditions by having increased numbers of naïve CD8+ T cells, naïve, immature and atypical memory B cells and diminished numbers of transitional memory, stem cell memory, central and effector memory CD4+ and CD8+ T cells, classical, activated memory B and plasma cells and monocyte (intermediate and non-classical) and dendritic cell (plasmacytoid and myeloid) subsets. All of the above alterations were significantly reversed at 6-9 months post-recovery in MIS-C. Thus, MIS-C is characterized by a distinct cellular signature that distinguishes it from other syndromes with overlapping clinical presentations. Trial Registration: ClinicalTrials.gov clinicaltrial.gov. No: NCT04844242.

QuantiFERON Supernatant-Based Host Biomarkers Predicting Progression to Active Tuberculosis Disease Among Household Contacts of Tuberculosis Patients.

BACKGROUND: The positive predictive value of tuberculin skin test and current generation interferon gamma release assays are very low leading to high numbers needed to treat. Therefore, it is critical to identify new biomarkers with high predictive accuracy to identify individuals bearing high risk of progression to active tuberculosis (TB). METHODS: We used stored QuantiFERON supernatants from 14 household contacts of index TB patients who developed incident active TB during a 2-year follow-up and 20 age and sex-matched non-progressors. The supernatants were tested for an expanded panel of 45 cytokines, chemokines, and growth factors using the Luminex Multiplex Array kit. RESULTS: We found significant differences in the levels of TB-antigen induced production of several analytes between progressors and non-progressors. Dominance analysis identified 15 key predictive biomarkers based on relative percentage importance. Principal component analysis revealed that these biomarkers could robustly distinguish between the 2 groups. Receiver operating characteristic analysis identified interferon-γ inducible protein (IP)-10, chemokine ligand (CCL)19, interferon (IFN)-γ, interleukin (IL)-1ra, CCL3, and granulocyte-macrophage colony-stimulating factor (GM-CSF) as the most promising predictive markers, with area under the curve (AUC) ≥90. IP-10/CCL19 ratio exhibited maximum sensitivity and specificity (100%) for predicting progression. Through Classification and Regression Tree analysis, a cutoff of 0.24 for IP-10/CCL19 ratio was found to be ideal for predicting short-term risk of progression to TB disease with a positive predictive value of 100 (95% confidence interval [CI] 85.8-100). CONCLUSIONS: The biomarkers identified in this study will pave way for the development of a more accurate test that can identify individuals at high risk for immediate progression to TB disease for targeted intervention.

Plasma Vitamin D levels in correlation with circulatory proteins could be a potential biomarker tool for pulmonary tuberculosis and treatment monitoring.

BACKGROUND: Tuberculosis (TB), a life-threatening immune challenging disease to the global human community has to be diagnosed earlier and eliminated in the upcoming era. Vitamin D, a fat-soluble micronutrient, mainly from epidermal cells of the skin and a few dietary sources, is associated with the immune system in various disease management. Therefore, a better understanding of vitamin D metabolism and immune function in tuberculosis should be studied for the consideration of biomarkers. METHODS: The study consist of Pulmonary Tuberculosis (PTB) patients (n = 32) at two-time points: Baseline (PTB BL) and after 6 months of anti-TB treatment (ATT) (PTB PT), latently Mtb infected (IFNγ + ) group (n = 32) and a non-LTB healthy control (IFNγ-) group (n = 32). Vitamin D levels were measured using High-performance liquid chromatography (HPLC). The cytokine data from the same participants assayed by ELISA from our earlier investigations were used to correlate it with serum Vitamin D levels. RESULTS: The assayed serum Vitamin D levels between the groups showed significantly lowered levels in PTB BL when compared with IFNγ + and IFNγ- groups. And, the Vitamin D levels in the PTB group after ATT were significantly lower than the baseline levels. The Vitamin D data were compared with pro- and anti-inflammatory cytokines and adipokines levels by performing a principal component regression analysis. Based on the PC scores, the study group showed distinct clusters for the TB group and control group. And, the correlation analysis between the study group and immunological indices showed significant correlations. Vitamin D significantly correlated with IFNγ, TNFα, IL17A, IL-4 and Resistin in the TB group, whereas IL-6 and G-CSF in the control group. CONCLUSION: The baseline measurement of Vitamin D levels was significantly decreased in the PTB group when compared with IFNγ + and IFNγ- groups showing the importance of Vitamin D as a preventive factor against the TB disease progression. The six-month post-treatment of TB showed a further decrease in Vitamin D levels in PTB. The significantly correlated immunological indices with Vitamin D levels are the biomarker profile that could predict TB.

