India International Center for Excellence in Research

印度国际卓越研究中心

• 批准号: 10014154
• 负责人: Thomas Nutman
• 金额: $ 191.76万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10014154
• 关键词: Address; Affect; Aftercare; Animal Model; Anthelmintics; Antigens; Antitubercular Agents; Area; B-Lymphocytes; Bacteriology; Bilateral; CD80 gene; CD86 gene; Characteristics; Communicable Diseases; Comorbidity; Country; Data; Developing Countries; Diabetes Mellitus; Disease; Disease Marker; Emerging Communicable Diseases; Endemic Diseases; Exhibits; Family; Fostering; Frequencies; Future; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Factor; HIV; Helminths; Human; ICAM1 gene; Immune; Impairment; India; Individual; Infection; Inflammation; Inflammatory; Institution; Interleukin-1; Interleukin-10; Interleukin-12; Interleukin-13; Interleukin-17; Interleukin-5; Interleukin-6; Lesion; Longitudinal cohort; Lung; Lymph Node Tuberculosis; Malaria; Mali; Measures; Mediating; Mediator of activation protein; Medical Research; Metformin; Mitogens; Newly Diagnosed; Outcome; Pathogenesis; Pathology; Patients; Pattern; Physicians; Plasma; Plasma Enhancement; Principal Component Analysis; Pulmonary Tuberculosis; Recurrence; Regimen; Research; Research Institute; Respiratory Burst; Risk; Role; Scientist; Severity of illness; Site; Sterility; Sterilization; Strongyloides stercoralis; T-Lymphocyte; Training; Treatment outcome; Tuberculosis; Uganda; base; burden of illness; chemotherapy; co-infection; cohort; cytokine; follow-up; helminth infection; innate immune function; interleukin-22; international center; lymph nodes; monocyte; mycobacterial; novel; programs; response; tuberculosis immunity; tuberculosis treatment; virtual

