Can systems immunology lead tuberculosis eradication?

Cardona, Pere-Joan; Català, Martí; Arch, Marta; Arias, Lilibeth; Alonso, Sergio; Cardona, Paula; López, Daniel; Vilaplana, Cristina; Prats, Clara

doi:10.1016/j.coisb.2018.10.004

Cited by 6 publications

(9 citation statements)

References 39 publications

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“…Tuberculosis (TB) is still a major threat for humankind, causing 10 million new cases and 1.5 million deaths every year [1]. Mycobacterium tuberculosis (Mtb) infection is caused by infected aerosols generated by patients with TB, which enter the alveolar space and are engulfed by alveolar macrophages [2]. However, the majority of subjects infected do not generate symptomatology or lung damage; in fact, it has been calculated that 25% of humankind is already infected [3], and it is generally accepted that around 10% of these people will generate TB [4].…”

Section: Introductionmentioning

confidence: 99%

Cording Mycobacterium tuberculosis Bacilli Have a Key Role in the Progression towards Active Tuberculosis, Which is Stopped by Previous Immune Response

Arias

Cardona

Català³

et al. 2020

Microorganisms

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Cording was the first virulence factor identified in Mycobacterium tuberculosis (Mtb). We aimed to ascertain its role in the induction of active tuberculosis (TB) in the mouse strain C3HeB/FeJ by testing the immunopathogenic capacity of the H37Rv strain. We have obtained two batches of the same strain by stopping their growth in Proskauer Beck liquid medium once the mid-log phase was reached, in the noncording Mtb (NCMtb) batch, and two days later in the cording Mtb (CMtb) batch, when cording could be detected by microscopic analysis. Mice were challenged with each batch intravenously and followed-up for 24 days. CMtb caused a significant increase in the bacillary load at an early stage post-challenge (day 17), when a granulomatous response started, generating exudative lesions characterized by neutrophilic infiltration, which promoted extracellular bacillary growth together with cording formation, as shown for the first time in vivo. In contrast, NCMtb experienced slight or no bacillary growth and lesions could barely be detected. Previous Bacillus Calmette-Guérin (BCG) vaccination or low dose aerosol (LDA) Mtb infection were able to delay the progression towards active TB after CMtb challenge. While BCG vaccination also reduced bacillary load when NCMtb was challenged, LDA did not, and its proliferative lesions experienced neutrophil infiltration. Analysis of lung cytokine and chemokine profiles points to their capacity to block the production of CXCL-1 and further amplification of IL-1β, IL-17 and neutrophilic extracellular trap formation, all of which are essential for TB progression. These data highlight the key role of cording formation in the induction of active TB.

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Section: Introductionmentioning

confidence: 99%

Cording Mycobacterium tuberculosis Bacilli Have a Key Role in the Progression towards Active Tuberculosis, Which is Stopped by Previous Immune Response

Arias

Cardona

Català³

et al. 2020

Microorganisms

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“…Tuberculosis (TB) is an infectious disease that in 2017 killed more than 1.6 million people. Mycobacterium tuberculosis (Mtb) causes TB, and this bacterium is the individual agent causing the highest mortality worldwide [1]. The World Health Organization (WHO) estimates that 25 to 30% of the population worldwide is infected with Mtb, and that around 10% of infected people will develop active tuberculosis (ATB) in a few years' time [2], although these percentages are being questioned and re-visited by recent studies [3].…”

Section: Introductionmentioning

confidence: 99%

“…Systems biology and computational models are fruitful tools for increasing understanding of the processes involved in TB [1]. Recently, different models have been useful in identifying several TB key factors [9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Modelling the dynamics of tuberculosis lesions in a virtual lung: Role of the bronchial tree in endogenous reinfection

