The current state of animal models and genomic approaches towards identifying and validating molecular determinants ofMycobacterium tuberculosisinfection and tuberculosis disease

Abstract

Animal models are important in understanding both the pathogenesis of and immunity to tuberculosis (TB). Unfortunately, we are beginning to understand that no animal model perfectly recapitulates the human TB syndrome, which encompasses numerous different stages. Furthermore, Mycobacterium tuberculosis infection is a very heterogeneous event at both the levels of pathogenesis and immunity. This review seeks to establish the current understanding of TB pathogenesis and immunity, as validated in the animal models of TB in active use today. We especially focus on the use of modern genomic approaches in these models to determine the mechanism and the role of specific molecular pathways. Animal models have significantly enhanced our understanding of TB. Incorporation of contemporary technologies such as single cell transcriptomics, high-parameter flow cytometric immune profiling, proteomics, proteomic flow cytometry and immunocytometry into the animal models in use will further enhance our understanding of TB and facilitate the development of treatment and vaccination strategies.

Evolution of Drug-Resistant Mycobacterium tuberculosis Strains and Their Adaptation to the Human Lung Environment

“…After M.tb infection, host innate and adaptive immune responses are mounted, resulting in bacterial clearance, active TB disease or establishment of a latent M.tb infection (LTBI), the latter characterized by persistent M.tb bacilli contained inside complex structures called granulomas, a highly heterogeneous and dynamic cellular environment in the lung ( Ehlers and Schaible, 2012 ; Guirado and Schlesinger, 2013 ) ( Figure 1D ). Depending of the granuloma stage (formation, maintenance, maturation, disruption leading to M.tb reactivation), these can be studied in vitro ( Guirado et al, 2015 ) and in vivo using animal models such as mouse, Guinea pigs, rabbit and non-human primate models (NHPs) ( Bucsan et al, 2019 ). Granulomas are composed of immune host cells including AMs, interstitial macrophages, foamy macrophages, monocytes, multi-nucleated giant cells, epithelial-like cells, DCs, NK cells, and neutrophils, surrounded by B and T cells, which tightly control M.tb replication and dissemination ( Torrelles and Schlesinger, 2017 ; Muefong and Sutherland, 2020 ) ( Figure 1D ).…”

SARS-CoV-2 infection leads to acute infection with dynamic cellular and inflammatory flux in the lung that varies across nonhuman primate species

“…Nonhuman primate (NHP) models of infectious diseases have proven useful for both investigating the pathogenesis of infection and testing therapeutic and vaccine candidates 2 . During the SARS and MERS outbreaks, NHP models were developed with a moderate degree of success 3 .…”

Screening of potential biomarkers for distinguishing between latent and active tuberculosis in children using bioinformatics analysis

“…[ 4 ] Due to the diversity of potential states and outcomes, we currently lack reliable methods to identify people who might develop active TB. [ 5 , 6 ] Previous studies have mainly focused on the development of new diagnostic tools for adult tuberculosis, while childhood TB has relatively been neglected. For most childhood cases, the detection rate is about 35% due to lack of effective diagnostic methods especially in early-stage TB and in some cases, the smears and cultures give false positives and negatives.…”