Alterations of adipokines, pancreatic hormones and incretins in acute and convalescent COVID-19 children.

BACKGROUND: The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), accountable for Coronavirus disease 2019 (COVID-19), may cause hyperglycemia and additional systemic complexity in metabolic parameters. It is unsure even if the virus itself causes type 1 or type 2 diabetes mellitus (T1DM or T2DM). Furthermore, it is still unclear whether even recuperating COVID-19 individuals have an increased chance to develop new-onset diabetes. METHODS: We wanted to determine the impact of COVID-19 on the levels of adipokines, pancreatic hormones, incretins and cytokines in acute COVID-19, convalescent COVID-19 and control children through an observational study. We performed a multiplex immune assay analysis and compared the plasma levels of adipocytokines, pancreatic hormones, incretins and cytokines of children presenting with acute COVID-19 infection and convalescent COVID-19. RESULTS: Acute COVID-19 children had significantly elevated levels of adipsin, leptin, insulin, C-peptide, glucagon and ghrelin in comparison to convalescent COVID-19 and controls. Similarly, convalescent COVID-19 children had elevated levels of adipsin, leptin, insulin, C-peptide, glucagon, ghrelin and Glucagon-like peptide-1 (GLP-1) in comparison to control children. On the other hand, acute COVID-19 children had significantly decreased levels of adiponectin and Gastric Inhibitory Peptide (GIP) in comparison to convalescent COVID-19 and controls. Similarly, convalescent COVID-19 children had decreased levels of adiponectin and GIP in comparison to control children. Acute COVID-19 children had significantly elevated levels of cytokines, (Interferon (IFN)) IFNγ, Interleukins (IL)-2, TNFα, IL-1α, IL-1ß, IFNα, IFNß, IL-6, IL-12, IL-17A and Granulocyte-Colony Stimulating Factors (G-CSF) in comparison to convalescent COVID-19 and controls. Convalescent COVID-19 children had elevated levels of IFNγ, IL-2, TNFα, IL-1α, IL-1ß, IFNα, IFNß, IL-6, IL-12, IL-17A and G-CSF in comparison to control children. Additionally, Principal component Analysis (PCA) analysis distinguishes acute COVID-19 from convalescent COVID-19 and controls. The adipokines exhibited a significant correlation with the levels of pro-inflammatory cytokines. CONCLUSION: Children with acute COVID-19 show significant glycometabolic impairment and exaggerated cytokine responses, which is different from convalescent COVID-19 infection and controls.

Enhanced Severe Acute Respiratory Syndrome Coronavirus 2 Antigen-Specific Systemic Immune Responses in Multisystem Inflammatory Syndrome in Children and Reversal After Recovery.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) presents with inflammation and pathology of multiple organs in the pediatric population in the weeks following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: We characterized the SARS-CoV-2 antigen-specific cytokine and chemokine responses in children with MIS-C, coronavirus disease 2019 (COVID-19), and other infectious diseases. RESULTS: MIS-C is characterized by elevated levels of type 1 (interferon-γ, interleukin [IL] 2), type 2 (IL-4, IL-13), type 17 (IL-17), and other proinflammatory cytokines (IL-1α, IL-6, IL-12p70, IL-18, and granulocyte-macrophage colony-stimulating factor) in comparison to COVID-19 and other infectious diseases following stimulation with SARS-CoV-2-specific antigens. Similarly, upon SARS-CoV-2 antigen stimulation, CCL2, CCL3, and CXCL10 chemokines were significantly elevated in children with MIS-C in comparison to the other 2 groups. Principal component analysis based on these cytokines and chemokines could clearly distinguish MIS-C from both COVID-19 and other infections. In addition, these responses were significantly diminished and normalized 6-9 months after recovery. CONCLUSIONS: Our data suggest that MIS-C is characterized by an enhanced production of cytokines and chemokines that may be associated with disease pathogenesis.

Heightened Microbial Translocation Is a Prognostic Biomarker of Recurrent Tuberculosis.

