Antimicrobial Peptides in Mycobacterial Infection,Dong Min Shin and Eun Kyeong Jo. Figure 1 A schematic diagram for the role of antimicrobial peptides such as cathelicidins and defensins in host immune system Left diagram. shows biological effects of cathelicidin hCAP 18 LL 37 in immunity hCAP 18 LL 37 is synthesized and released from epithelial cells in response. to microbial infection or physical injury hCAP 18 LL 37 participates in the recruitment of neutrophils and other circulating cells including. monocytes macrophages at sites of infection by chemotaxis through secretion of several cytokines chemokines Release of hCAP 18 LL 37 from. keratinocytes results in induced wound healing Also they contribute to direct killing activity against invading pathogens and to indirect. antimicrobial activity by promoting autophagy activation maturation in monocytes macrophages Right diagram shows immunological functions. of defensins in various immune cells Defensins induced by various physiological sitimuli including TLRs or infection defensins are synthesized. and released from monocytes macrophages or neutrophils eosinophils whereas defensins are synthesized and released from not only their. cells but also DCs airway epitheliums or skin Released peptides have direct antimicrobial killing effects and they also have indirect killing. effects by interacting with various target cells and tissues to promote secondary responses that may be crucial for modulating inflammation. the recruitment of immune cells and activation maturation of several type of immune cell. to be clarified Thus understanding the molecular mecha activated macrophages and assist in elimination of ingested. nisms of expression of antimicrobial peptides and their role bacteria 4 5 Antimicrobial peptides such as cathelicidins. as immune modulators during the host innate response to and defensins play a crucial role in biological processes in. mycobacteria will help in the design of new therapies against cluding antimicrobial activities and immunomodulatory func. tuberculosis Due to the increasing global incidence of multi tions summarized in Fig 1 Cathelicidins are bipartite mole. drug resistant tuberculosis peptide derived microbicides rep cules consisting of an N terminal cathelin domain and a C ter. resent promising candidate therapeutics in the struggle against minal domain which has antimicrobial activity 12 13 The. resistant mycobacteria N terminal cathelin domain is known as a hallmark of the in. tracellular storage part of cathelicidins 12 13 Cathelicidins. GENERAL OVERVIEW OF ANTIMICROBIAL show constitutive and or inducible expression in various cells. PEPTIDES PROTEINS and tissues 12 13 Their tissue cell specific expression is. regulated by several stimuli including infection of microbes. Antimicrobial defense peptides proteins can be produced by inflammatory cytokines 13 15 Many studies reported that. 246 IMMUNE NETWORK http www ksimm or kr Volume 11 Number 5 October 2011. Antimicrobial Peptides in Mycobacterial Infection,Dong Min Shin and Eun Kyeong Jo. hCAP 18 LL 37 contributes to elimination of bacteria 14 sys striction of mycobacterial growth 28 Additionally the neu. temic protection against microbial invasion 13 chemo trophil peptides cathelicidin LL 37 and lipocalin2 Lcn2 also. taxis attraction through secretion of several cytokines chemo known as neutrophil gelatinase associated lipocalin NGAL. kines 16 wound healing 16 and autophagy activation ma contributed to inhibition of mycobacterial growth and im. turation 17 mune defense against tuberculosis 28 Earlier studies show. Defensins are antimicrobial cytotoxic peptides which con ed that the synthetic peptide LL 37 had broad antimicrobial. tain 29 35 amino acid residues including 6 invariant cys activity in airway epithelial cells of the lung 29 and in bron. teine residues 18 Defensins are expressed by various phys choalveolar lavage fluids 30 Recently we reported that M. iological biological stimuli including TLRs or infection 18 ulcerans infection significantly induces antimicrobial peptide. The antimicrobial spectrum of defensins include not only LL 37 in human primary keratinocytes via TLR2 and. gram positive microbes but also gram negative bacteria in Dectin 1 dependent pathways 31 These reports emphasize. cluding mycobacteria Treponema pallidum fungi and some a role for LL 37 in the early innate response to mycobacteria. viruses 18 20 Defensins exert nonspecific antimicrobial cy In mycobacterial infection of human mononuclear cells. totoxic activity against mammalian target