Attenuation of Toll-Like Receptor Expression and Function in Latent Tuberculosis by Coexistent Filarial Infection with Restoration Following Antifilarial Chemotherapy

Mycobacterium tuberculosis (Mtb) and filarial coinfection is highly prevalent, and the presence of filarial infections may regulate the Toll-like receptor (TLR)-dependent immune response needed to control Mtb infection. By analyzing the baseline and mycobacterial antigen–stimulated expression of TLR1, 2, 4, and 9 (in individuals with latent tuberculosis [TB] with or without filarial infection), we were able to demonstrate that filarial infection, coincident with Mtb, significantly diminishes both baseline and Mtb antigen-specific TLR2 and TLR9 expression. In addition, pro-inflammatory cytokine responses to TLR2 and 9 ligands are significantly diminished in filaria/TB-coinfected individuals. Definitive treatment of lymphatic filariasis significantly restores the pro-inflammatory cytokine responses in individuals with latent TB. Coincident filarial infection exerted a profound inhibitory effect on protective mycobacteria-specific TLR-mediated immune responses in latent tuberculosis and suggests a novel mechanism by which concomitant filarial infections predispose to the development of active tuberculosis in humans

Incidence of active pulmonary tuberculosis in patients with coincident filarial and/or intestinal helminth infections followed longitudinally in South India.

Filarial (and other helminth) infections are known to modulate mycobacteria-specific pro-inflammatory cytokine responses necessary for maintaining latency in tuberculosis (TB). We sought to address whether helminth co-infection alters progression to active pulmonary TB in a co-endemic area of South India.Incidence of active pulmonary TB was assessed in 5096 subjects from five villages among helminth-infected (hel⁺) and -uninfected (hel⁻) groups. Baseline stool examinations, circulating filarial antigen, and tuberculin skin testing (PPD) were performed along with chest radiographs, sputum microscopy, and culture. During three follow-up visits each 2.5 years, patients were assessed using PPD tests and questionnaires and--for those with potential symptoms of TB--sputum microscopy and culture. Of the 5096 subjects, 1923 were found to be hel⁺ and 3173 were hel⁻. Follow up interval stool examination could not be performed. In each group, 21 developed active TB over the course of the study. After adjusting for sex, age, BCG vaccination status, and PPD positivity, no difference was seen in active TB incidence between hel⁺ and hel- groups either at baseline (relative risk (RR) 1.60; 95% confidence interval (CI): 0.69, 3.71, P = 0·27), or when followed prospectively (RR 1.24; 95% CI: 0.48, 3.18, P = 0·66).Our findings suggest that, despite the immunomodulatory effects of helminth infection, baseline co-morbid infection with these parasites had little effect on the clinical progression from latent to active pulmonary TB

Human Type 1 and 17 Responses in Latent Tuberculosis Are Modulated by Coincident Filarial Infection through Cytotoxic T Lymphocyte Antigen–4 and Programmed Death–1

Mycobacterium tuberculosis and filarial coinfection is highly prevalent, and the presence of a tissue-invasive helminth may modulate the predominant type 1 T helper (Th1; interferon [IFN]–g–mediated) response needed to control M. tuberculosis infection. By analyzing the cellular responses to mycobacterial antigens in patients who had latent tuberculosis with or without filarial infection, we were able to demonstrate that filarial infection coincident with M. tuberculosis infection significantly diminishes M. tuberculosis–specific Th1 (interleukin [IL]–12 and IFN-g) and type 17 T helper (Th17; IL-23 and IL-17) responses related to increased expression of cytotoxic T lymphocyte antigen (CTLA)–4 and programmed death (PD)–1. Blockade of CTLA-4 restored production of both IFN-g and IL-17, whereas PD-1 blockade restored IFN-g production only. Thus, coincident filarial infection exerted a profound inhibitory effect on protective mycobacteria-specific Th1 and Th17 responses in latent tuberculosis, suggesting a mechanism by which concomitant filarial (and other systemic helminth) infections predispose to the development of active tuberculosis in humans

Characteristics of Patients with Active TB at Baseline and on Prospective Assessment.

a<p>Bacillus Calmette-Guérin.</p>b<p>Lymphatic filariasis (circulating filaria antigen).</p>c<p>LF and hookworm.</p

Baseline Characteristics of Study Population (n = 5096).

a<p>663/5096 subjects missing tuberculin skin testing.</p

Severity of disease among subjects with active TB.

<p>Subjects in each group with bilateral lesions on chest radiographs (expressed as a percentage of all subjects with active TB who had complete chest X-ray data was available at the particular time point of evaluation) are shown for helminth-infected (dark bars) and helminth-uninfected (open bars) at each assessment time point. The percentage of subjects with evidence of severe disease in the hel⁺ and hel– groups, respectively, were: 3/10 (30%) and 2/7 (29%) at baseline; 1/3 (33%) and 3/6 (50%) at 2.5-year follow-up; 1/3 (33%) and 0 at 5-year follow-up; and 1/3 (33%) and 0/1 at 7·5-year follow-up with no significant differences seen between groups overall or at each time point of evaluation.</p

Results Using the Generalized Linear Model for Baseline Data.

a<p>Bacillus Calmette-Guérin.</p

Flow diagram showing the numbers of subjects with active TB and total number evaluated, along with loss-to-follow-up at each evaluation time point of the study.

<p>Flow diagram showing the numbers of subjects with active TB and total number evaluated, along with loss-to-follow-up at each evaluation time point of the study.</p