Chapter 3 - Experimental Models Used to Study Human Tuberculosis
Introduction
Tuberculosis (Tb) is the leading cause of death from a single infectious organism (National Institute of Allergy and Infectious Diseases, 2006). In 2007 alone, 9.27 million people developed tuberculosis and 1.78 million died of the disease (WHO, 2009). The causative agent, Mycobacterium tuberculosis, is transmitted via aerosols and enters the lung from where it can cause active clinical Tb or persist in latent form over the lifetime of the host (Parrish et al., 1998). Predisposing factors that influence the onset of clinical disease include HIV infection, diabetes, smoking, alcoholism, malnutrition, and overcrowded living conditions (Lonnroth et al., 2009). Clinical tuberculosis invariably commences with the pulmonary form of the disease; however, the pathogen can subsequently disseminate via the circulatory or lymphatic systems and multiply in extrapulmonary host sites such as the skin, lymph nodes, central nervous system, genitourinary tract, and skeleton (Kritski and de Melo, 2007).
The earliest direct evidence of tuberculosis in humans originates from several thousand years ago. Traces of M. tuberculosis DNA, mycolic acid lipids, and paleopathological tubercular lesions have been identified in skeletal remains excavated from the submerged site of Atlit-Yam in the Eastern Mediterranean which dates from 9250 to 8160 BP (Hershkovitz et al., 2008). Indirect evidence is derived from the analysis of phylogenetic markers present in animal and human mycobacterial isolates. This has resulted in an estimation that the most common ancestor of the M. tuberculosis complex emerged approximately 40,000 years ago from its progenitor in East Africa, a time which is believed to coincide with the expansion of “modern” human populations from this area (Wirth et al., 2008).
Despite our long association with M. tuberculosis, we have not yet been able to effectively control or eradicate this pathogen. Previous targets of halving the incidence of tuberculosis between 2006 and 2015 or of eliminating the disease by 2050 will need to be reexamined (Lonnroth and Raviglione, 2008). The World Health Organization has concluded that new preventative, diagnostic, and treatment measures are needed to bring tuberculosis under control (WHO, 2006). The capacity of researchers to deliver new tools to control tuberculosis is acutely dependent on the relevance of the experimental models they use to study the disease and its etiological agent.
Section snippets
Use of Surrogate Models to Study Tuberculosis
M. tuberculosis has a very limited host range with no known natural hosts beyond humans (Brosch et al., 2002). Despite this, the pathogen does not require a zoonotic or environmental reservoir for persistence between episodes of clinical disease. The World Health Organization has estimated that one-third of the world's population is latently infected with the pathogen (Dye et al., 1999). This high-carriage rate provides a reservoir for subsequent disease in susceptible hosts whereby the
Fast-growing mycobacterial species
The value of using fast-growing species of mycobacteria in tuberculosis research was recognized by Selman Waksman in the 1940s. Waksman found that screening for antimycobacterial compounds using the pathogenic M. tuberculosis was a slow process (Sneader, 2005). He decided to screen against the fast-growing nonpathogenic species, M. phlei, and this ultimately led to the discovery of streptomycin, the first antibiotic effective in the treatment of tuberculosis. Since then, other fast-growing
Macrophages and cell cultures
As with in vitro models of tuberculosis, a variety of cell culture models have been used to study the disease. Based on the phagocytosis of M. tuberculosis at an early stage of infection of the host lung, many of the cell culture models have focused on the use of murine or human monocyte-derived macrophages or dendritic cells (de Chastellier, 2009). The use of cell cultures enables researchers to isolate the bacterial processes, which are central to uptake and survival and, in addition, the
The Study of Tuberculosis Pathogenesis in Human Patients
There is little doubt that the more an experimental model recreates the events that occur during the natural infection of humans by M. tuberculosis, the more relevant the data generated will be to the human disease. Improvements can be made to animal models of tuberculosis is to based on our knowledge of the natural history of tuberculosis in humans (Smith et al., 2000). For example, humans acquire tuberculosis through aerosol infection and only a small number of viable bacilli are required to
Conclusions and Future Prospects
It is clear that a large number of in vitro and in vivo models have been developed for the study of human tuberculosis. As well as the biological questions to be addressed, the choice of model will often depend on the financial resources and facilities available to a researcher. It is important that new tuberculosis research is not impeded by local limitations in technology or expertise. The sharing of experimental models to study human tuberculosis will likely hasten progress towards more
Acknowledgments
The support of the Health Research Council of New Zealand (grant number 07/379), the Wellington Medical Research Foundation (grant no. 2006/121), and the University Research Fund, Victoria University of Wellington (grant no. 26211/1496), is gratefully acknowledged.
