Abstract
Infection with Mycobacterium tuberculosis (Mtb) can induce two kinds of lesions, namely proliferative and exudative. The former are based on the presence of macrophages with controlled induction of intragranulomatous necrosis, and are even able to stop its physical progression, thus avoiding the induction of active tuberculosis (TB). In contrast, the most significant characteristic of exudative lesions is their massive infiltration with polymorphonuclear neutrophils (PMNs), which favor enlargement of the lesions and extracellular growth of the bacilli. We have built an individual-based model (IBM) (known as “TBPATCH”) using the NetLogo interface to better understand the progression from Mtb infection to TB. We have tested four main factors previously identified as being able to favor the infiltration of Mtb-infected lesions with PMNs, namely the tolerability of infected macrophages to the bacillary load; the capacity to modulate the Th17 response; the breathing amplitude (BAM) (large or small in the lower and upper lobes respectively), which influences bacillary drainage at the alveoli; and the encapsulation of Mtb-infected lesions by the interlobular septae that structure the pulmonary parenchyma into secondary lobes. Overall, although all the factors analyzed play some role, the small BAM is the major factor determining whether Mtb-infected lesions become exudative, and thus induce TB, thereby helping to understand why this usually takes place in the upper lobes. This information will be very useful for the design of future prophylactic and therapeutic approaches against TB.
Highlights
Tuberculosis is still a major threat to humankind, causing up to 1.5 million deaths so far (World Health Organization, 2015)
Even though it originally seems that bacillary load tolerability (BLTOL) is the most important factor for lesions to become exudative, a proposal supported by the global statistical analysis (Table 2), which seems to show that BLTOL is slightly more influential than Breathing Amplitude (BAM), it is clear that, qualitatively speaking, exudative lesions are always induced at low BAM but the encapsulation process can abrogate this at low BLTOL
Namely the BAM and the encapsulation capacity of the intralobar septae, are anatomical. These two factors have been combined with another two that facilitate neutrophilic infiltration, which could be related to the quality of the immune response and, to some extent, to some degree of genetic susceptibility (Tobin et al, 2012). These are the tolerability of the intracellular bacillary load (BLTOL) (Ayres and Schneider, 2008) and the ability to counterbalance the Th17 response during the immune phase
Summary
Tuberculosis is still a major threat to humankind, causing up to 1.5 million deaths so far (World Health Organization, 2015). This has been related to the mechanics of the respiration process, which is influenced by the force of gravity, thereby impairing the breathing amplitude (BAM) in the upper lobes while enhancing it in the lower regions thanks to the force generated by the diaphragm This small amplitude in the upper lobes (Guo et al, 2011) could allow the local accumulation of bacilli, thereby attracting PMNs. This small amplitude in the upper lobes (Guo et al, 2011) could allow the local accumulation of bacilli, thereby attracting PMNs Another factor that helps control lesion progression is the encapsulation process that takes place in large mammals (Peake and Pinkerton, 2015). The encapsulation process plays a crucial role, it depends on the speed of lesion growth, which can overcome encapsulation when intense enough
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