cells and micro LL 37 is induced in a vitamin D dependent manner and plays. organisms 18 In addition to their antimicrobial cytotoxic an important role in inhibition of intracellular mycobacteria. properties some defensins act as opsonins 18 contribute through NADPH oxidase 2 dependent mechanisms 6 32. to selective chemo attractants for monocytes 18 DCs and Similarly M bovis bacillus Calmette Gu rin BCG induced. T cells 21 and promote to wound healing 8 22 23 and up regulation of the antimicrobial peptide cathelicidin LL 37. regulation of inflammation 24 25 in human epithelial cells was dependent on NADPH ROS sig. naling pathways 33 Of note vitamin D is crucial for the. CATHELICIDIN hCAP 18 LL 37 regulation of LL 37 induction which can be expressed in hu. man monocytes and respiratory epithelial cells through con. The cathelicidin family a key member of host defense pep version of vitamin D into its active metabolites 6 7. tide families is derived from leukocytes and epithelial cells Recently emerging roles of autophagy in the regulation of. and has an important role in elimination of pathogenic mi innate immune functions have been reported 34 Impor. crobes 13 15 26 Various inflammatory or infectious stimuli tantly the autophagy pathway has been known to be a key. can induce cathelicidin LL 37 which then exhibits anti defensive mechanism to eliminate M tuberculosis through. microbial activity against a number of bacteria and fungi 12 phagosomal maturation 35 Our recent data have shown. 14 22 hCAP 18 LL 37 is currently the only identified human that vitamin D3 actively induces autophagy in human mono. cathelicidin and profoundly affects multiple biological and cytes and inhibits intracellular mycobacterial growth through. pathological conditions 14 26 Cathelicidins contain a con increased autophagosomal maturation 17 In this study we. served N terminal cathelin domain and a variable C terminal found that LL 37 plays an important role in the induction and. cationic antimicrobial domain that becomes active and has an maturation of autophagy pathways activated by vitamin D3. timicrobial activity The mature peptide LL 37 comprises the in human monocytes 17 LL 37 regulated the transcriptional. C terminal portion and is expressed in various cell and tissue expression of the autophagy related genes beclin 1 and atg 5. types including neutrophils monocytes keratinocytes lym via C EBP and MAPK activation 17 In addition both de. phocytes and epithelial cells of the skin testis and the gas fensin 4 and cathelicidin are induced by distinct pathways. trointestinal and respiratory tracts 12 15 in human monocytes but cooperate to activate the TLR2 1. Accumulating evidence supports an early defensive role for mediated antimycobacterial activity 9 Furthermore recent. LL 37 at various sites During mycobacterial infection the studies have shown that the mycobacterial lipoprotein LpqH. highest expression of LL 37 was observed in alveolar macro actively induces autophagy through functional vitamin D re. phages 27 Other studies showed the importance of neu ceptor signaling and following induction of LL 37 dependent. trophils in host defense against mycobacteria When the over pathways 36. all immunity of blood cells to mycobacterial infection was Besides autophagy regulation additional novel functions of. evaluated in tuberculosis contactors neutrophil counts were LL 37 have been reported regulation of chemoattraction in. associated with a high risk of tuberculosis infection and re hibition of apoptosis wound healing angiogenesis and re. IMMUNE NETWORK http www ksimm or kr Volume 11 Number 5 October 2011 247. Antimicrobial Peptides in Mycobacterial Infection,Dong Min Shin and Eun Kyeong Jo. lease of cytokines chemokines 15 16 LL 37 can also func 44 Moreover a protective role for defensin against my. tion as an immune regulator mediating M tuberculosis in cobacterial infection has been reported in human eosinophils. duced ROS release and production of pro inflammatory cyto 19 defensin is induced in eosinophils upon stimulation. kines and chemokines 32 In mice the only cathelicidin with M bovis BCG and lipomannan and shows a synergistic. CRAMP was reported and structurally similar but shorter effect with eosinophil cationic protein on mycobacterial. than human LL 37 12 Both human LL 37 and murine growth inhibition 19. CRAMP has a similar pattern of tissue distribution and bio The human defensins HBD 1 and HBD 2 are predom. logical function 15 For example both LL 37 and CRAMP inately expressed at epithelial sites and less