*2.2. Vitamin D and the Induction of Anti-Microbial Peptides*

Anti-microbial peptides like cathelicidins are components of the innate immune system whose synthesis is induced by mycobacterial ligands through binding to Toll-like receptors (TLRs), especially TLR2 and TLR9 [41]. Cathelicidin LL37 represents a major example of this class of molecules, is expressed by neutrophils and macrophages and participates in anti-TB defense through pore-forming capability in the bacterial membranes [42,43].

It has been shown that vitamin D promotes synthesis and release of LL37 [44], which in turn helps in autophagy [45,46]. Moreover, vitamin D enhances the ability of monocytes to respond to interferon gamma (IFN-γ) [47]. Various clinical trials which included vitamin D in addition to the standard regimen have been performed, sometimes with variable results [48–50]. It seems evident that key issues for successful use of vitamin D in TB therapy are proper dosing and possibly also genetic background and comorbidities of the patient. A recently published study by Aibana and co-workers suggested that vitamin D deficiency is associated with increased probability of developing TB in HIV-positive people [51]. However, further investigations are needed to clarify whether vitamin D supplementation might play a significant role in reducing the risk of TB.

Another vitamin whose antitubercular effects have been evaluated is vitamin A, which limits *M. tuberculosis* replication in macrophages by promoting acidification [52,53]. However, while studies in rats showed a beneficial impact of vitamin A supplementation [54], the same was not observed in humans [55,56].

Regulation of anti-microbial peptide expression is also controlled by histone deacetylase inhibitors (for instance 4-phenylbutyrate) through epigenetic mechanisms [57,58]. In the context of *M. tuberculosis* infection of human macrophages, it was demonstrated that phenylbutyrate, alone or in combination with vitamin D3, was able to counteract the suppressive effect of the bacilli on LL-37 expression, thus promoting autophagy [59].

In addition to cathelicidins, another group of anti-microbial peptides plays an important role in anti-TB mechanisms. These are defensins. Defensins are arginine-rich, cationic peptides resistant to proteolysis. They are usually stored in the granules and in the lysosomes of innate immune cells, such as neutrophils, and are released upon pathogen invasion [60]. *M. tuberculosis* stimulates production of beta defensin-2 (HBD-2), which reduces bacterial multiplication and has a chemotactic effect [61]. Despite these features, exploitation of HBD-2 in HDT against TB is far from clinical use, due to high costs and poor stability in vivo [62]. Clinical trials where these compounds are being investigated are listed in Table 1.
