Dataset Information

Secretory phosphatases deficient mutant of Mycobacterium tuberculosis imparts protection at the primary site of infection in guinea pigs.

ABSTRACT:

Background

The failure of Mycobacterium bovis Bacille Calmette-Guérin to impart satisfactory protection against adult pulmonary tuberculosis has necessitated the development of more effective TB vaccines. The assumption that the vaccine strain should be antigenically as similar as possible to the disease causing pathogen has led to the evaluation of M.tuberculosis mutants as candidate tuberculosis vaccines.

Methods/principal findings

In this study, we have generated a mutant of M.tuberculosis (Mtb?mms) by disrupting 3 virulence genes encoding a mycobacterial secretory acid phosphatase (sapM) and two phosphotyrosine protein phosphatases (mptpA and mptpB) and have evaluated its protective efficacy in guinea pigs. We observed that Mtb?mms was highly attenuated in THP-1 macrophages. Moreover, no bacilli were recovered from the lungs and spleens of guinea pigs after 10 weeks of Mtb?mms inoculation, although, initially, the mutant exhibited some growth in the spleens. Subsequently, when Mtb?mms was evaluated for its protective efficacy, we observed that similar to BCG vaccination, Mtb?mms exhibited a significantly reduced CFU in the lungs of guinea pigs when compared with the unvaccinated animals at 4 weeks after challenge. In addition, our observations at 12 weeks post challenge demonstrated that Mtb?mms exhibited a more sustainable and superior protection in lungs as compared to BCG. However, the mutant failed to control the hematogenous spread as the splenic bacillary load between Mtb?mms vaccinated and sham immunized animals was not significantly different. The gross pathological observations and histopathological observations corroborated the bacterial findings. Inspite of disruption of phosphatase genes in Mtb?mms, the lipid profiles of M.tuberculosis and Mtb?mms were identical indicating thereby that the phenotype of the mutant was ascribed to the loss of phosphatase genes and the influence was not related to any alteration in the lipid composition.

Conclusions/significance

This study highlights the importance of M.tuberculosis mutants in imparting protection against pulmonary TB.

SUBMITTER: Chauhan P

PROVIDER: S-EPMC3799640 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Secretory phosphatases deficient mutant of Mycobacterium tuberculosis imparts protection at the primary site of infection in guinea pigs.

Chauhan Priyanka P Reddy P Vineel PV Singh Ramandeep R Jaisinghani Neetika N Gandotra Sheetal S Tyagi Anil K AK

PloS one 20131018 10

<h4>Background</h4>The failure of Mycobacterium bovis Bacille Calmette-Guérin to impart satisfactory protection against adult pulmonary tuberculosis has necessitated the development of more effective TB vaccines. The assumption that the vaccine strain should be antigenically as similar as possible to the disease causing pathogen has led to the evaluation of M.tuberculosis mutants as candidate tuberculosis vaccines.<h4>Methods/principal findings</h4>In this study, we have generated a mutant of M. ...[more]

PMID: 24205032

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Project description:Hyperglycemia, the diagnostic feature of diabetes also occurs in non-diabetics associated with chronic inflammation and systemic insulin resistance. Since the increased risk of active TB in diabetics has been linked to the severity and duration of hyperglycemia, we investigated what effect diet-induced hyperglycemia had on the severity of Mycobacterium tuberculosis (Mtb) infection in non-diabetic guinea pigs. Post-prandial hyperglycemia was induced in guinea pigs on normal chow by feeding a 40% sucrose solution daily or water as a carrier control. Sucrose feeding was initiated on the day of aerosol exposure to the H37Rv strain of Mtb and continued for 30 or 60 days of infection. Despite more severe hyperglycemia in sucrose-fed animals on day 30, there was no significant difference in lung bacterial or lesion burden until day 60. However the higher spleen and lymph node bacterial and lesion burden at day 30 indicated earlier and more severe extrapulmonary TB in sucrose-fed animals. In both sucrose- and water-fed animals, serum free fatty acids, important mediators of insulin resistance, were increased by day 30 and remained elevated until day 60 of infection. Hyperglycemia mediated by Mtb infection resulted in accumulation of advanced glycation end products (AGEs) in lung granulomas, which was exacerbated by sucrose feeding. However, tissue and serum AGEs were elevated in both sucrose and water-fed guinea pigs by day 60. These data indicate that Mtb infection alone induces insulin resistance and chronic hyperglycemia, which is exacerbated by sucrose feeding. Moreover, Mtb infection alone resulted in the accumulation tissue and serum AGEs, which are also central to the pathogenesis of diabetes and diabetic complications. The exacerbation of insulin resistance and hyperglycemia by Mtb infection alone may explain why TB is more severe in diabetics with poorly controlled hyperglycemia compared to non-diabetics and patients with properly controlled blood glucose levels.

Dataset Information

Secretory phosphatases deficient mutant of Mycobacterium tuberculosis imparts protection at the primary site of infection in guinea pigs.

Background

Methods/principal findings

Conclusions/significance

Publications

Secretory phosphatases deficient mutant of Mycobacterium tuberculosis imparts protection at the primary site of infection in guinea pigs.

Similar Datasets

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