A novel therapeutic strategy of lipidated promiscuous peptide against Mycobacterium tuberculosis by eliciting Th1 and Th17 immunity of host

Regardless of the fact that potent drug-regimen is currently available, tuberculosis continues to kill 1.5 million people annually. Tuberculosis patients are not only inflicted by the trauma of disease but they also suffer from the harmful side-effects, immune suppression and drug resistance instigated by prolonged therapy. It is an exigency to introduce radical changes in the existing drug-regime and discover safer and better therapeutic measures. Hence, we designed a novel therapeutic strategy by reinforcing the efficacy of drugs to kill Mtb by concurrently boosting host immunity by L91. L91 is chimera of promiscuous epitope of Acr1 antigen of Mtb and TLR-2 agonist Pam2Cys. The adjunct therapy using drugs and L91 (D-L91) significantly declined the bacterial load in Mtb infected animals. The mechanism involved was through enhancement of IFN-γ+TNF-α+ polyfunctional Th1 cells and IL-17A+IFN-γ+ Th17 cells, enduring memory CD4 T cells and downregulation of PD-1. The down-regulation of PD-1 prevents CD4 T cells from undergoing exhaustion and improves their function against Mtb. Importantly, the immune response observed in animals could be replicated using T cells of tuberculosis patients on drug therapy. In future, D-L91 therapy can invigorate drugs potency to treat tuberculosis patients and reduce the dose and duration of drug-regime

Pulmonary tuberculosis and mucormycosis co-infection in a diabetic patient

Uncontrolled diabetes mellitus is associated with a variety of infections which pose management difficulties. Herein, we report a case of diabetic patient who developed combined pulmonary tuberculosis and mucormycosis. The case illustrates management of this rare co-infection which despite being potentially fatal was treated successfully

The impact of “World Health Organization - Government of India guidelines on chronic obstructive pulmonary diseases-2003” on quality of life

<b>Background:</b> The World Health Organization-Government of India (WHO-GOI) Guidelines - 2003 for management of chronic obstructive pulmonary diseases (COPD) is a consensus statement. However, the outcome and impact of its implementation on quality of life (QOL) among COPD patients has not been studied so far. <b> Materials and</b> <b> Methods:</b> The patients were randomized to intervention group (n = 50) and control group (n = 40). All were treated and followed up for 6 months. A pulmonary physician reviewed patients of both the groups, at least 3 times in 6 months period. St. George&#x2032;s Respiratory Questionnaire was measured at baseline and at 6 months. Patients in control group visited the center on a "need to" basis and were prescribed conventional treatment by the doctor on duty. <b> Results:</b> Forty-two patients in the intervention group and 32 in the control group completed 3 visits over the period of 6 months and were included in analysis. The severity as per the guidelines was moderate in 74&#x0025; and severe in 26&#x0025; in intervention group while it was moderate in 64&#x0025; and severe in 36&#x0025; cases in control group. Follow-up QOL scores were significantly better as compared with baseline values (<i> P</i>&lt; 0.001).The QOL of the patients treated according to the guidelines were significantly better (<i> P</i>&lt; 0.001) than those in the control group with conventional treatment. <b> Conclusion:</b> The consensus derived recommendations of WHO-GOI Guidelines for COPD-2003 are beneficial for management of COPD patients over conventional management

Multidrug-resistant tuberculosis and leprosy: An unsolved mystery

Tuberculosis (TB) and leprosy are two age-old infections, which we are facing even today. With drug-resistant TB on the rise, we report a case of multidrug-resistant TB with leprosy, which has never been reported previously. The peculiar course of this case forces us to rethink about the upcoming challenges due to their cooccurrence

A lipidated bi-epitope vaccine comprising of MHC-I and MHC-II binder peptides elicits protective CD4 T cell and CD8 T cell immunity against Mycobacterium tuberculosis

Abstract Background The clinical trials conducted at Chingleput India suggest that BCG fails to protect against tuberculosis (TB) in TB-endemic population. Recent studies advocate that non-tuberculous mycobacteria and latent Mycobacterium tuberculosis (Mtb) infection interferes in the antigen processing and presentation of BCG in inducing protective immunity against Mtb. Thereby, indicating that any vaccine that require extensive antigen processing may not be efficacious in TB-endemic zones. Recently, we have demonstrated that the vaccine candidate L91, which is composed of lipidated promiscuous MHC-II binder epitope, derived from latency associated Acr1 antigen of Mtb is immunogenic in the murine and Guinea pig models of TB and conferred better protection than BCG against Mtb. Methods In this study, we have used a multi-stage based bi-epitope vaccine, namely L4.8, comprising of MHC-I and MHC-II binding peptides of active (TB10.4) and latent (Acr1) stages of Mtb antigens, respectively. These peptides were conjugated to the TLR-2 agonist Pam2Cys. Results L4.8 significantly elicited both CD8 T cells and CD4 T cells immunity, as evidenced by increase in the enduring polyfunctional CD8 T cells and CD4 T cells. L4.8 efficiently declined Mtb-burden and protected animals better than BCG and L91, even at the late stage of Mtb infection. Conclusions The BCG-L4.8 prime boost strategy imparts a better protection against TB than the BCG alone. This study emphatically denotes that L4.8 can be a promising future vaccine candidate for controlling active and latent TB

Antibody response against PhoP efficiently discriminates among healthy individuals, tuberculosis patients and their contacts

<div><p>Tuberculosis continues to be one of the most devastating global health problem. Its diagnosis will benefit in timely initiation of the treatment, cure and therefore reduction in the transmission of the disease. Tests are available, but none can be comprehensively relied on for its diagnosis; especially in TB-endemic zones. PhoP is a key player in <i>Mycobacterium tuberculosis</i> virulence but nothing has been known about its role in the diagnosis of TB. We monitored the presence of anti-PhoP antibodies in the healthy, patients and their contacts. In addition, we also measured antibodies against early secretory antigens ESAT-6 and CFP-10, and latency associated antigen Acr-1 to include proteins that are associated with the different stages of disease progression. Healthy subjects showed high antibody titer against PhoP than patients and their contacts. In addition, a distinct pattern in the ratio of Acr-1/PhoP was observed among all cohorts. This study for the first time demonstrates a novel role of anti-PhoP antibodies, as a possible marker for the diagnosis of TB and therefore will contribute in the appropriate action and management of the disease.</p></div

Ratio of Acr-1/PhoP antibody titer, discriminates among patients, contacts and healthy subjects.

<p>Antibodies ratio of (A) Acr-1/PhoP; (B) PhoP/Acr-1 were measured using the antibody titer against PhoP and Acr-1 in the serum of healthy, TB patients and close contacts. Median with 95% Cl represent the antibodies ratio between two antigens and each dot symbolizes single individual (N: number of individuals). *p<0.05, ****p<0.0001.</p

PhoP showed maximum antibody titer compared to ESAT-6, CFP-10 and Acr-1.

<p>Antibodies against PhoP, Acr1, ESAT-6 and CFP-10 were measured in the serum of (A) patients; (B) contacts; (C) healthy. Median with 95% Cl represent the antibodies titers and each dot symbolizes single individual (N: number of individuals). **p<0.01, ***p<0.001, ****p<0.0001, ns: non-significant.</p