BACKGROUND: Microbial translocation is a known characteristic of pulmonary tuberculosis (PTB). Whether microbial translocation is also a biomarker of recurrence in PTB is not known. METHODS: We examined the presence of microbial translocation in a cohort of newly diagnosed, sputum smear, and culture positive individuals with drug-sensitive PTB. Participants were followed up for a year following the end of anti-tuberculosis treatment. They were classified as cases (in the event of recurrence, n = 30) and compared to age and gender matched controls (in the event of successful, recurrence free cure; n = 51). Plasma samples were used to measure the circulating microbial translocation markers. All the enrolled study participants were treatment naïve, HIV negative and with or without diabetes mellitus. RESULTS: Baseline levels of lipopolysaccharide (LPS) (P = .0002), sCD14 (P = .0191), and LPS-binding protein (LBP) (P < .0001) were significantly higher in recurrence than controls and were associated with increased risk for recurrence, whereas intestinal fatty acid binding protein (I-FABP) and Endocab showed no association. Receiver operating characteristic (ROC) curve analysis demonstrated the utility of these individual microbial markers in discriminating recurrence from cure with high sensitivity, specificity, and area under the curve (AUC). CONCLUSIONS: Recurrence following microbiological cure in PTB is characterized by heightened baseline microbial translocation. These markers can be used as a rapid prognostic tool for predicting recurrence in PTB.

Restoration of dendritic cell homeostasis and Type I/Type III interferon levels in convalescent COVID-19 individuals.

BACKGROUND: Plasmacytoid and myeloid dendritic cells play a vital role in the protection against viral infections. In COVID-19, there is an impairment of dendritic cell (DC) function and interferon secretion which has been correlated with disease severity. RESULTS: In this study, we described the frequency of DC subsets and the plasma levels of Type I (IFNα, IFNß) and Type III Interferons (IFNλ1), IFNλ2) and IFNλ3) in seven groups of COVID-19 individuals, classified based on days since RT-PCR confirmation of SARS-CoV2 infection. Our data shows that the frequencies of pDC and mDC increase from Days 15-30 to Days 61-90 and plateau thereafter. Similarly, the levels of IFNα, IFNß, IFNλ1, IFNλ2 and IFNλ3 increase from Days 15-30 to Days 61-90 and plateau thereafter. COVID-19 patients with severe disease exhibit diminished frequencies of pDC and mDC and decreased levels of IFNα, IFNß, IFNλ1, IFNλ2 and IFNλ3. Finally, the percentages of DC subsets positively correlated with the levels of Type I and Type III IFNs. CONCLUSION: Thus, our study provides evidence of restoration of homeostatic levels in DC subset frequencies and circulating levels of Type I and Type III IFNs in convalescent COVID-19 individuals.

Baseline IL-6 is a biomarker for unfavourable tuberculosis treatment outcomes: a multisite discovery and validation study.

BACKGROUND: Biomarkers of unfavourable tuberculosis (TB) treatment outcomes are needed to accelerate new drug and regimen development. Whether plasma cytokine levels can predict unfavourable TB treatment outcomes is unclear. METHODS: We identified and internally validated the association between 20 a priori selected plasma inflammatory markers and unfavourable treatment outcomes of failure, recurrence and all-cause mortality among adults with drug-sensitive pulmonary TB in India. We externally validated these findings in two independent cohorts of predominantly diabetic and HIV co-infected TB patients in India and South Africa, respectively. RESULTS: Pre-treatment interferon-γ, interleukin (IL)-13 and IL-6 were associated with treatment failure in the discovery analysis. Internal validation confirmed higher pre-treatment IL-6 concentrations among failure cases compared with controls. External validation among predominantly diabetic TB patients found an association between pre-treatment IL-6 concentrations and subsequent recurrence and death. Similarly, external validation among predominantly HIV co-infected TB patients found an association between pre-treatment IL-6 concentrations and subsequent treatment failure and death. In a pooled analysis of 363 TB cases from the Indian and South African validation cohorts, high pre-treatment IL-6 concentrations were associated with higher risk of failure (adjusted OR (aOR) 2.16, 95% CI 1.08-4.33; p=0.02), recurrence (aOR 5.36, 95% CI 2.48-11.57; p<0.001) and death (aOR 4.62, 95% CI 1.95-10.95; p<0.001). Adding baseline IL-6 to a risk prediction model comprised of low body mass index, high smear grade and cavitation improved model performance by 15% (C-statistic 0.66 versus 0.76; p=0.02). CONCLUSIONS: Pre-treatment IL-6 is a biomarker for unfavourable TB treatment outcomes. Future studies should identify optimal IL-6 concentrations for point-of-care risk prediction.

