Aktuelle Literatur zur Bedeutung antibakterieller Peptide bei bakteriellen
Darminfektionen
Autor: William B. Grant, Ph.D.
Sunlight, Nutrition, and Health Research Center (SUNARC)
P.O. Box 641603
San Francisco, CA 94164-1603, USA
www.sunarc.org
wbgrant@infionline.net
Der mögliche aktuelle Zusammenhang zwischen EHEC-Infektionen und Vitamin D
Mangel wurde m.E. erstmals erwogen durch Raimund von Helden
http://www.vitamindelta.de/ehec.html
J Immunol. 2005 Apr 15;174(8):4901-7.
Cathelicidin mediates innate intestinal defense against colonization with epithelial adherent bacterial
pathogens.
Iimura M, Gallo RL, Hase K, Miyamoto Y, Eckmann L, Kagnoff MF.
Source
Department of Medicine, University of California at San Diego, La Jolla, CA 92093-0623, USA.
Abstract
Cathelicidin-related antimicrobial peptide (mCRAMP), the sole murine cathelicidin, is encoded by the gene
Cnlp. We show that mCRAMP expression in the intestinal tract is largely restricted to surface epithelial
cells in the colon. Synthetic mCRAMP had antimicrobial activity against the murine enteric pathogen
Citrobacter rodentium, which like the related clinically important human pathogens enteropathogenic
Escherichia coli and enterohemorrhagic E. coli, adheres to the apical membrane of intestinal epithelial
cells. Colon epithelial cell extracts from Cnlp+/+ mice had significantly greater antimicrobial activity
against C. rodentium than those of mutant Cnlp-/- mice that lack mCRAMP. Cnlp-/- mice developed
significantly greater colon surface and crypt epithelial cell colonization, surface epithelial cell damage, and
systemic dissemination of infection than Cnlp+/+ mice after oral infection with C. rodentium. Moreover,
Cnlp+/+ mice were protected from oral infections with C. rodentium inocula that infected the majority of
Cnlp-/- mice. These results establish cathelicidin as an important component of innate antimicrobial
defense in the colon.
Additional support:
Biochim Biophys Acta. 2006 Sep;1758(9):1408-25. Epub 2006 Apr 4.
LL-37, the only human member of the cathelicidin family of antimicrobial peptides.
Dürr UH, Sudheendra US, Ramamoorthy A.
Source
Biophysics Research Division and Department of Chemistry, 930 N. University Avenue, University of
Michigan, Ann Arbor, MI 48109-1055, USA.
Abstract
Antimicrobial peptides and their precursor molecules form a central part of human and mammalian innate
immunity. The underlying genes have been thoroughly investigated and compared for a considerable
number of species, allowing for phylogenetic characterization. On the phenotypical side, an ever-increasing
number of very varied and distinctive influences of antimicrobial peptides on the innate immune system are
reported. The basic biophysical understanding of mammalian antimicrobial peptides, however, is still very
limited. This is especially unsatisfactory since knowledge of structural properties will greatly help in the
understanding of their immunomodulatory functions. The focus of this review article will be on LL-37, the
only cathelicidin-derived antimicrobial peptide found in humans. LL-37 is a 37-residue, amphipathic,
helical peptide found throughout the body and has been shown to exhibit a broad spectrum of antimicrobial
activity. It is expressed in epithelial cells of the testis, skin, the gastrointestinal tract, and the respiratory
tract, and in leukocytes such as monocytes, neutrophils, T cells, NK cells, and B cells. It has been found to
have additional defensive roles such as regulating the inflammatory response and chemo-attracting cells of
the adaptive immune system to wound or infection sites, binding and neutralizing LPS, and promoting reepthelialization and wound closure. The article aims to report the known biophysical facts, with an
emphasis on structural evidence, and to set them into relation with insights gained on phylogenetically
related antimicrobial peptides in other species. The multitude of immuno-functional roles is only outlined.
