Globally, tuberculosis (TB) continues to exact an unacceptably high toll of disease and death among children, particularly in the wake of the HIV epidemic. Increased international travel and immigration have seen childhood TB rates increase even in traditionally low burden, industrialised settings, and threaten to facilitate the emergence and spread of multi-drug resistant strains. While intense scientific and clinical research efforts into novel diagnostic, therapeutic and preventative interventions have focused on TB in adults, childhood TB has been relatively neglected. However, children are particularly vulnerable to severe disease and death following infection, and those with latent infection become the reservoir of disease reactivation in adulthood, fueling the future epidemic. Further research into the epidemiology, immune mechanisms, diagnosis, treatment and prevention of childhood TB is urgently needed. Advances in our understanding of TB in children would provide wider insights and opportunities to facilitate efforts to control this ancient disease.

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A single oral dose of 2.5 mg vitamin D significantly enhanced the ability of participants' whole blood to restrict BCG-lux luminescence in vitro without affecting antigen-stimulated IFN-gamma responses. Clinical trials should be performed to determine whether vitamin D supplementation prevents reactivation of latent TB infection. Clinical trial registered with www.clinicaltrials.gov (NCT 00157066).

Neutrophils contain antimicrobial peptides with antituberculous activity, but their contribution to immune resistance to tuberculosis (TB) infection has not been previously investigated to our knowledge. We determined differential white cell counts in peripheral blood of 189 adults who had come into contact with patients diagnosed with active TB in London, United Kingdom, and evaluated them for evidence of TB infection and capacity to restrict mycobacterial growth in whole-blood assays. Risk of TB infection was inversely and independently associated with peripheral blood neutrophil count in contacts of patients diagnosed with pulmonary TB. The ability of whole blood to restrict growth of Mycobacterium bovis bacille Calmette Guérin and Mycobacterium tuberculosis was impaired 7.3-and 3.1-fold, respectively, by neutrophil depletion. In microbiological media, human neutrophil peptides (HNPs) 1-3 killed M. tuberculosis. The neutrophil peptides cathelicidin LL-37 and lipocalin 2 restricted growth of the organism, the latter in an iron-dependent manner. Black African participants had lower neutrophil counts and lower circulating concentrations of HNP1-3 and lipocalin 2 than south Asian and white participants. Neutrophils contribute substantially to innate resistance to TB infection, an activity associated with their antimicrobial peptides. Elucidation of the regulation of neutrophil antimicrobial peptides could facilitate prevention and treatment of TB. IntroductionTuberculosis (TB) is a leading global cause of morbidity and death (1). Primary TB infection is acquired by the inhalation of droplets containing Mycobacterium tuberculosis (MTB) bacilli. If innate immunity is insufficient to eliminate infection, the acquired T cell response results in containment of infection in the majority of cases. The immune sensitization that arises can be detected by the delayed-type hypersensitivity reaction to MTB antigens in the form of the tuberculin skin test (TST).It has long been recognized that some individuals exposed to infectious TB resist developing positive TST for longer periods than their peers despite similar exposure levels (2), raising the possibility that the innate immune response can clear infection without induction of an acquired response. Until recently, investigation of factors associated with innate resistance to MTB infection was hampered by the poor sensitivity and specificity of the TST (3). The development of more sensitive and specific blood-based methods to evaluate the T cell response to TB (known as IFN-γ release assays [IFNGRAs]) is therefore an important advance. One such test, the ELISPOT, has recently been used to determine factors associated with resistance to MTB infection in children (4).

Vitamin D deficiency is associated with susceptibility to tuberculosis, and its biologically active metabolite, 1α,25 dihydroxyvitamin D3 (1α,25(OH)2D3), has pleiotropic immune effects. The mechanisms by which 1α,25(OH)2D3 protects against tuberculosis are incompletely understood. 1α,25(OH)2D3 reduced the growth of mycobacteria in infected human PBMC cultures in a dose-dependent fashion. Coculture with agonists or antagonists of the membrane or nuclear vitamin D receptors indicated that these effects were primarily mediated by the nuclear vitamin D receptors. 1α,25(OH)2D3 reduced transcription and secretion of protective IFN-γ, IL-12p40, and TNF in infected PBMC and macrophages, indicating that 1α,25(OH)2D3 does not mediate protection via these cytokines. Although NOS2A was up-regulated by 1α,25(OH)2D3, inhibition of NO formation marginally affected the suppressive effect of 1α,25(OH)2D3 on bacillus Calmette Guérin in infected cells. By contrast, 1α,25(OH)2D3 strongly up-regulated the cathelicidin hCAP-18 gene, and some hCAP-18 polypeptide colocalized with CD14 in 1α,25(OH)2D3 stimulated PBMC, although no detectable LL-37 peptide was found in supernatants from similar 1α,25(OH)2D3-stimulated PBMC cultures. A total of 200 μg/ml of the active peptide LL-37, in turn, reduced the growth of Mycobacterium tuberculosis in culture by 75.7%. These findings suggest that vitamin D contributes to protection against TB by “nonclassical” mechanisms that include the induction of antimicrobial peptides.