Experimental Tuberculosis in the Wistar Rat: A Model for Protective Immunity and Control of Infection

Amit Singhal,Vanessa Mathys,Jie Yee Siew,Véronique Dartois,Mehdi Kiass,El Moukhtar Aliouat,Colette Creusy,Maxime Hervé,Hui Chien Tay,Baptiste Delaire,Barun Mathema,Laurence Fleurisse,Liana Tsenova,Warda Boukhouchi,Pablo Bifani,Julie Bertout,Gilla Kaplan,Luis R Camacho ,Márta Romano ,Damian Guang Wei Foo

doi:10.1371/journal.pone.0018632

Abstract

BackgroundDespite the availability of many animal models for tuberculosis (TB) research, there still exists a need for better understanding of the quiescent stage of disease observed in many humans. Here, we explored the use of the Wistar rat model for the study of protective immunity and control of Mycobacterium tuberculosis (Mtb) infection.Methodology/Principal FindingsThe kinetics of bacillary growth, evaluated by the colony stimulating assay (CFU) and the extent of lung pathology in Mtb infected Wistar rats were dependent on the virulence of the strains and the size of the infecting inoculums. Bacillary growth control was associated with induction of T helper type 1 (Th1) activation, the magnitude of which was also Mtb strain and dose dependent. Histopathology analysis of the infected lungs demonstrated the formation of well organized granulomas comprising epithelioid cells, multinucleated giant cells and foamy macrophages surrounded by large numbers of lymphocytes. The late stage subclinical form of disease was reactivated by immunosuppression leading to increased lung CFU.ConclusionThe Wistar rat is a valuable model for better understanding host-pathogen interactions that result in control of Mtb infection and potentially establishment of latent TB. These properties together with the ease of manipulation, relatively low cost and well established use of rats in toxicology and pharmacokinetic analyses make the rat a good animal model for TB drug discovery.

Highlights

The emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) strains and more recently, extensively drug-resistant (XDR) strains is a serious health care problem worldwide [1,2,3,4]
The Wistar rat is a valuable model for better understanding host-pathogen interactions that result in control of Mtb infection and potentially establishment of latent TB
In the present study we explored the features of the Wistar rat model of Mtb infection and disease

Summary

Introduction

The emergence of multidrug-resistant (MDR) Mtb strains and more recently, extensively drug-resistant (XDR) strains is a serious health care problem worldwide [1,2,3,4]. MDR strains are resistant to isoniazid (INH) and rifampicin (RIF). XDR strains are defined as resistant to fluoroquinolones and one of the three injectable drugs – capreomycin, amikacin and kanamycin, in addition to INH and RIF. The loss of use of these drugs in patients with MDR or XDR TB has highlighted the urgent need to develop new therapeutic interventions with novel targets, to successfully treat drug resistant TB. The majority of first and second line drugs that target growing bacilli are less efficient at killing non-replicating organisms. The stop TB partnership and other funding organizations have stepped up efforts to develop new drugs that target both growing as well as non-replicating bacteria, thereby reducing the probability of development of latent disease. We explored the use of the Wistar rat model for the study of protective immunity and control of Mycobacterium tuberculosis (Mtb) infection

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