We believe that this review will aid the future work on the biophysical, biochemical and immunological
investigations of this highly intriguing molecule.
Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):E77-81. Epub 2011 Apr 4.
PNAS Plus: Real-time attack on single Escherichia coli cells by the human antimicrobial peptide LL37.
Sochacki KA, Barns KJ, Bucki R, Weisshaar JC.
Source
Department of Chemistry, University of Wisconsin, Madison, WI 53706.
Abstract
Natural antimicrobial peptides (AMPs) provide prototypes for the design of unconventional antimicrobial
agents. Existing bulk assays measure AMP activity but do not provide details of the growth-halting
mechanism. We use fluorescence microscopy to directly observe the attack of the human antimicrobial
peptide LL-37 on single Escherichia coli cells in real time. Our findings strongly suggest that disruption of
the cytoplasmic membrane is not the growth-halting mechanism. At 8 μM, LL-37 binding saturates the
outer membrane (OM) within 1 min. Translocation across the OM and access to the periplasmic space (525 min later) correlates in time with the halting of growth. Septating cells are attacked more readily than
nonseptating cells. The halting of growth may occur because of LL-37 interference with cell wall
biogenesis. Only well after growth halts does the peptide permeabilize the cytoplasmic membrane to GFP
and the small dye Sytox Green. The assay enables dissection of antimicrobial design criteria into two parts:
translocation across the OM and the subsequent halting of growth.
PLoS Pathog. 2010 Jul 22;6(7):e1001010.
Uropathogenic Escherichia coli modulates immune responses and its curli fimbriae interact with the
antimicrobial peptide LL-37.
Kai-Larsen Y, Lüthje P, Chromek M, Peters V, Wang X, Holm A, Kádas L, Hedlund KO, Johansson J,
Chapman MR, Jacobson SH, Römling U, Agerberth B, Brauner A.
Source
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Abstract
Bacterial growth in multicellular communities, or biofilms, offers many potential advantages over singlecell growth, including resistance to antimicrobial factors. Here we describe the interaction between the
biofilm-promoting components curli fimbriae and cellulose of uropathogenic E. coli and the endogenous
antimicrobial defense in the urinary tract. We also demonstrate the impact of this interplay on the
pathogenesis of urinary tract infections. Our results suggest that curli and cellulose exhibit differential and
complementary functions. Both of these biofilm components were expressed by a high proportion of
clinical E. coli isolates. Curli promoted adherence to epithelial cells and resistance against the human
antimicrobial peptide LL-37, but also increased the induction of the proinflammatory cytokine IL-8.
Cellulose production, on the other hand, reduced immune induction and hence delayed bacterial elimination
from the kidneys. Interestingly, LL-37 inhibited curli formation by preventing the polymerization of the
major curli subunit, CsgA. Thus, even relatively low concentrations of LL-37 inhibited curli-mediated
biofilm formation in vitro. Taken together, our data demonstrate that biofilm components are involved in
the pathogenesis of urinary tract infections by E. coli and can be a target of local immune defense
mechanisms.
Microbiology. 2010 Feb;156(Pt 2):570-8. Epub 2009 Nov 19.
Different effects of transcriptional regulators MarA, SoxS and Rob on susceptibility of Escherichia
coli to cationic antimicrobial peptides (CAMPs): Rob-dependent CAMP induction of the marRAB
operon.
Warner DM, Levy SB.
Source
Center for Adaptation Genetics and Drug Resistance, Tufts University School of Medicine, Boston, MA
02111, USA.