et al. 2020

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Tuberculosis (TB) is an infectious disease that still causes more than 1.5 million deaths annually. The World Health Organization estimates that around 30% of the world's population is latently infected. However, the mechanisms responsible for 10% of this reserve (i.e., of the latently infected population) developing an active disease are not fully understood, yet. The dynamic hypothesis suggests that endogenous reinfection has an important role in maintaining latent infection. In order to examine this hypothesis for falsifiability, an agentbased model of growth, merging, and proliferation of TB lesions was implemented in a computational bronchial tree, built with an iterative algorithm for the generation of bronchial bifurcations and tubes applied inside a virtual 3D pulmonary surface. The computational model was fed and parameterized with computed tomography (CT) experimental data from 5 latently infected minipigs. First, we used CT images to reconstruct the virtual pulmonary surfaces where bronchial trees are built. Then, CT data about TB lesion' size and location to each minipig were used in the parameterization process. The model's outcome provides spatial and size distributions of TB lesions that successfully reproduced experimental data, thus reinforcing the role of the bronchial tree as the spatial structure triggering endogenous reinfection. A sensitivity analysis of the model shows that the final number of lesions is strongly related with the endogenous reinfection frequency and maximum growth rate of the lesions, while their mean diameter mainly depends on the spatial spreading of new lesions and the maximum radius. Finally, the model was used as an in silico experimental platform to explore the transition from latent infection to active disease, identifying two main triggering factors: a high inflammatory response and the combination of a moderate inflammatory response with a small breathing amplitude.

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“…Tuberculosis natural history has an extraordinary complexity and, in fact, there are still too many unknowns [ 4 ]. Tuberculosis infection starts when an Mtb is phagocyted by an alveolar macrophage (AM) at a pulmonary alveolus.…”

Section: Introductionmentioning

confidence: 99%

“…Systems biology and computational models are great tools for increasing TB understanding [ 12 ]. Last years, several TB models have been built for a better understanding of different processes related with TB natural history [ 4 ]. In particular, GranSim [ 13 ] is a hybrid model that, under several modifications, is able to reproduce granulomas formation [ 14 ], encapsulation [ 15 ] and study drug resistance [ 16 ], among others.…”

Section: Introductionmentioning

confidence: 99%

A reaction-diffusion model to understand granulomas formation inside secondary lobule during tuberculosis infection

et al. 2020

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Mycobacterium tuberculosis ( Mtb ) is the causative agent for tuberculosis, the most extended infectious disease around the world. When Mtb enters inside the pulmonary alveolus it is rapidly phagocytosed by the alveolar macrophage. Although this controls the majority of inhaled microorganisms, in this case, Mtb survives inside the macrophage and multiplies. A posterior chemokine and cytokine cascade generated by the irruption of monocytes, neutrophils and posteriorly, by T-cells, does not necessarily stop the growth of the granuloma. Interestingly, the encapsulation process built by fibroblasts is able to surround the lesion and stop its growing. The success of this last process determines if the host enters in an asymptomatic latent state or continues into a life-threatening and infective active tuberculosis disease (TB). Understanding such dichotomic process is challenging, and computational modeling can bring new ideas. Thus, we have modeled the different stages of the infection, first in a single alveolus (a sac with a radius of 0.15 millimeters) and, second, inside a secondary lobule (a compartment of the lungs of around 3 cm 3 ). We have employed stochastic reaction-diffusion equations to model the interactions among the cells and the diffusive transport to neighboring alveolus. The whole set of equations have successfully described the encapsulation process and determine that the size of the lesions depends on its position on the secondary lobule. We conclude that size and shape of the secondary lobule are the relevant variables to control the lesions, and, therefore, to avoid the evolution towards TB development. As lesions appear near to interlobular connective tissue they are easily controlled and their growth is drastically stopped, in this sense secondary lobules with a more flattened shape could control better the lesion.

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Can systems immunology lead tuberculosis eradication?

Cited by 6 publications

References 39 publications

Cording Mycobacterium tuberculosis Bacilli Have a Key Role in the Progression towards Active Tuberculosis, Which is Stopped by Previous Immune Response

Cording Mycobacterium tuberculosis Bacilli Have a Key Role in the Progression towards Active Tuberculosis, Which is Stopped by Previous Immune Response

Modelling the dynamics of tuberculosis lesions in a virtual lung: Role of the bronchial tree in endogenous reinfection

A reaction-diffusion model to understand granulomas formation inside secondary lobule during tuberculosis infection

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