Abstract
In a study of household contacts (HHC), households were categorized into High (HT) and Low (LT) transmission groups based on the proportion of HHC with a positive tuberculin skin test. The Mycobacterium tuberculosis (Mtb) strains from HT and LT index cases of the households were designated Mtb-HT and Mtb-LT, respectively. We found that C3HeB/FeJ mice infected with Mtb-LT strains exhibited significantly higher bacterial burden compared to Mtb-HT strains and also developed diffused inflammatory lung pathology. In stark contrast, a significant number of mice infected with Mtb-HT strains developed caseating granulomas, a lesion type with high potential to cavitate. None of the Mtb-HT infected animals developed diffused inflammatory lung pathology. A link was observed between increased in vitro replication of Mtb-LT strains and their ability to induce significantly high lipid droplet formation in macrophages. These results support that distinct early interactions of Mtb-HT and Mtb-LT strains with macrophages and subsequent differential trajectories in pathological disease may be the mechanism underlying their transmission potential.
Highlights
Mycobacterium tuberculosis (Mtb) is one of the most successful pathogens known; yet mechanisms underlying variability in transmission remain poorly understood
We found that C3HeB/FeJ mice infected with Mtb-LT strains developed diffused inflammatory lesions characteristic of granulocytic tuberculous pneumonia
The target of Mepenzolate bromide (MPN) in Mtb remains unclear, these data indicate that in vitro growth characteristics of Mtb-High Transmission” (HT) and Mtb-LT strains are not predictive of its intracellular growth pattern in macrophages, the latter we propose being more relevant to in vivo infections and further that lipid droplet formation is a factor in the enhanced intracellular growth of the Mtb-LT strains
Summary
Mtb is one of the most successful pathogens known; yet mechanisms underlying variability in transmission remain poorly understood. Pioneering work from Riley and colleagues [1] using TST conversion in guinea pigs that were exposed to air from a TB ward as a measure of infectiousness, found significant variability in infectiousness among untreated patients with drug susceptible Mtb. Despite having comparable sputum positivity, only 8 of the 61 patients in the TB ward were found to transmit infection [1]. Using a similar model of air sampling analysis in test animals, a great degree of variability in infectiousness was reported for HIVinfected patients with drug susceptible and resistant TB [2,3,4]. Variability in transmission could result from differences in the variability of infectious aerosols produced during coughing by patients with pulmonary tuberculosis [11]
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