Abstract
Cationic antimicrobial peptides (CAMPs), a component of the mammalian immune system, protect the host
from bacterial infections. The roles of the Escherichia coli transcriptional regulators MarA, SoxS and Rob
in susceptibility to these peptides were examined. Overexpression of marA, either in an antibiotic-resistant
marR mutant or from a plasmid, decreased bacterial susceptibility to CAMPs. Overexpression of the soxS
gene from a plasmid, which decreased susceptibility to antibiotics, unexpectedly caused no decrease in
CAMP susceptibility; instead it produced increased susceptibility to different CAMPs. Deletion or
overexpression of rob had little effect on CAMP susceptibility. The marRAB operon was upregulated when
E. coli was incubated in sublethal amounts of CAMPs polymyxin B, LL-37 or human beta-defensin-1;
however, this upregulation required Rob. Deletion of acrAB increased bacterial susceptibility to polymyxin
B, LL-37 and human beta-defensin-1 peptides. Deletion of tolC yielded an even greater increase in
susceptibility to these peptides and also led to increased susceptibility to human alpha-defensin-2.
Inhibition of cellular proton-motive force increased peptide susceptibility for wild-type and acrAB deletion
strains; however, it decreased susceptibility of tolC mutants. These findings demonstrate that CAMPs are
both inducers of marA-mediated drug resistance through interaction with Rob and also substrates for efflux
in E. coli. The three related transcriptional regulators show different effects on bacterial cell susceptibility
to CAMPs.
Eur J Gastroenterol Hepatol. 2008 Dec;20(12):1151-8.
Antimicrobial host defense in the upper gastrointestinal tract.
Hosaka Y, Koslowski M, Nuding S, Wang G, Schlee M, Schäfer C, Saigenji K, Stange EF, Wehkamp J.
Source
Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
Abstract
BACKGROUND:
With the exception of fungi, microbial infections are rare in the oesophagus. Herein, we aimed to
systematically assess the distribution and quantity of different antimicrobial host factors as well as, for the
first time, functional mucosal antimicrobial activity in the upper gastrointestinal tract.
METHODS:
We investigated biopsies from the healthy oesophagus, three different locations in the stomach and the
duodenum in a total of 12 individuals. Using real-time PCR with external standards, we compared absolute
expression of mRNA encoding antimicrobial peptides including defensins, cathelicidin,
bactericidal/permeability-increasing protein, psoriasin, and elafin. In addition, we performed
immunostaining for human-beta-defensin-1 (HBD1), elafin, and psoriasin. To test functional relevance, we
assessed antimicrobial as well as antifungal activity of cationic extracts from biopsies against E. coli ATCC
25922 and a clinical isolate of Candida albicans.
RESULTS:
In contrast to HBD1 which was similarly expressed in all tissues, inducible beta-defensins in the healthy
oesophagus were much higher compared with the stomach and duodenum (for HBD2-4: P<0.01). In
addition, the antiproteases elafin and psoriasin were also predominantly expressed in the oesophagus
(P<0.005). In contrast, LL-37 and bactericidal/permeability-increasing protein were only marginally
expressed. Cationic tissue extracts from both the oesophagus as well as the stomach showed potent
antibacterial activity against E. coli. Consistent with susceptibility to Candida infection, the esophageal
extracts exhibited a weaker activity against C. albicans (P=0.026).
CONCLUSION:
Despite dominant expression of antimicrobial host peptides, oesophageal tissue shows a weakened potency
to kill C. albicans. These data suggest an important role of yet unknown antimicrobial molecules.
Front Biosci. 2008 May 1;13:3760-7.
The role of the multifunctional peptide LL-37 in host defense.
Kai-Larsen Y, Agerberth B.
Source
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm,
Sweden. ylva.kai-larsen@ki.se
Abstract
Neutrophil granules contain several antimicrobial peptides (AMPs) that are important effector molecules of
innate immunity. In mammals, the main families of these peptides are the cathelicidins and defensins.