Decreased leukocyte exhaustion is associated with decreased IFN-ß and increased α-defensin-1 levels in type-2 diabetes.

Pan-leukocyte exhaustion is a physiological process associated with immune homeostasis. Too much of immune exhaustion can lead to immune impairment and increased susceptibility to infections and cancer; too little can lead to chronic inflammation. Since type-2 diabetes subjects have both impaired immunity and metainflammation, we looked at TLR induced pan-immune exhaustion and its regulation, in these subjects. TLR induced expression of PD-1 and CTLA-4 in T cells, B cells, monocytes and neutrophils, in whole blood cultures, were quantified by flowcytometry. Circulating levels and in vitro secretion of IFN-ß and α-Defensin-1 (α-DEF-1) were quantified by ELISA. TLR induced expression of PU.1, IRF-3,-4 and -5 in whole blood cultures was quantified by qRT-PCR. Systemic lipid and protein peroxidation was quantified by spectrophotometry. TLR induced expression of PD-1 (in monocytes) and CTLA-4 expression (in B cells and neutrophils) were decreased in drug naive newly diagnosed diabetes patients. This was associated with decreased secretion and circulating levels of IFN-ß and increased secretion and circulating levels of α-DEF-1 in these subjects. No major derangement in the transcriptional network was seen. Many of these defects were only partially rectified in those under treatment. Together, we hypothesize that the high defensin levels could inhibit TLR signalling leading to reduced IFN-ß levels, which in turn could lead to reduced expression of PD-1 and CTLA-4 in the immune cells. This effect along with systemic redox stress could fuel metainflammation in type-2 diabetes.

Effect of SARS-CoV-2 seropositivity on antigen - specific cytokine and chemokine responses in latent tuberculosis.

SARS-CoV-2 and latent Mycobacterium tuberculosis infection are both highly co-prevalent in many parts of the globe. Whether exposure to SARS-CoV-2 influences the antigen specific immune responses in latent tuberculosis has not been investigated. We examined the baseline, mycobacterial antigen and mitogen induced cytokine and chemokine responses in latent tuberculosis (LTBI) individuals with or without SARS-CoV-2 seropositivity, LTBI negative individuals with SARS-CoV-2 seropositivity and healthy control (both LTBI and SARS-CoV-2 negative) individuals. Our results demonstrated that LTBI individuals with SARS-CoV-2 seropositivity (LTBI+/IgG +) were associated with increased levels of unstimulated and TB-antigen stimulated IFNγ, IL-2, TNFα, IL-17, IL-1ß, IL-6, IL-12, IL-4, CXCL1, CXCL9 and CXCL10 when compared to those without seropositivity (LTBI+/IgG-). In contrast, LTBI+/IgG+ individuals were associated with decreased levels of IL-5 and IL-10. No significant difference in the levels of cytokines/chemokines was observed upon mitogen stimulation between the groups. SARS-CoV-2 seropositivity was associated with enhanced unstimulated and TB-antigen stimulated but not mitogen stimulated production of cytokines and chemokines in LTBI+ compared to LTBI negative individuals. Finally, most of these significant differences were not observed when LTBI negative individuals with SARS-CoV-2 seropositivity and controls were examined. Our data clearly demonstrate that both baseline and TB - antigen induced cytokine responses are augmented in the presence of SARS-CoV-2 seropositivity, suggesting an augmenting effect of prior SARS-CoV-2 infection on the immune responses of LTBI individuals.

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.

Diminished Circulating Levels of Angiogenic Factors and Rage Ligands in Helminth-Diabetes Comorbidity and Reversal Following Anthelmintic Treatment.

