Review
L-arginine and vitamin D: novel adjunctive immunotherapies in tuberculosis

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Worsening drug resistance and the need for prolonged treatment in tuberculosis (TB) require innovative solutions including investigation of inexpensive, safe adjunctive immunotherapies. L-arginine, the precursor of nitric oxide, and vitamin D recently have elucidated mycobactericidal and immunomodulatory actions against TB and are deficient in people with TB. We review the potential of these agents as adjunctive TB immunotherapies and explore how comparative clinical trials might help clarify their relative importance in the human TB immune response. By enhancing mycobacterial killing in macrophages, L-arginine and vitamin D might have the potential to enable shorter duration of treatment, reduced infectivity and improved response in drug-resistant TB.

Section snippets

Nitric oxide and vitamin D as adjunctive tuberculosis immunotherapies

Mycobacterium tuberculosis (MTB) is one of the most successful human pathogens, infecting an estimated one-third of the human population for a lifelong duration and accounting for the greatest number of deaths from a curable infectious disease 1, 2. Shortening the duration of tuberculosis (TB) treatment by using strategies such as revised regimens or modes of delivery of existing drugs, the development of new antimicrobial agents and successful adjunctive immunotherapies could profoundly impact

Adjunctive therapy in tuberculosis

Immunosuppressants and proimmune mediators (i.e. enhancers of immunological function) both have roles as adjuncts to TB treatment. Corticosteroids, possibly by suppressing tumour necrosis factor-α (TNF-α) and other proinflammatory cytokines, can ameliorate excessive host inflammatory T-cell responses and subsequent organ damage and have the best recognized role as TB adjunctive treatments [13]. Positive results have been obtained in some trials with thalidomide, also acting via TNF-α [14].

L-arginine

L-arginine is a conditionally essential (semiessential) amino acid in humans. In vivo, arginine derives from exogenous sources (diet) and endogenous sources (whole-body protein degradation plus synthesis from citrulline) [23]. In adults de novo arginine synthesis accounts for only 5%–15% of endogenous arginine flux [23]. Whole-body protein turnover contributes the majority of endogenous arginine turnover. Citrulline is synthesized in the gut and then converted to arginine in the kidneys via

Nitric oxide as a mycobactericidal mediator

L-arginine-derived NO plays a key role in the innate immune system and, specifically, in the defense against mycobacteria 7, 40 (Table 1). NO kills MTB by direct bacterial cell damage through deamination of bacterial DNA, proteins and lipids and by induction of apoptosis of TB-harbouring macrophages [41]. NO is noted to be capable of killing TB bacilli in vitro with a molar potency comparable to that of antibiotics [42]. Early in vitro studies of human monocyte and macrophage responses to MTB

Immunomodulatory role of vitamin D in TB

Pre-antibiotic era efforts at TB treatment (Box 1) might have exploited immunomodulatory effects of vitamin D. These have been the subject of recent reviews both in TB 12, 54 and the broader immunological context [55].

Interactions between L-arginine–NO and vitamin D–cathelicidin pathways

Macrophages can be activated either by TLR triggering, leading to increased intracellular vitamin D3 and cathelicidin induction, or by IFN-γ, acting via Janus tyrosine kinase (JAK) and signal transducer and activator of the transcription (STAT-1)-signaling pathway to upregulate NOS2 and thereby increase NO release (Figure 2). Interactions between the L-arginine–NO and vitamin D–TLR–cathelicidin pathways are probable. First, CYP27b1 requires an extracellular source of L-arginine for full

Potential for attenuation of lung pathology

TB results in significant tissue destruction and long-term impairment of lung function [68]. Attenuation of lung pathology has the potential to minimize long-term pulmonary disability. Both NO and vitamin D share a propensity to bolster innate immune responses but attenuate overexuberant CMI responses 54, 55, 69, 70. Profound T-cell depression, exemplified by HIV, is significantly detrimental to host containment of mycobacterial growth, but lesser degrees of T-cell depression, such as is

Trials of L-arginine and NO in human TB

Extensive experience with therapeutic L-arginine in humans has been gained from clinical trials of L-arginine in the oral, intravenous or inhaled form in studies of both endovascular and immunological functions 53, 76, 77, 78. Pharmacokinetic and modest side-effect properties are well described elsewhere [79]. There has been one randomized controlled trial (RCT) of L-arginine in TB to date. Low dose L-arginine supplementation (1 g orally daily) in Ethiopian TB patients was safe and well

Concluding remarks and further directions

TB is a disease of the highest global public health significance, requiring the pursuit of innovative research directions (Box 2). Improvements in TB therapeutic regimens through the use of adjunctive immunotherapies could have profound impacts, and these are recognized as priority TB research fields [16]. Evidence for the suitability of L-arginine and vitamin D as candidate adjunctive TB or latent TB treatments include the following: (i) human macrophages use activated vitamin D and L

Acknowledgements

We acknowledge the many authors who have contributed to the fields reviewed here whose work we have been unable to cite due to space constraints. In keeping with the journal's requirements, we frequently have been obliged to cite reviews instead. The National Health and Medical Research Council (Australia) supports A.R. (Postgraduate Medical Research scholarship), P.K. (Career Development Award) and N.A. (Practitioner Fellowship, ICRG and Program Grant).

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