Several defensins have been characterized in humans, while there is only one human cathelicidin,
designated LL-37. This peptide is stored in specific granules of neutrophils in an inactive proform, which is
processed extracellularly to the mature active peptide LL-37 and the propart cathelin after neutrophil
degranulation. Apart from exhibiting a broad antimicrobial spectra, it is now evident that LL-37 possesses
several additional functions that are related to host defense. Examples of such functions are chemotactic,
endotoxin neutralizing, angiogenic and wound healing activities. These effects of LL-37 reveal a role as a
mediator between innate and adaptive immunity. This review is giving an overview of the different
immunological effects exerted by LL-37 and the physiological significance of these functions in immunity.
Pediatr Res. 2007 May;61(5 Pt 1):530-6.
Antimicrobial components of the neonatal gut affected upon colonization.
Kai-Larsen Y, Bergsson G, Gudmundsson GH, Printz G, Jörnvall H, Marchini G, Agerberth B.
Source
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm,
Sweden.
Abstract
Antimicrobial peptides (AMP) produced throughout our body are important effectors in the defense barrier
of innate immunity. Here, we have analyzed antimicrobial activity and polypeptide composition of
meconium versus neonatal feces to address the development of antimicrobial defense of the neonatal gut.
Extracts of meconium exhibited antimicrobial activity against Bacillus megaterium, Escherichia coli, and
group B streptococci (GBS) but not against the yeast Candida albicans. Extracts of neonatal feces were
found to possess low activity against E. coli, GBS, and C. albicans. However, the anti-B. megaterium
activity was higher in the fecal extracts than in meconium. All activities were reduced or abolished when
salt was added to the antimicrobial assay. The AMP cathelicidin LL-37, alpha-defensin HNP-1-2, alphadefensin HD 5, and lysozyme were identified in both meconium and fecal extracts. In addition, HNP-3 and
a fragment of azurocidin were found in meconium, whereas the holoprotein azurocidin was detected in
feces. In meconium, histones H2A and H4 were isolated and identified by their antimicrobial activity.
Notably, LL-37 and lysozyme were found at significantly higher levels in feces than in meconium. Our
findings reveal that meconium and feces contain AMP, acting in the defense of the neonatal gut, and may
be implicated in the control of the initial colonization.
Antimicrob Agents Chemother. 2006 May;50(5):1672-9.
LL-37 protects rats against lethal sepsis caused by gram-negative bacteria.
Cirioni O, Giacometti A, Ghiselli R, Bergnach C, Orlando F, Silvestri C, Mocchegiani F, Licci A,
Skerlavaj B, Rocchi M, Saba V, Zanetti M, Scalise G.
Source
Università Politecnica delle Marche, Clinica Malattie Infettive, c/o Ospedale Regionale, Via Conca 71,
60020 Torrette, Ancona, Italy.
Abstract
We investigated the efficacy of LL-37, the C-terminal part of the only cathelicidin in humans identified to
date (termed human cationic antimicrobial protein), in three experimental rat models of gram-negative
sepsis. Adult male Wistar rats (i) were given an intraperitoneal injection of 1 mg Escherichia coli 0111:B4
LPS, (ii) were given 2 x 10(10) CFU of Escherichia coli ATCC 25922, or (iii) had intra-abdominal sepsis
induced via cecal ligation and puncture. For each model, all animals were randomized to receive
intravenously isotonic sodium chloride solution, 1-mg/kg LL-37, 1-mg/kg polymyxin B, 20-mg/kg
imipenem, or 60-mg/kg piperacillin. Lethality; growth of bacteria in blood, peritoneum, spleen, liver, and
mesenteric lymph nodes; and endotoxin and tumor necrosis factor alpha (TNF-alpha) concentrations in
plasma were evaluated. All compounds reduced lethality compared to levels in controls. Endotoxin and
TNF-alpha plasma levels were significantly higher in conventional antibiotic-treated rats than in LL-37and polymyxin B-treated animals. All drugs tested significantly reduced bacterial growth compared to
saline treatment. No statistically significant differences between LL-37 and polymyxin B were noted for
antimicrobial and antiendotoxin activities. LL-37 and imipenem proved to be the most effective treatments
in reducing all variables measured. Due to its multifunctional properties, LL-37 may become an important
future consideration for the treatment of sepsis.
