A new model for chronic and reactivation tuberculosis: Infection with genetically attenuated Mycobacterium tuberculosis in mice with polar susceptibility

Dec 6, 2018Tuberculosis (Edinburgh, Scotland)

A new mouse model of long-term and reactivated tuberculosis using weakened tuberculosis bacteria in mice with specific vulnerability

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Abstract

ΔACDE mycobacteria multiplied only in the lungs of susceptible I/St mice, while their counts decreased over time in the more resistant B6 mice.

In I/St mice, TB foci formation was delayed compared to B6 mice, which showed early condensed foci by week 4.
At late infection stages, I/St mice exhibited extensive pneumonia due to the fusion of TB foci, while B6 mice had limited pathology.
Neutrophil accumulation was greater in I/St lungs, whereas B6 lungs had a higher presence of macrophages.
Chemokine gene expression related to neutrophil influx was elevated in I/St compared to B6 lungs.
B6 lung cells produced more immune signaling molecules (IFN-γ, IL-6, and IL-11) throughout the infection compared to I/St cells.

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TB infection in mice develops relatively rapidly which interferes with experimental dissection of immune responses and lung pathology features that differ between genetically susceptible and resistant hosts. Earlier we have shown that the M. tuberculosis strain lacking four of five Rpf genes (ΔACDE) is seriously attenuated for growth in vivo. Using this strain, we assessed key parameters of lung pathology, immune and inflammatory responses in chronic and reactivation TB infections in highly susceptible I/St and more resistant B6 mice. ΔACDE mycobacteria progressively multiplied only in I/St lungs, whilst in B6 lung CFU counts decreased with time. Condensed TB foci apeared in B6 lungs at week 4 of infection, whilst in I/St their formation was delayed. At the late phase of infection, in I/St lungs TB foci fused resulting in extensive pneumonia, whereas in B6 lungs pathology was limited to condensed foci. Macrophage and neutrophil populations characteristically differed between I/St and B6 mice at early and late stages of infection: more neutrophils accumulated in I/St and more macrophages in B6 lungs. The expression level of chemokine genes involved in neutrophil influx was higher in I/St compared to B6 lungs. B6 lung cells produced more IFN-γ, IL-6 and IL-11 at the early and late phases of infection. Overall, using a new mouse model of slow TB progression, we demonstrate two important features of ineffective infection control underlined by shifts in lung inflammation: delay in early granuloma formation and fusion of granulomas resulting in consolidated pneumonia late in the infectious course.

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Abstract

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