Tuberculosis is an ongoing threat to global health, especially with the emergence of multi drug-resistant (MDR) and extremely drug-resistant strains that are motivating the search for new treatment strategies. One potential strategy is immunotherapy using Innate Defence Regulator (IDR) peptides that selectively modulate innate immunity, enhancing chemokine induction and cell recruitment while suppressing potentially harmful inflammatory responses. IDR peptides possess only modest antimicrobial activity but have profound immunomodulatory functions that appear to be influential in resolving animal model infections. The IDR peptides HH2, 1018 and 1002 were tested for their activity against two M. tuberculosis strains, one drug-sensitive and the other MDR in both in vitro and in vivo models. All peptides showed no cytotoxic activity and only modest direct antimicrobial activity versus M. tuberculosis (MIC of 15–30 µg/ml). Nevertheless peptides HH2 and 1018 reduced bacillary loads in animal models with both the virulent drug susceptible H37Rv strain and an MDR isolate and, especially 1018 led to a considerable reduction in lung inflammation as revealed by decreased pneumonia. These results indicate that IDR peptides have potential as a novel immunotherapy against TB.

Tuberculosis is one of the most important infectious diseases worldwide. The susceptibility to this disease depends to a great extent on the innate immune response against mycobacteria. Host defense peptides (HDP) are one of the first barriers to counteract infection. Cathelicidin (LL-37) is an HDP that has many immunomodulatory effects besides its weak antimicrobial activity. Despite advances in the study of the innate immune response in tuberculosis, the immunological role of LL-37 during M. tuberculosis infection has not been clarified. Monocyte-derived macrophages were infected with M. tuberculosis strain H37Rv and then treated with 1, 5, or 15 g/ml of exogenous LL-37 for 4, 8, and 24 h. Exogenous LL-37 decreased tumor necrosis factor alpha (TNF-␣) and interleukin-17 (IL-17) while inducing anti-inflammatory IL-10 and transforming growth factor ␤ (TGF-␤) production. Interestingly, the decreased production of anti-inflammatory cytokines did not reduce antimycobacterial activity. These results are consistent with the concept that LL-37 can modulate the expression of cytokines during mycobacterial infection and this activity was independent of the P2X7 receptor. Thus, LL-37 modulates the response of macrophages during infection, controlling the expression of proinflammatory and anti-inflammatory cytokines.T uberculosis (TB), caused by Mycobacterium tuberculosis, is the single deadliest communicable disease. In 2013, an estimated 9.0 million people developed TB and 1.5 million died from the disease (1).The main cells involved in the control of tuberculosis are macrophages, and together with epithelial cells, they are the first antiinfective immunological barriers encountered, with a primary task to initiate pathogen clearance. In the progress of cellular immunity against M. tuberculosis, macrophages can also function as antigen-presenting cells, in which the antigens of M. tuberculosis are degraded into immunogenic polypeptides and presented on T lymphocytes by the major histocompatibility complex to trigger adaptive immunity. However, M. tuberculosis has developed a wide assortment of strategies to counteract the bactericidal activities of these cells, enabling it to successfully establish a niche for long-term survival within macrophages. This M. tuberculosis replication causes mild inflammation, which promotes cell-mediated immunity that often leads to M. tuberculosis retention through granuloma (tubercle) formation (2). When infection becomes reactivated at a low rate, the granuloma suffers caseous necrosis, and this results in lung cavitation and pulmonary disease, inducing a prominent inflammation (3). Several molecules of the immune system are involved throughout this process, including host defense peptides (HDP) such as cathelicidin and defensins (4-6).LL-37 is the unique member of cathelicidin family in humans; this multifunctional immunomodulatory HDP is produced mainly by phagocytic leukocytes and epithelial cells as well as being normally found at concentrations varying from 2 to 5 g/ml in several fl...

Diabetic foot ulcers (DFU) are one of the most common diabetes-related cause of hospitalization and often lead to severe infections and poor healing. It has been recently reported that patients with DFU have lower levels of antimicrobial peptides (AMPs) at the lesion area, which contributes with the impairment of wound healing. The aim of this study was to determine whether 1,25-dihydroxyvitamin D3 (1,25 (OH)2 D3) and L-isoleucine induced HBD-2 and LL-37 in primary cultures from DFU. We developed primary cell cultures from skin biopsies from 15 patients with DFU and 15 from healthy donors. Cultures were treated with 1,25 (OH)2D3 or L-isoleucine for 18 h. Keratinocytes phenotype was identified by western blot and flow cytometry. Real time qPCR for DEFB4, CAMP and VDR gene expression was performed as well as an ELISA to measure HBD-2 and LL-37 in supernatant. Antimicrobial activity, in vitro, wound healing and proliferation assays were performed with conditioned supernatant. The results show that primary culture from DFU treated with 1,25(OH)2D3, increased DEFB4 and CAMP gene expression and increased the production of HBD-2 and LL-37 in the culture supernatant. These supernatants had antimicrobial activity over E. coli and induced remarkable keratinocyte migration. In conclusion the 1,25(OH)2D3 restored the production of AMPs in primary cell from DFU which were capable to improve the in vitro wound healing assays, suggesting their potential therapeutic use on the treatment of DFU.