Expert Opin Ther Targets. 2007 Aug;11(8):993-1004.
Cathelicidins and functional analogues as antisepsis molecules.
Mookherjee N, Rehaume LM, Hancock RE.
Source
University of British Columbia, Centre for Microbial Diseases and Immunity Research, Department of
Microbiology and Immunology, Vancouver, BC, Canada.
Abstract
The emergence of antibiotic-resistant bacteria together with the limited success of sepsis therapeutics has
lead to an urgent need for the development of alternative strategies for the treatment of systemic
inflammatory response syndrome and related disorders. Immunomodulatory compounds that do not target
the pathogen directly (therefore limiting the development of pathogen resistance), and target multiple
inflammatory mediators, are attractive candidates as novel therapeutics. Cationic host defence peptides
such as cathelicidins have been demonstrated to be selectively immunomodulatory in that they can confer
anti-infective immunity and modulate the inflammatory cascade through multiple points of intervention.
The human cathelicidin LL-37, for example, has modest direct antimicrobial activity under physiological
conditions, but has been demonstrated to have potent antiendotoxin activity in animal models, as well as
the ability to resolve certain bacterial infections. A novel synthetic immunomodulatory peptide, IDR-1,
built on this same theme has no direct antimicrobial activity, but is effective in restricting many types of
infection, while limiting pro-inflammatory responses. The ability of these peptides to selectively suppress
harmful pro-inflammatory responses, while maintaining beneficial infection-fighting components of host
innate defences makes them a good model for antisepsis therapies that merit further investigation.
J Transl Med. 2009 Apr 23;7:28.
Alterations in vitamin D status and anti-microbial peptide levels in patients in the intensive care unit
with sepsis.
Jeng L, Yamshchikov AV, Judd SE, Blumberg HM, Martin GS, Ziegler TR, Tangpricha V.
Source
Division of Endocrinology, Diabetes & Lipids, Department of Medicine, Emory University School of
Medicine, Atlanta, GA, USA. jengleo@gmail.com
Abstract
BACKGROUND:
Vitamin D insufficiency is common in hospitalized patients. Recent evidence suggests that vitamin D may
enhance the innate immune response by induction of cathelicidin (LL-37), an endogenous antimicrobial
peptide produced by macrophages and neutrophils. Thus, the relationship between vitamin D status and
LL-37 production may be of importance for host immunity, but little data is available on this subject,
especially in the setting of human sepsis syndrome and other critical illness.
METHODS:
Plasma concentrations of 25-hydroxyvitamin D (25(OH)D), vitamin D binding protein (DBP) and LL-37 in
critically ill adult subjects admitted to intensive care units (ICUs) with sepsis and without sepsis were
compared to healthy controls.
RESULTS:
Critically ill subjects had significantly lower plasma 25(OH)D concentrations compared to healthy controls.
Mean plasma LL-37 levels were significantly lower in critically ill subjects compared to healthy controls.
Vitamin D binding protein levels in plasma were significantly lower in critically ill subjects with sepsis
compared to critically ill subjects without sepsis. There was a significant positive association between
circulating 25(OH)D and LL-37 levels.
CONCLUSION:
This study demonstrates an association between critical illness and lower 25(OH)D and DBP levels in
critically ill patients as compared to healthy controls. It also establishes a positive association between
vitamin D status and plasma LL-37, which suggests that systemic LL-37 levels may be regulated by
vitamin D status. Optimal vitamin D status may be important for innate immunity especially in the setting
of sepsis. Further invention studies to examine this association are warranted.
J Immunol. 2007 Jun 1;178(11):7190-8.
IFN-gamma- and TNF-independent vitamin D-inducible human suppression of mycobacteria: the
role of cathelicidin LL-37.
