Induction of β-defensins by l-isoleucine as novel immunotherapy in experimental murine tuberculosis

Abstract

SummaryTuberculosis 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 beta-defensin expression and its potential therapeutic efficiency were studied in a mouse model of progressive pulmonary tuberculosis. 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. 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. Thus, induction of beta-defensins might be a potential therapy that can aid in the control of this significant infectious disease.

Loss of TMF/ARA160 Protein Renders Colonic Mucus Refractory to Bacterial Colonization and Diminishes Intestinal Susceptibility to Acute Colitis

“…The pivotal role of MUC2 and the colonic mucus layer in protection from the onset of IBD was underscored previously by the severe colonic inflammation, which develops spontaneously in MUC2-deficient mice (33). Furthermore, the lowered levels of the murine cytokine KC and of the antibacterial peptide mBD3, which are produced in response to microbial stimuli (34,35), coincide with the observation that bacterial presence is significantly lower in colons of TMF Ϫ/Ϫ mice. TMF/ARA160 was shown previously to direct the proteasomal degradation of the NF-B subunit, p65 (2).…”

Air Pollution Particulate Matter Alters Antimycobacterial Respiratory Epithelium Innate Immunity

“…The HBD-2 mRNA fold changes and protein production in PM 2.5 -exposed cells followed bell-shaped (quantal) dose-responses ( Fig. 2A and B) (18). It is worth noting that the HBD-2 protein expression profile correlated with HBD-2 mRNA fold changes ( Fig.…”

“…3G). Studies in murine models have demonstrated a correlation between deficiencies in HBD-2 and HBD-3 production and significantly increased risk of TB development (17,18). Based on these antecedents and the suppressive effect of PM exposure on HBD-2 and HBD-3 mRNA expression in M. tuberculosis-infected A549 cells observed here, we assessed the effects of PM 2.5 and PM 10 on growth control of M. tuberculosis in A549 cells.…”

“…HBD-2 and HBD-3 are small cationic peptides that belong to the family of antimicrobial peptides (16). Due to their antimicrobial and immunomodulatory properties, HBD-2 and HBD-3 play important roles in the early control of M. tuberculosis infection (17) by decreasing the pulmonary bacterial load, as shown in experimentally infected rodents (18).…”

Molecular Defense Mechanisms during Urinary Tract Infection

“…Hertting et al [82] show that vitamin D increases LL-37 in bladder biopsies that are infected with UPEC. Rivas-Santiago et al [83] reports that L-isoleucine upregulates HBD3 and HBD4 in mice. Furthermore, according to a study of Schwab et al [84], butyrate upregulates LL-37 mRNA.…”