The lack of a big picture in tuberculosis: the clinical point of view, the problems of experimental modeling and immunomodulation. The factors we should consider when designing novel treatment strategies

Vilaplana, Cristina; Cardona, Père-Joan

doi:10.3389/fmicb.2014.00055

Cited by 17 publications

(20 citation statements)

References 73 publications

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“…A perplexing problem is that pulmonary TB, the contagious form of TB, most commonly occurs in immune-competent individuals who remain immunologically responsive to mycobacterial antigens and do not have TH1 defects ( Hunter et al, 2006 ; Modlin and Bloom, 2013 ; Andersen and Woodworth, 2014 ; Nunes-Alves et al, 2014 ; Vilaplana and Cardona, 2014 ). Thus, although TH1 immunity is a requirement for resistance, its presence does not prevent disease in susceptible individuals.…”

Section: Introductionmentioning

confidence: 99%

Lung necrosis and neutrophils reflect common pathways of susceptibility toMycobacterium tuberculosisin genetically diverse, immune competent mice

Niazi

Dhulekar

Schmidt

et al. 2015

Disease Models &Amp; Mechanisms

107

129

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Pulmonary tuberculosis (TB) is caused by Mycobacterium tuberculosis in susceptible humans. Here, we infected Diversity Outbred (DO) mice with ∼100 bacilli by aerosol to model responses in a highly heterogeneous population. Following infection, ‘supersusceptible’, ‘susceptible’ and ‘resistant’ phenotypes emerged. TB disease (reduced survival, weight loss, high bacterial load) correlated strongly with neutrophils, neutrophil chemokines, tumor necrosis factor (TNF) and cell death. By contrast, immune cytokines were weak correlates of disease. We next applied statistical and machine learning approaches to our dataset of cytokines and chemokines from lungs and blood. Six molecules from the lung: TNF, CXCL1, CXCL2, CXCL5, interferon-γ (IFN-γ), interleukin 12 (IL-12); and two molecules from blood – IL-2 and TNF – were identified as being important by applying both statistical and machine learning methods. Using molecular features to generate tree classifiers, CXCL1, CXCL2 and CXCL5 distinguished four classes (supersusceptible, susceptible, resistant and non-infected) from each other with approximately 77% accuracy using completely independent experimental data. By contrast, models based on other molecules were less accurate. Low to no IFN-γ, IL-12, IL-2 and IL-10 successfully discriminated non-infected mice from infected mice but failed to discriminate disease status amongst supersusceptible, susceptible and resistant M.-tuberculosis-infected DO mice. Additional analyses identified CXCL1 as a promising peripheral biomarker of disease and of CXCL1 production in the lungs. From these results, we conclude that: (1) DO mice respond variably to M. tuberculosis infection and will be useful to identify pathways involving necrosis and neutrophils; (2) data from DO mice is suited for machine learning methods to build, validate and test models with independent data based solely on molecular biomarkers; (3) low levels of immunological cytokines best indicate a lack of exposure to M. tuberculosis but cannot distinguish infection from disease.

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Section: Introductionmentioning

confidence: 99%

Lung necrosis and neutrophils reflect common pathways of susceptibility toMycobacterium tuberculosisin genetically diverse, immune competent mice

Niazi

Dhulekar

Schmidt

et al. 2015

Disease Models &Amp; Mechanisms

107

129

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“…The mouse is not a natural host for M . tuberculosis , and lung cavitation, a key characteristic for the disease transmission in humans [ 16 ], is not observed for the 2 most-used mouse strains (Balb/c and BL6) [ 13 ]. Necrotizing responses to M .…”

