Pigs used as a model for studying human tuberculosis, for the first time

The Unitat de Tuberculosi Experimental (UTE), Institut per a la Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP) has developed a new experimental model in minipigs for Mycobacterium tuberculosis, in collaboration with the CReSA. The mini-pig model highlights new aspects that could be a key to a better understanding tuberculosis infection control in humans.

M. tuberculosis causes up to 100 million new cases of latent tuberculosis infection (LTBI) every year. The fact that this infection can persist in the host for years explains why LTBI is so prevalent. Indeed, it is estimated that a third of humankind (more than 2.5 billion people) already has LTBI. Progression towards active tuberculosis (TB) (from 5 to 25% of infected people) is relatively low, although even this low percentage represents the induction of 9 million new TB cases every year.

Different experimental models have been used to better understand LTBI evolution, such as mice, rabbits, guinea pigs and macaques. However, the human parenchyma structure is different in these species but almost identical to that in pigs. The UTE, in collaboration with the CReSA, has developed a new experimental model in mini-pigs for M. tuberculosis for the first time.

Imatge de minipigs allotjats a l’estabulari NBS3 del CReSA

Image of minipigs located in the BSL3 facilities of the CReSA

Lesions en pulmó de porc provocada per M. tuberculosis

Lung lesions in pigs caused by M. tuberculosis

 

The high-tech facilities as well the highly-trained professionals of the CReSA have allowed developing this new experimental model. Animals were infected at a low dose of M. tuberculosis by transthoracic method. The animal housing and the laboratory work were carried out under a controlled, biosafety level 3 conditions.

Investigators of the CReSA developed and exhaustive study of the physiopathology of the disease and evaluated the cell-mediated and humoral immunological responses in: 1) infected animals, 2) infected animals and treated with Isoniazide and 3) infected animals and treated with Isoniazide and inoculated with 2 doses of a vaccine based in M. tuberculosis fragments. Immunological analysis were carried out by means of ELISPOT for IFN-γ and ELISA for detection of IFN-γ, TNF-α, IL-4, IL-10 and IL-12, against 4 antigens (PPD, ESAT-6, 85B and 16KDa) of the pathogen and against an attenuated strain (BCG). For the study of the humoral response a ELISA homemade was developed for detecting the antibodies created against the PPD.
Results of this study have been recently published in the prestigious journal  PLoS ONE (Gil O, Díaz I, Vilaplana C, Tapia G, Díaz J, Fort M, Cáceres N, Pinto S, Caylà J, Corner L, Domingo M, Cardona PJ. Granuloma encapsulation is a key factor for containing tuberculosis infection in minipigs. PLoS One. 2010 Apr 6;5(4):e10030. PubMed PMID: 20386605; PubMed Central PMCID: PMC2850319).


Conclusions

  1. The mini-pig model highlights new aspects that could be key to a better understanding tuberculosis infection control in humans.
  2. These findings also support the Dynamic Hypothesis, which postulates that maintenance of an LTBI requires a constant endogenous reinfection and might explain the success of humans in controlling TB infections and the low progression towards active TBC.
  3. Lesions surrounded by fibers of collagen seem to significantly reduce the movement capacity of bacteria and therefore reinfections. This phenomenon could explain why only a 10% of the patients get diseased.
  4. The predominant immunological response against the pathogen was Th1. The therapeutic use of the vaccine based on M. tuberculosis fragments increased both Th1 and antibodies (humoral) responses and lung lesions were reduced.

To contact with the authors of this article:

Ivan Díaz Luque                   
Investigator
E-mail: ivan.diaz@cresa.uab.cat
Telephone no.: +34 93 581 10 46                
Edifici CReSA. Campus UAB         
08193 Bellaterra (Barcelona) Spain      

Mariano Domingo Álvarez                    
Director of the CReSA                                 
E-mail: mariano.domingo@cresa.uab.cat
Telephone no.: +34  93 581 44 92            
Edifici CReSA. Campus UAB          
08193 Bellaterra (Barcelona) Spain

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