BACKGROUND: Various epidemiological and experimental studies propose that helminths could play a preventive role against the progression of type 2 diabetes mellitus (T2DM). T2DM induces microvascular and large vessel complications mediated by elevated levels of angiogenic factors and soluble receptor for advanced glycation end product (RAGE) ligands. However, the interactions between helminths and host angiogenic factors and RAGE ligands are unexplored. METHODS: To assess the relationship between a soil-transmitted helminth, Strongyloides stercoralis (Ss), and T2DM, we measured plasma levels of vascular endothelial growth factor (VEGF)-A, -C, and -D; angiopoietins 1 and 2 (Ang-1 and Ang-2); and their receptors VEGF-R1, -R2, and -R3 as well as soluble RAGE (sRAGE) and their ligands advanced glycation end products (AGEs), S100A12, and high mobility group box 1 (HMGB-1) in individuals with T2DM with or those without Ss infection. In Ss-infected individuals, we also measured the levels of aforementioned factors 6 months following anthelmintic therapy. RESULTS: Ss-infected individuals exhibited significantly decreased levels of VEGF-A, VEGF-C, VEGF-D, Ang-1, and Ang-2 and their soluble receptors VEGF-R1, -R2, and -R3, that increased following anthelmintic therapy. Likewise, Ss-infected individuals exhibited significantly decreased levels of AGEs and their ligands sRAGE, S100A12, and HMGB-1, which reversed following anthelmintic therapy. CONCLUSIONS: Our data suggest that Ss infection could play a beneficial role by limiting or delaying T2DM-related vascular complications.

Plasma Chemokines Are Baseline Predictors of Unfavorable Treatment Outcomes in Pulmonary Tuberculosis.

BACKGROUND: Plasma chemokines are biomarkers of greater disease severity, higher bacterial burden, and delayed sputum culture conversion in pulmonary tuberculosis (PTB). Whether plasma chemokines could also serve as biomarkers of unfavorable treatment outcomes in PTB is not known. METHODS: A cohort of newly diagnosed, sputum smear- and culture-positive adults with drug-sensitive PTB were recruited under the Effect of Diabetes on Tuberculosis Severity study in Chennai, India. Plasma chemokine levels measured before treatment initiation were compared between 68 cases with unfavorable outcomes (treatment failure, death, or recurrence) and 136 control individuals who had recurrence-free cure. A second validation cohort comprising newly diagnosed, culture-positive adults with drug-sensitive TB was used to measure plasma chemokine levels in 20 cases and 40 controls. RESULTS: Six chemokines (CCL2, CCL3, CCL4, CXCL8, CXCL10, and CX3CL1) were associated with increased risk, while CXCL1 was associated with decreased risk of unfavorable outcomes in unadjusted and adjusted analyses in the test cohort. Similarly, CCL3, CXCL8, and CXCL10 were associated with increased risk of unfavorable treatment outcomes in the validation cohort. Receiver operating characteristic analysis revealed that combinations of CCL3, CXCL8, and CXCL10 exhibited very high sensitivity and specificity in differentiating cases vs controls. CONCLUSIONS: Our study reveals a plasma chemokine signature that can be used as a novel biomarker for predicting adverse treatment outcomes in PTB.

Altered plasma levels of ßC and γC chain cytokines and post-treatment modulation in tuberculous lymphadenitis.

BACKGROUND: Alterations in ß common (ßC) and γ common (γC) chain cytokines have been described in pulmonary tuberculosis. However, their role in tuberculous lymphadenitis (TBL) disease has not been assessed. METHODS: Thus, in the present study, we have examined the systemic levels of ßC and γC chain cytokines in TBL, latent tuberculosis (LTB) and healthy control (HC) individuals. We have examined the discriminatory potential of both family of cytokines using ROC analysis. Finally, we measured the pre and post-treatment responses of these cytokines after anti-tuberculosis treatment. RESULTS: TBL individuals exhibit significantly increased (IL-3) and diminished systemic levels of (IL-5, GM-CSF) ßC cytokines compared to LTB and HC individuals. TBL individuals also exhibit significantly diminished (IL-2, IL-7) and elevated (IL-4, IL-9) levels of γC cytokines compared to LTB and/or HC. ROC analysis shows a clear discriminatory capacity of both ßC (IL-5) and γC (IL-2) chain cytokines to distinguish TBL from LTB and HCs. The systemic levels of ßC chain cytokines were not significantly altered, but in contrast γC (IL-2 and IL-7) cytokines were significantly modulated after treatment. Finally, no significant correlation was observed for ßC and γC chain cytokines with their respective lymphocyte count of TBL individuals. CONCLUSIONS: Hence, we conclude that altered plasma levels of ßC and γC cytokines are the characteristics of immune alteration in TBL disease and certain cytokines were modulated after treatment.