Section: In Vivo Models In Tb Researchmentioning

confidence: 99%

Experimental study of tuberculosis: From animal models to complex cell systems and organoids

et al. 2017

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Tuberculosis (TB) is a devastating disease to mankind that has killed more people than any other infectious disease. Despite many efforts and successes from the scientific and health communities, the prospect of TB elimination remains distant. On the one hand, sustainable public health programs with affordable and broad implementation of anti-TB measures are needed. On the other hand, achieving TB elimination requires critical advances in three areas: vaccination, diagnosis, and treatment. It is also well accepted that succeeding in advancing these areas requires a deeper knowledge of host—pathogen interactions during infection, and for that, better experimental models are needed. Here, we review the potential and limitations of different experimental approaches used in TB research, focusing on animal and human-based cell culture models. We highlight the most recent advances in developing in vitro 3D models and introduce the potential of lung organoids as a new tool to study Mycobacterium tuberculosis infection.

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“…Hence, the mouse model has been largely a suitable infection model ( Orme, 2005b ; Cooper, 2014 ). Surprisingly, there is still no ideal and validated model of experimental tuberculosis disease ( Vilaplana and Cardona, 2014 ), and the mechanisms leading to latency and reactivation of are still unclear ( Parikka et al, 2012 ).…”

Section: From Classic To Alternative Models In Studying Relevant Bactmentioning

confidence: 99%

“…As relevant characteristic, we can mention the absence of granulomas formation in lungs from mice ( Grumbach et al, 1967 ; Karakousis et al, 2004 ; Mollenkopf et al, 2004 ; Orme, 2005a , b ; Hunter et al, 2007 ; Dharmadhikari and Nardell, 2008 ; Young, 2009 ; Apt, 2011 ). The immune response elicited in mice after mycobacterial infection is able to control bacillary load even without causing marked lesions ( Vilaplana and Cardona, 2014 ). Therefore, mice are generally resistant to TB infection when compared with other rodents, and even humans, as evidenced by their ability to tolerate relatively large bacterial numbers within their lungs without signs of disease ( Be et al, 2008 ; Dharmadhikari and Nardell, 2008 ; De Steenwinkel et al, 2009 ).…”

Section: From Classic To Alternative Models In Studying Relevant Bactmentioning

confidence: 99%

Animals devoid of pulmonary system as infection models in the study of lung bacterial pathogens

Hernández¹,

Yero

Pinos-Rodríguez

et al. 2015

Front. Microbiol.

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Biological disease models can be difficult and costly to develop and use on a routine basis. Particularly, in vivo lung infection models performed to study lung pathologies use to be laborious, demand a great time and commonly are associated with ethical issues. When infections in experimental animals are used, they need to be refined, defined, and validated for their intended purpose. Therefore, alternative and easy to handle models of experimental infections are still needed to test the virulence of bacterial lung pathogens. Because non-mammalian models have less ethical and cost constraints as a subjects for experimentation, in some cases would be appropriated to include these models as valuable tools to explore host–pathogen interactions. Numerous scientific data have been argued to the more extensive use of several kinds of alternative models, such as, the vertebrate zebrafish (Danio rerio), and non-vertebrate insects and nematodes (e.g., Caenorhabditis elegans) in the study of diverse infectious agents that affect humans. Here, we review the use of these vertebrate and non-vertebrate models in the study of bacterial agents, which are considered the principal causes of lung injury. Curiously none of these animals have a respiratory system as in air-breathing vertebrates, where respiration takes place in lungs. Despite this fact, with the present review we sought to provide elements in favor of the use of these alternative animal models of infection to reveal the molecular signatures of host–pathogen interactions.

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The lack of a big picture in tuberculosis: the clinical point of view, the problems of experimental modeling and immunomodulation. The factors we should consider when designing novel treatment strategies

Cited by 17 publications

References 73 publications

Lung necrosis and neutrophils reflect common pathways of susceptibility toMycobacterium tuberculosisin genetically diverse, immune competent mice

Lung necrosis and neutrophils reflect common pathways of susceptibility toMycobacterium tuberculosisin genetically diverse, immune competent mice

Experimental study of tuberculosis: From animal models to complex cell systems and organoids

Animals devoid of pulmonary system as infection models in the study of lung bacterial pathogens

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