Abstract
BackgroundEvaluation of a quick and easy model to determine the intrinsic ability of clinical strains to generate active TB has been set by assuming that this is linked to the fitness of Mycobacterium tuberculosis strain at the innate phase of the infection. Thus, the higher the bacillary load, the greater the possibility of inducting liquefaction, and thus active TB, once the adaptive response is set.Methodology/Principal FindingsThe virulence of seven clinical Mycobacterium tuberculosis strains isolated in Spain was tested by determining the bacillary concentration in the spleen and lung of mice at weeks 0, 1 and 2 after intravenous (IV) inoculation of 104 CFU, and by determining the growth in vitro until the stationary phase had been reached. Cord distribution automated analysis showed two clear patterns related to the high and low fitness in the lung after IV infection. This pattern was not seen in the in vitro fitness tests, which clearly favored the reference strain (H37Rv). Subsequent determination using a more physiological low-dose aerosol (AER) inoculation with 102 CFU showed a third pattern in which the three best values coincided with the highest dissemination capacity according to epidemiological data.Conclusions/SignificanceThe fitness obtained after low dose aerosol administration in the presence of the innate immune response is the most predictive factor for determining the virulence of clinical strains. This gives support to a mechanism of the induction of active TB derived from the dynamic hypothesis of latent tuberculosis infection.
Highlights
The concept of virulence has been interpreted from both a host and pathogen point of view [1]
As results from our previous experiments suggested that a constant endogenous reinfection occurs during Latent Tuberculosis Infection (LTBI) [15], we considered that the speed of growth before the onset of the specific immune response, together with reinfection in the upper lobe, where a higher oxygen pressure promotes faster bacillary growth, could be crucial for the infection to progress to active disease
At the experimental basis, we decided to focus in the pathogen behavior in the mouse model taking into account the infection route, considering the concept of virulence determined by the growth rate and defined in the Introduction section
Summary
The concept of virulence has been interpreted from both a host and pathogen point of view [1]. Virulence studies are highly focused on analyzingthe increase or decrease of the fitness of drugresistant clinical and mutant strains. These emerging drugresistant strains are studied retrospectively from an epidemiological point of view and their virulence is subsequently characterized experimentally. These studies have shown that there is a strong selection pressure for drug-resistance-conferring mutations that cause minimal fitness defects [4]. Evaluation of a quick and easy model to determine the intrinsic ability of clinical strains to generate active TB has been set by assuming that this is linked to the fitness of Mycobacterium tuberculosis strain at the innate phase of the infection. The higher the bacillary load, the greater the possibility of inducting liquefaction, and active TB, once the adaptive response is set
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