PURPOSE: Tuberculosis is a worldwide health problem, and multidrug-resistant (MDR) and extensively multidrug-resistant (XMDR) strains are rapidly emerging and threatening the control of this disease. These problems motivate the search for new treatment strategies. One potential strategy is immunotherapy using cationic anti-microbial peptides. The capacity of l-isoleucine to induce β-defensin expression and its potential therapeutic efficiency were studied in a mouse model of progressive pulmonary tuberculosis
METHODS: BALB/c mice were infected with Mycobacterium tuberculosis strain H37Rv or with a MDR clinical isolate by the intratracheal route. After 60 days of infection, when disease was in its progressive phase, mice were treated with 250 mg of intratracheal l-isoleucine every 48 h. Bacillary loads were determined by colony-forming units, protein and cytokine gene expression were determined by immunohistochemistry and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), respectively, and tissue damage was quantified by automated morphometry.
RESULTS: Administration of l-isoleucine induced a significant increase of beta-defensins 3 and 4 which was associated with decreased bacillary loads and tissue damage. This was seen in animals infected with the antibiotic-sensitive strain H37Rv and with the MDR clinical isolate
CONCLUSIONS: Our results show that repeated intrapulmonary administration of l-isoleucine induced b-defensin production in vivo, and that this correlated with improved protective immunity and higher resistance to mycobacterial infection when administered during late progressive disease induced by drug-sensitive or drug-resistant virulent mycobacteria. Although this treatment was not completely curative, these results suggest that continuous administration of l-isoleucine by the respiratory route is a potential therapy that might aid the control of this significant infectious disease.
CLINICAL IMPLICATIONS: Induction of beta-defensins might be a potential therapy that can aid in the control of this significant infectious disease. Moreover, there are efficient devices for deep administration of aerosols to human lungs that might reach the infected areas more reliably than the simple intratracheal injection used here.
DISCLOSURE: The following authors have nothing to disclose: César Rivas, Bruno Rivas-Santiago, Diana Aguilar-Leon, Jazmin Mendez-Ramos, Julio Castañeda-Delgado, Rogelio Hernandez-Pando
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