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Adjunctive Phosphodiesterase-4 Inhibitor Therapy Improves Antibiotic Response to Pulmonary Tuberculosis in a Rabbit Model
2016, EBioMedicineCitation Excerpt :It is likely that the specific PDE4 isoforms targeted by CC-11050 differ from those targeted by rolipram. In addition, unlike the rabbit, the standard mouse model of pulmonary Mtb infection does not recapitulate the pathologic sequence of TB manifestations found in humans, such as necrosis, hypoxic lesions and cavitation (Gupta & Katoch, 2005; O'Toole, 2010). Since the effect of immune modulators on TB pathology and associated host gene expression varies significantly between murine and rabbit models, the results obtained in the two models cannot be directly comparable In addition, the divergent results between the current study and a report by Maiga et al. (2013) may be due to the difference in the treatment regimen (single-versus multi-drug combinatorial therapy).
Transcriptomic Approaches in the Zebrafish Model for Tuberculosis—Insights Into Host- and Pathogen-specific Determinants of the Innate Immune Response
2016, Advances in GeneticsCitation Excerpt :This highlights the need for developing novel therapeutic approaches requiring a better understanding of the mechanistic basis of the host–pathogen interactions underlying tuberculosis (Hawn, Matheson, Maley, & Vandal, 2013). In order to address this topic, a combination of functional genomics approaches and modern cell biology is required in animal models that mimic the human disease (O'Toole, 2010). The zebrafish has become a valuable addition to the animal models used for tuberculosis research (Cronan & Tobin, 2014; van Leeuwen, van der Sar, & Bitter, 2015; Meijer, 2015; Ramakrishnan, 2013).
Genetic engineering of Mycobacterium tuberculosis: A review
2012, TuberculosisCitation Excerpt :Defining M. tuberculosis–host interactions Several animal and cellular (e.g., macrophage) models for tuberculosis143–145 have been improved upon through M. tuberculosis genetic engineering. The mariner-derived transposon Himar1 was used to detect genes involved in the survival of M. tuberculosis CDC1551 in mouse,101,102 guinea pig101 and primate models.100
Tools for cellular immunology and vaccine research the in the guinea pig: Monoclonal antibodies to cell surface antigens and cell lines
2012, VaccineCitation Excerpt :Therefore the mouse is still the most widely used animal for medical research, although for many diseases it is certainly not the best. There is an abundance of reviews emphasizing the versatility of guinea pigs as research models in general [5–13] or with reference to infectious diseases and vaccination [14–22], with a strong focus on tuberculosis research [4,23–34]. Guinea pigs represent the “gold standard” among small animal models to test the efficiency of new and established vaccines against tuberculosis [35–37], and are useful for vaccination studies against other diseases [38–40], but most authors agree that the limited availability of immunological reagents in this species strongly restricts its usefulness for modern experimental approaches.
2050: Ending the odyssey of the great white plague: Part of a series on Pediatric Pharmacology, guest edited by Gianvincenzo Zuccotti, Emilio Clementi, and Massimo Molteni
2011, Pharmacological ResearchCitation Excerpt :Rabbits and cynomolgus monkeys may even serve as models in the study of chemotherapy for latent TB. Non-murine models are limited by high cost and varying extrapulmonary pathology [4]. Enhancing the development of antituberculous therapy in both preclinical and clinical stages requires more effective diagnostics and the use of surrogate biomarkers as end-points for clinical trials.
Strain-dependent CNS dissemination in guinea pigs after Mycobacterium tuberculosis aerosol challenge
2011, TuberculosisCitation Excerpt :By the time of diagnosis, the patient often exhibits progressive disease, with hydrocephalus and vasculitis leading to infarction.1 Over the course of more than a century of TB research, many models have been employed as tools for the study of TB pathogenesis and disease mechanisms.2 However, the majority of model systems for CNS TB have employed direct inoculation of bacilli into the cerebrospinal fluid (CSF) or cerebrum.3,4