Development and evaluation of murine models for mycobacterial infection

Abstract

This Ph.D. thesis is the result of research work performed under the supervision of Dr. Arunava Dasgupta, in the Microbiology Division of CSIR-Central Drug Research Institute, Lucknow, India during the period of 2015-2019 and was funded by the Council of Scientific and Industrial Research (CSIR), New Delhi. The genus mycobacterium consists of many infectious species which cause various diseases, of which tuberculosis (TB) caused by bacillus Mycobacterium tuberculosis (Mtb) is prominent. Based on the World Health Organization (WHO) report, 2018; nearly one third of the world's population has TB. Besides Mtb, genus Mycobacterium contains lots of other infectious species which are known as non-tuberculous mycobacteria (NTM) like M. fortuitum, M. abscessus and M. chelonae etc., responsible for various diseases ranging from Central Nervous System (CNS), localized abscesses to pulmonary disease and spread disease, especially to in immunocompromised individuals. Increasing occurrence of mycobacteriosis that co-occur with HIV infection and drug resistant strains has drawn significant attention to NTM infections, particularly M. abscessus, M. fortuitum. Presently, we are facing the scarcity of antibiotics against drug resistant Mtb and NTMs; especially for M. abscessus because of its extreme drug resistance properties. Host-pathogen interaction analysis to understand the establishment of disease and in vivo screening of the efficacy of new hit molecules are most important steps in the sense of developing new antibiotics. Thus, different animal models are required to implement this process successfully. Moreover, despite of some unique characteristics, all type of animal models are not well characterized and remain costly, time-consuming, required critical handling and may not represent the predictive value needed for compound research as well as host-pathogen interaction studies. In my doctoral work, my Preface 2 objective was to develop and evaluate of murine models for mycobacterial infection and detailed biological evaluation of hit molecules. To fulfill the objectives, we established an immunocompromised, neutropenic murine model of Mycobacterium abscessus and validated this model with standard drugs. Our lab previously identified neuronal disorder in M. fortuitum infected mice. On the basis of this observation, we have also developed a murine brain infection model of M. abscessus that ultimately leads to neurodegeneration disease. Furthermore, we were successfully repurposed disulfiram against M. fortuitum as well as M. abscessus.