Martineau AR, Wilkinson KA, Newton SM, Floto RA, Norman AW, Skolimowska K, Davidson RN,
Sørensen OE, Kampmann B, Griffiths CJ, Wilkinson RJ.
Source
Wellcome Trust Center for Research in Clinical Tropical Medicine, Division of Medicine, Wright Fleming
Institute, Imperial College London, United Kingdom.
Erratum in
 J Immunol. 2007 Dec 15;179(12):8569-70.
Abstract
Vitamin D deficiency is associated with susceptibility to tuberculosis, and its biologically active metabolite,
1alpha,25 dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)), has pleiotropic immune effects. The
mechanisms by which 1alpha,25(OH)(2)D(3) protects against tuberculosis are incompletely understood.
1alpha,25(OH)(2)D(3) reduced the growth of mycobacteria in infected human PBMC cultures in a dosedependent 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.
1alpha,25(OH)(2)D(3) reduced transcription and secretion of protective IFN-gamma, IL-12p40, and TNF
in infected PBMC and macrophages, indicating that 1alpha,25(OH)(2)D(3) does not mediate protection via
these cytokines. Although NOS2A was up-regulated by 1alpha,25(OH)(2)D(3), inhibition of NO formation
marginally affected the suppressive effect of 1alpha,25(OH)(2)D(3) on bacillus Calmette Guérin in infected
cells. By contrast, 1alpha,25(OH)(2)D(3) strongly up-regulated the cathelicidin hCAP-18 gene, and some
hCAP-18 polypeptide colocalized with CD14 in 1alpha,25(OH)(2)D(3) stimulated PBMC, although no
detectable LL-37 peptide was found in supernatants from similar 1alpha,25(OH)(2)D(3)-stimulated PBMC
cultures. A total of 200 mug/ml of the active peptide LL-37, in turn, reduced the growth of Mycobacterium
tuberculosis in culture by 75.7%. These fi
J Immunol. 2007 Aug 15;179(4):2060-3.
Cutting edge: vitamin D-mediated human antimicrobial activity against Mycobacterium tuberculosis
is dependent on the induction of cathelicidin.
Liu PT, Stenger S, Tang DH, Modlin RL.
Source
Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of
California, Los Angeles, CA 90095, USA.
Abstract
Host defense against intracellular pathogens depends upon innate and adaptive antimicrobial effector
pathways. TLR2/1-activation of monocytes leads to the vitamin D-dependent production of cathelicidin
and, at the same time, an antimicrobial activity against intracellular Mycobacterium tuberculosis. To
determine whether induction of cathelicidin was required for the vitamin D-triggered antimicrobial activity,
the human monocytic cell line THP-1 was infected with M. tuberculosis H37Ra and then activated with the
active vitamin D hormone 1,25-dihydroxyvitamin D(3) (1,25D(3)). 1,25D(3) stimulation resulted in
antimicrobial activity against intracellular M. tuberculosis and expression of cathelicidin mRNA and
protein. Using small interfering RNA (siRNA) specific for cathelicidin, 1,25D(3)-induced cathelicidin
mRNA and protein expressions were efficiently knocked down, whereas a nonspecific siRNA control had
little effect. Finally, 1,25D(3)-induced antimicrobial activity was completely inhibited in the presence of
siRNA against cathelicidin, instead leading to enhanced intracellular growth of mycobacteria. These data
demonstrate that cathelicidin is required for the 1,25D(3)-triggered antimicrobial activity against
intracellular M. tuberculosis.
J Steroid Biochem Mol Biol. 2010 Jul;121(1-2):234-8. Epub 2010 Mar 17.
Vitamin D as an inducer of cathelicidin antimicrobial peptide expression: past, present and future.
White JH.