Plasma chemokines as immune biomarkers for diagnosis of pediatric tuberculosis.

BACKGROUND: Diagnosing tuberculosis (TB) in children is challenging due to paucibacillary disease, and lack of ability for microbiologic confirmation. Hence, we measured the plasma chemokines as biomarkers for diagnosis of pediatric tuberculosis. METHODS: We conducted a prospective case control study using children with confirmed, unconfirmed and unlikely TB. Multiplex assay was performed to examine the plasma CC and CXC levels of chemokines. RESULTS: Baseline levels of CCL1, CCL3, CXCL1, CXCL2 and CXCL10 were significantly higher in active TB (confirmed TB and unconfirmed TB) in comparison to unlikely TB children. Receiver operating characteristics curve analysis revealed that CCL1, CXCL1 and CXCL10 could act as biomarkers distinguishing confirmed or unconfirmed TB from unlikely TB with the sensitivity and specificity of more than 80%. In addition, combiROC exhibited more than 90% sensitivity and specificity in distinguishing confirmed and unconfirmed TB from unlikely TB. Finally, classification and regression tree models also offered more than 90% sensitivity and specificity for CCL1 with a cutoff value of 28 pg/ml, which clearly classify active TB from unlikely TB. The levels of CCL1, CXCL1, CXCL2 and CXCL10 exhibited a significant reduction following anti-TB treatment. CONCLUSION: Thus, a baseline chemokine signature of CCL1/CXCL1/CXCL10 could serve as an accurate biomarker for the diagnosis of pediatric tuberculosis.

Coexistent Helminth Infection-Mediated Modulation of Chemokine Responses in Latent Tuberculosis.

Coexistent helminth infections are known to modulate T cell and cytokine responses in latent infection with Mycobacterium tuberculosis However, their role in modulating chemokine responses in latent tuberculosis (LTB) has not been explored. Because chemokines play a vital role in the protective immune responses in LTB, we postulated that coexistent helminth infection could modulate chemokine production in helminth-LTB coinfection. To test this, we measured the levels of a panel of CC and CXC chemokines at baseline and following mycobacterial Ag or mitogen stimulation in individuals with LTB with (Strongyloides stercoralis +LTB+) or without S. stercoralis (S. stercoralis -LTB+) infection and in individuals without both infections, healthy controls (HC). At baseline (in the absence of a stimulus), S. stercoralis +LTB+ individuals exhibited significantly diminished production of CCL1, CCL2, CCL4, CCL11, CXCL9, CXCL10, and CXCL11 in comparison with S. stercoralis -LTB+ and/or HC individuals. Upon mycobacterial Ag stimulation, S. stercoralis +LTB+ individuals exhibited significantly diminished production of CCL1, CCL2, CCL4, CCL11, CXCL2, CXCL9, and CXCL10 in comparison with S. stercoralis -LTB+ and/or HC individuals. No differences were observed upon mitogen stimulation. Finally, after anthelmintic treatment, the baseline levels of CCL1, CCL2, CCL4, CCL11, and CXCL11 and mycobacterial Ag-stimulated levels of CCL1, CCL2, CCL11, CXCL2, and CXCL10 were significantly increased in S. stercoralis +LTB+ individuals. Thus, our data demonstrate that S. stercoralis +LTB+ individuals are associated with a compromised ability to express both CC and CXC chemokines and that this defect is at least partially reversible upon treatment. Hence, coexistent helminth infection induces downmodulation of chemokine responses in LTB individuals with likely potential effects on tuberculosis pathogenesis.

Antibody responses to the BBV152 vaccine in individuals previously infected with SARS-CoV-2: A pilot study.

