India International Center for Excellence in Research

$982,538ZIAFY2011AINIH

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

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Abstract

In the past year, we have completed a number of sudies in lymphatic filariasis, pediatric tuberculosis and the influence of filarial infection on the prevalence of Type 1 and Type 2 diabetes mellitus. In addition, we have begun two new studies to examine the role of treatment induced latency in pulmonary tuberculosis and the identification of biomarkers/morbidity markers in Lymphatic filariasis pathogenesis -- lymphatic filarial pathology including both bancroftian and brugian filariasis. Lymphatic filariasis can be associated with the development of serious pathology in the form of lymphedema, hydrocele, and elephantiasis in a subset of infected patients. Lymphatic filariasis (LF) pathogenesis: Lymphatic filariasis can be associated with the development of serious pathology in the form of lymphedema, hydrocele, and elephantiasis in a subset of infected patients. Toll-like receptors (TLRs) are thought to play a major role in the development of filarial pathology. To elucidate the role of TLRs in the development of lymphatic pathology, we examined responses to different TLR ligands in patients with lymphatic pathology (CP), infected patients with subclinical pathology (INF), and uninfected, endemic normal (EN) individuals. TLR 2, 7 and 9 ligands induced significantly elevated production of Th1 and other pro-inflammatory cytokines in CP patients and did so as a consequence of ERK1/2 and p38 MAP kinases phosphorylation as well as increased activation of NF-κB. To examine the association between TLR function and the development of lymphangiogenesis in filarial infections, we examined TLR- and filarial antigen-induced expression and production of various angiogenic growth factors. We demonstrated that in patients with lymphatic pathology (CP), TLR ligands induce significantly increased expression/production of vascular endothelial growth factor-A (VEGF-A), angiopoietin-1 (Ang-1).Similarly, filarial antigens induced significantly enhanced production of VEGF-A and VEGF-C in those with CP that was associated with MAPK and NF-κB signaling. Dysregulated host inflammatory responses, lymphatic dysfunction, endothelial activation and extracellular matrix remodeling play central roles in filarial disease pathogenesis. In a large study of >200 subjects, we were able to show that plasma levels of LPS, alpha 2m,, haptoglobulin, serum amyloid A were associated with the development of lymphatic pathology as were VEGF-A and -C (p<0.0001), ANG-1, and the soluble VEGFRs (R1, R2, R3). The presence of circulating immune complexes (CIC) is a characteristic feature of human lymphatic filariasis.. Significantly increased levels of CIC and enhanced functional efficiency of the classical and Mannose-binding lectin (MBL) pathway of the complement system was observed in those with active INF compared to those with pathology associated with LF. Co-incidental diseases Epidemiological and animal studies have shown an inverse correlation between the incidence of helminth infections including LF and the incidence of atopy and autoimmunity. However, the interrelationship between LF and Type-1 and Type-2 diabetes (T1DM and T2DM, respectively) in humans is not known. Two cross-sectional studies to assess the baseline prevalence and the correlates of seropositivity of LF among diabetic subjects were undertaken in Chennai, India. The first study demonstrated asignificantly lower prevalence of LF among T1DM subjects (0%;n=200) compared to non-diabetic subjects (2.6%;n=500). More importantly, in the second study, there was a significantly lower prevalence of LF among T2DM subjects (both newly diagnosed 5.7%;n=158 and those under treatment 4.3%;n=161) compared to pre-diabetic subjects 9.1%;n=154 (p=0.0095) and non-diabetic subjects 10.4%;n=943 (p=0.0463). Among those with filarial infection, there were significantly lower filarial antigen loads among T2DM subjects compared to non-diabetic subjects (Geometric Mean of 354 U/ml in T2DM vs. 1594 U/ml in non-diabetic subjects;p=0.04). Serum levels of the pro-inflammatory cytokines - IL-6 and GM-CSF -- were significantly lower in T2DM subjects who were LF positive compared to those who were LF negative.. Thus, there appears to be a striking inverse relationship between the prevalence of LF and diabetes, which is reflected by a diminished serum pro-inflammatory cytokine response in subjects with diabetes and concomitant LF. Having shown a decreased prevalence of LF among type-2 diabetic subjects which was associated with significant immunomodulation, we next assessed the baseline prevalence and the correlates of seropositivity of LF among subjects without (n=236) and with (n=217) coronary arterial disease (CAD) carried out as part of the Chennai Urban Rural Epidemiology Study (CURES). In contrast to diabetes, the prevalence of LF was not significantly different between control and CAD subjects. Serum cytokine profililing showed a moderate upregulation of inflammatory markers in LF positive compared to LF negative CAD subjects. Although a direct causal link is yet to be shown, unlike type-2 diabetes there appears to be a no association between the prevalence of LF and CAD, in the Asian Indian population. Tuberculosis Studies Type 1 cytokine responses are known to play an important role in immunity to tuberculosis (TB) in children and children are more prone to develop extrapulmonary manifestations of TB compared to adults. To identify the immune responses important both in control of infection and in extrapulmonary dissemination, we examined mycobacteriaspecific cytokine responses of children with pulmonary TB (PTB) and extrapulmonary TB (ETB) and compared them with those of healthy control children (HC). Children with active TB (PTB or ETB) showed markedly diminished production of Types 1 (IFN γand TNF α), 2 (IL-4 and IL-13), and 17 (IL-17A, IL-21, and IL-23) associated cytokines at homeostasis as well as in response to mycobacterial antigens We next sought to identify the immune responses important in control of infection as well as extra-pulmonary dissemination in pediatric TB. Pediatric TB was shown to be characterized by elevated levels of acute phase proteins, MMPs/TIMP-1, IL-22 and TGFb suggesting that these responses may play a crucial role in protection against disease. It is also possible that these analytes may be used as biomarkers to monitor the progress of disease.

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