Source
Department of Physiology, McGill University, Montreal, QC, Canada. john.white@mcgill.ca
Abstract
Vitamin D was discovered as the preventive agent of nutritional rickets, a defect in bone development due
to inadequate uptake of dietary calcium. However, a variety of studies over the last several years has
revealed that vitamin D controls much more than calcium homeostasis. For example, recent research has
underlined the key role of vitamin D signaling in regulation of innate immunity in humans. Vitamin D is
converted to 25-hydroxyvitamin D (25D), its major circulating form, and then to hormonal 1,25dihydroxyvitamin D (1,25D) in target cells. We now know that when cells of the immune system such a
macrophages sense a bacterial infection they acquire the capacity to convert circulating 25D into 1,25D.
Moreover, 1,25D thus produced is a direct inducer of expression of genes encoding antimicrobial peptides,
in particular cathelicidin antimicrobial peptide (CAMP). Antimicrobial peptides such as CAMP are
vanguards of innate immune responses to bacterial infection and can act as signaling molecules to regulate
immune system function. This review covers what we have learned in the past few years about the
expression and function of CAMP under physiological and pathophysiological conditions, and addresses
the potential future applications of vitamin D analogues to therapeutic regulation of CAMP expression.
Lancet. 2011 Jan 15;377(9761):242-50. Epub 2011 Jan 5.
High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a
double-blind randomised controlled trial.
Martineau AR, Timms PM, Bothamley GH, Hanifa Y, Islam K, Claxton AP, Packe GE, Moore-Gillon JC,
Darmalingam M, Davidson RN, Milburn HJ, Baker LV, Barker RD, Woodward NJ, Venton TR, Barnes
KE, Mullett CJ, Coussens AK, Rutterford CM, Mein CA, Davies GR, Wilkinson RJ, Nikolayevskyy V,
Drobniewski FA, Eldridge SM, Griffiths CJ.
Source
Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, UK.
a.martineau@qmul.ac.uk
Abstract
BACKGROUND:
Vitamin D was used to treat tuberculosis in the pre-antibiotic era, and its metabolites induce
antimycobacterial immunity in vitro. Clinical trials investigating the effect of adjunctive vitamin D on
sputum culture conversion are absent.
METHODS:
We undertook a multicentre randomised controlled trial of adjunctive vitamin D in adults with sputum
smear-positive pulmonary tuberculosis in London, UK. 146 patients were allocated to receive 2·5 mg
vitamin D(3) or placebo at baseline and 14, 28, and 42 days after starting standard tuberculosis treatment.
The primary endpoint was time from initiation of antimicrobial treatment to sputum culture conversion.
Patients were genotyped for TaqI and FokI polymorphisms of the vitamin D receptor, and interaction
analyses were done to assess the influence of the vitamin D receptor genotype on response to vitamin D(3).
This trial is registered with ClinicalTrials.gov number NCT00419068.
FINDINGS:
126 patients were included in the primary efficacy analysis (62 assigned to intervention, 64 assigned to
placebo). Median time to sputum culture conversion was 36·0 days in the intervention group and 43·5 days
in the placebo group (adjusted hazard ratio 1·39, 95% CI 0·90-2·16; p=0.14). TaqI genotype modified the
effect of vitamin D supplementation on time to sputum culture conversion (p(interaction)=0·03), with
enhanced response seen only in patients with the tt genotype (8·09, 95% CI 1·36-48·01; p=0·02). FokI
genotype did not modify the effect of vitamin D supplementation (p(interaction)=0·85). Mean serum 25hydroxyvitamin D concentration at 56 days was 101·4 nmol/L in the intervention group and 22·8 nmol/L in
the placebo group (95% CI for difference 68·6-88·2; p<0·0001).
INTERPRETATION:
Administration of four doses of 2·5 mg vitamin D(3) increased serum 25-hydroxyvitamin D concentrations
in patients receiving intensive-phase treatment for pulmonary tuberculosis. Vitamin D did not significantly
affect time to sputum culture conversion in the whole study population, but it did significantly hasten
sputum culture conversion in participants with the tt genotype of the TaqI vitamin D receptor
polymorphism.