Background & objectives: Vaccination against SARS-CoV-2 is a recommendation from the World Health Organization as the foremost preference in the current situation to control the COVID-19 pandemic. BBV152 is one of the approved vaccines against SARS-CoV-2 in India. In this study, we determined SARS-CoV-2-specific antibody levels at day 0 (baseline, before vaccination), day 28 ± 2 post-first dose (month 1) and day 56 ± 2 post-first dose (month 2) of BBV152 whole-virion-inactivated SARS-CoV-2 recipients, and compared the antibody responses of individuals with confirmed pre-vaccination SARS-CoV-2 infection to those individuals without prior evidence of infection. Methods: Blood samples were collected from 114 healthcare professionals and frontline workers who received BBV152 vaccine from February to May & June 2021. Prior infection with SARS-CoV-2 was determined at baseline. Serum samples were used to estimate SARS-CoV-2 nucleoprotein-specific IgG [IgG (N)], spike protein-specific IgG [IgG (S)] and neutralizing antibodies (NAb). Results: Participants with previous SARS-CoV-2 infection after a single vaccine dose elicited IgG (N) and IgG (S) antibody levels along with NAb binding inhibition responses levels were similar to infection-naïve vaccinated participants who had taken two doses of vaccine. Interpretation & conclusions: Our preliminary data suggested that a single dose of BBV152-induced humoral immunity in previously infected individuals was equivalent to two doses of the vaccine in infection-naïve individuals. However, these findings need to be confirmed with large sized cohort studies.

Strongyloides stercoralis Coinfection Is Associated With Greater Disease Severity, Higher Bacterial Burden, and Elevated Plasma Matrix Metalloproteinases in Pulmonary Tuberculosis.

BACKGROUND: Helminths and tuberculosis (TB) largely overlap at the population level. Whether helminth infections influence disease severity and bacterial burdens in TB is not well understood. METHODS: This study was conducted to examine the disease severity in a cohort of pulmonary TB (PTB) individuals with (Ss+) or without (Ss-) seropositivity for Strongyloides stercoralis infection. RESULTS: Ss+ was associated with increased risk of cavitation (odds ratio [OR], 4.54; 95% confidence interval [CI], 2.33-9.04; P < .0001) and bilateral lung involvement (OR, 5.97; 95% CI, 3.03-12.09; P < .0001) in PTB individuals. Ss+ was also associated with higher bacterial burdens (OR, 7.57; 95% CI, 4.18-14.05; P < .0001) in PTB individuals. After multivariate analysis adjusting for covariates, Ss+ was still associated with greater risk of cavitation (adjusted OR [aOR], 3.99; 95% CI, 1.73-9.19; P = .0014), bilateral lung involvement (aOR, 4.09; 95% CI, 1.78-9.41; P = .0011), and higher bacterial burden (aOR, 9.32; 95% CI, 6.30-13.96; P < .0001). Finally, Ss+ was also associated with higher plasma levels of matrix metalloproteinases ([MMP]-1, -2, -7, -8, and -9) in PTB individuals. CONCLUSIONS: Therefore, our data demonstrate that coexistent Ss infection is associated with greater disease severity and higher bacterial burden in PTB. Our data also demonstrate enhanced plasma levels of MMPs in coinfected individuals, suggesting a plausible biological mechanism for these effects.

Impact of Diabetes and Low Body Mass Index on Tuberculosis Treatment Outcomes.

BACKGROUND: Diabetes was identified as a tuberculosis (TB) risk factor mostly in retrospective studies with limited assessments of metabolic variables. The prospective Effects of Diabetes on Tuberculosis Severity study compared adults with pulmonary TB in Chennai, India, who were classified as having either diabetes or a normal glucose tolerance at enrollment. METHODS: Baseline TB severity, sputum conversion, and treatment outcomes (cure, failure, death, or loss to follow-up) were compared between groups with respect to glycemic status and body mass index (BMI). RESULTS: The cohort of 389 participants included 256 with diabetes and 133 with a normal glucose tolerance. Low BMIs (<18.5 kg/m2) were present in 99 (74.4%) of nondiabetic participants and 85 (33.2%) of those with diabetes. Among participants with normal or high BMIs, rates of cure, treatment failure, or death did not vary by glycemic status. Participants with low BMIs had the highest radiographic severity of disease, the longest time to sputum culture conversion, and the highest rates of treatment failure and death. Among participants with low BMIs, poorly controlled diabetes (glycohemoglobin [HbA1c] ≥8.0%) was unexpectedly associated with better TB treatment outcomes. A high visceral adiposity index was associated with adverse outcomes and, despite an overall correlation with HbA1c, was elevated in some low-BMI individuals with normal glucose tolerance. CONCLUSIONS: In this South Indian cohort, a low BMI was significantly associated with an increased risk for adverse TB treatment outcomes, while comorbid, poorly controlled diabetes lessened that risk. A high visceral adiposity index, either with or without dysglycemia, might reflect a novel TB susceptibility mechanism linked to adipose tissue dysfunction.