A. Plasma pro-inflammatory cytokines are markers of disease severity and bacterial burden in pulmonary tuberculosis Type 1, Type 17 and other pro-inflammatory cytokines are important in host immunity to tuberculosis (TB) in animal models. However, their role in human immunity to TB is not completely understood. To examine the association of pro-inflammatory cytokines with pulmonary TB (PTB), we examined the plasma levels of Type 1 (IFNg and TNFa), Type 17 (IL-17A and IL-17F) and other pro-inflammatory (IL-6, IL-12 and IL-1b) cytokines in individuals with PTB, latent TB (LTB) or healthy controls (HC). PTB individuals exhibited significantly higher plasma levels of most of the above cytokines in comparison to LTB or HC individuals. PCA analysis based on these cytokines could clearly distinguish PTB from both LTB or HC individuals. PTB individuals with bilateral or cavitary disease exhibited significantly higher levels of IFNg, TNFa, IL-17A and IL-1b compared to those with unilateral or non-cavitary disease. PTB individuals also exhibited a significant positive relationship between IFNg, TNFa and IL-17A levels and bacterial burdens. In addition, PTB individuals with delayed culture conversion exhibited significantly higher levels of IFNg, TNFa, IL-17A and IL-1b at baseline. Finally, the plasma levels of all the cytokines examined were significantly reduced following successful chemotherapy. Therefore, our data demonstrate that PTB is associated with heightened levels of plasma pro-inflammatory cytokines, which are reversed followed chemotherapy. Our data also reveal that pro-inflammatory cytokines are markers of disease severity, bacterial burden and delayed culture conversion in PTB. B. Helminth mediated modulation of the systemic and mycobacterial antigen - stimulated cytokine profiles in extra-pulmonary tuberculosis Helminth infections are known to regulate cytokine responses in both pulmonary and latent tuberculosis infection. Whether helminth infections also modulate cytokine responses in extra-pulmonary tuberculosis, specifically tuberculous lymphadenitis (TBL), has not been examined thus far. Hence, to determine the cytokine profile in helminth-TBL coinfection, we measured the systemic and mycobacterial (TB)-antigen stimulated levels of Type 1, Type 2, Type 17, regulatory and pro-inflammatory cytokines in TBL individuals coinfected with or without Strongyloides stercoralis (Ss) infection. TBL-Ss+ individuals have significantly higher bacterial burdens in the affected lymph nodes in comparison to TBL-Ss- individuals. TBL-Ss+ individuals exhibit significantly enhanced plasma levels of Type 2 (IL-5 and IL-13), Type 17 (IL-17 and IL-22) and regulatory (IL-10) cytokines in comparison to TBL-Ss- individuals. In contrast, TBL-Ss+ individuals exhibit significantly diminished plasma levels of pro-inflammatory cytokines (IL-1 and GM-CSF) in comparison to TBL-Ss- individuals. TBL-Ss+ individuals also exhibit significantly diminished unstimulated or mycobacterial-antigen stimulated levels of Type 1, Type 17 or IL-1 family cytokines in comparison to TBL-Ss- individuals but no differences in mitogen stimulated cytokine levels. Therefore, our data reveal a profound influence of Ss infection on the bacteriological profile of TBL and suggesting that the underlying modulation of cytokine responses might be a mechanism by which this helminth infection could impart a detrimental effect on the pathogenesis of TBL disease. C. Persistent inflammation during anti-tuberculosis treatment with diabetes comorbidity Diabetes mellitus (DM) increases risk for pulmonary tuberculosis (TB) and adverse treatment outcomes. Systemic hyper-inflammation is characteristic in people with TB and concurrent DM (TBDM) at baseline, but the impact of TB treatment on this pattern has not been determined. We measured 17 plasma cytokines and growth factors in longitudinal cohorts of Indian and Brazilian pulmonary TB patients with or without DM. Principal component analysis revealed virtually complete separation of TBDM from TB individuals in both cohorts at baseline, with hyper-inflammation in TBDM that continued through treatment completion at six months. By one year after treatment completion, there was substantial convergence of mediator levels between groups within the India cohort. Non-resolving systemic inflammation in TBDM comorbidity could reflect delayed lesion sterilization or non-resolving sterile inflammation. Either mechanism portends unfavorable long-term outcomes including risk for recurrent TB and for damaging immune pathology. D. Elevated circulating levels of monocyte activation markers among tuberculosis patients with diabetes co-morbidity Alteration in the frequency of monocyte subsets is a hallmark of tuberculosis-diabetes co-morbidity (TB-DM). Circulating levels of sCD14, sCD163 and sTF were significantly increased in TB-DM and DM compared with TB and HC; however, CRP was significantly increased in TB-DM and TB compared with DM and HC. During longitudinal follow up, sCD14, CRP and sTF levels remained significantly increased in TB-DM compared with TB from baseline (pre-treatment), during treatment (2nd month) and at the completion (6th month) of anti-TB treatment (ATT), whereas sCD163 was significantly higher in TB-DM compared with TB only at baseline. Within the TB-DM group, those with known diabetes before incident TB (KDM) exhibited significantly higher levels of sCD14 and sCD163 compared with individuals with newly diagnosed DM with TB (NDM). Finally, KDM individuals on metformin treatment exhibited significantly lower levels of sCD14, sCD163 and CRP compared with those on non-metformin-containing regimens. Our data demonstrate that systemic monocyte activation marker levels reflect baseline disease severity and extent in TB-DM, differentiate KDM from NDM and are modulated by ATT and metformin therapy. E. Helminth coinfection alters monocyte activation, polarization and function in latent Mycobacterial tuberculosis infection Helminth infections are known to influence T- and B- cell responses in latent Mycobacterium tuberculosis infection (LTBI). Whether helminth infections also modulate monocyte responses in helminth-LTBI co-infection has not been fully explored. To this end, we examined the activation, polarization and function of monocytes isolated from patients with LTBI with (n=25) or without (n=25) co-incident Stronglyoides stercoralis infection (Ss+ and Ss- respectively). Our data reveal that the presence of Ss infection is associated with lower frequencies of monocytes expressing activation markers (CD54, CD80, CD86) at baseline (absence of stimulation) and in response to mycobacterial-antigen stimulation than monocytes from Ss-individuals. In contrast, Ss infection is associated with higher frequencies of M2 polarized monocytes, as determined by increased expression of CD206 and CD163. Moreover, monocytes from Ss+ had a reduced capacity to phagocytose or exhibit respiratory burst activity following mycobacterial-antigen or LPS stimulation. In addition, the monocytes from Ss+ individuals were less capable of expression of IL-1b, TNFa, IL-6 and IL-12 at baseline and/or following mycobacterial-antigen stimulation compared to those without Ss infection. Finally, definitive treatment of Ss infection resulted in a significant reversal of the altered monocyte function 6 months after anthelmintic therapy. Our data highlights the induction of dampened monocyte activation, enhanced M2 polarization and impaired monocyte function in helminth-LTBI coinfection. Our data also reveal a novel mechanism by which helminth infection modulates innate immune function in LTBI, thereby potentially increasing the risk of active tuberculosis.