well defined than. have been shown to be chemotactic for various immune cells defensin family 23 25 Both HBD 1 and HBD 2 has bac. including neutrophils monocytes macrophages and T cells tericidal activity against both Gram positive and Gram neg. 37 38 Further increasing evidence indicates that various cy ative acteria 23 25 At least six HBD 1 isoforms range in. tokines and signals affect induction of cathelicidin expression length from 36 to 47 amino acids have been identified in. 16 The Th1 cytokine IFN up regulates whereas the Th2 urine whereas a single isoform of HBD 2 41 amino acids. cytokine IL 4 down regulates TLR2 1 mediated induction of in length has been isolated from respiratory epithelial secre. cathelicidin 39 In this way cell mediated immune re tions and saliva 23 While HBD 1 is constitutively ex. sponses can cross talk with innate immune pathways via cath pressed HBD 2 is upregulated during bacterial infection or. elicidin and other AMPs 39 Collectively these data suggest in response to endogenous inflammatory cytokines 23 45. that cathelicidin LL 37 exerts not only direct antimicrobial ac 46 suggesting a role for HBD 2 in regulation of antimicrobial. tivity but is also an important immune modulator of autoph and inflammatory responses During mycobacterial infection. agy regulation during mycobacterial infection HBD 2 can be transported into mycobacteria containing mac. rophage phagosomes to exert mycobactericidal and myco. DEFENSINS bacteristatic activity 20 In airway epithelial cells HBD 2. mRNA is induced by M bovis BCG infection and is upregu. Human defensins constitute a large portion of the pulmonary lated by TNF produced by M bovis BCG infected cells 46. innate host defense system Earlier studies showed that de HBD 2 expression is also triggered by bacterial LPS TLR4. fensins are present in high concentrations on respiratory epi stimulation through a CD14 dependent mechanism and ulti. thelia and selectively target microbial structures 40 Additio mately results in activation of NF B 24. nally defensins function as signaling molecules which link Recent studies have emphasized the role of HBD4 in the. the adaptive immune system to invader microorganisms 40 innate immune defense against mycobacteria 9 35 TLR2 1. Similar to cathelicidins precursors of defensins that contain mediated IL 1 is required for up regulation of HBD4 ex. a characteristic sheet rich fold and a framework of six di pression which has antimicrobial activity against intracellular. sulfide linked cysteines require proteolytic cleavage for anti mycobacterial infection 9 Moreover intratracheal admin. microbial activity 41 The small 3 5 kDa human cationic istration of l isoleucine into mice infected with the antibiotic. defensins are a delineated family of effectors of host defense sensitive strain H37Rv and a multidrug resistant clinical isolate. inflammation and cytotoxicity 18 Defensins are divided in significantly up regulated defensins 3 and 4 and inhibited. to three subfamilies and defensins 25 Six bacillary loads 47 M bovis BCG mediated expression of. defensins four human defensins HBD1 4 reviewed in HBD2 was found to be regulated by the protein kinase C. Ref 25 and additional defensin gene clusters have been PKC JNK and PI3K Akt pathways in airway epithelial cells. identified by computational analysis 42 46 Of interest more highly virulent M bovis strains exhibit. High throughput studies using microarray analyses of gene lower murine defensin 4 expression and vice versa during. expression profiles of PBMCs from patients with tuberculosis early infection 48 In experimental tuberculosis initial ex. and M tuberculosis infected healthy donors found that the ef pression of murine defensin 3 and defensin 4 in airway. fector molecules defensin 1 3 and 4 are upregulated in epithelial cells was correlated with temporary control of my. patients with tuberculosis 43 Human defensins show syn cobacterial growth 49 Additionally high and stable pro. ergy with antituberculous drugs thus suggesting that they duction of mouse defensins mBD3 and mBD4 during la. may be a promising adjunct to antituberculous chemotherapy tent infection is associated with long term control of myco. 248 IMMUNE NETWORK http www ksimm or kr Volume 11 Number 5 October 2011. Antimicrobial Peptides in Mycobacterial Infection,Dong Min Shin and Eun Kyeong Jo. Table I The roles of AMPs in immune system,AMPs Expressed cells organs Functions References. hCAP 18 LL 37 Neutrophails monocytes macrophages Elimination of pathogenic microbes e g Mycobacteria fungi Ref 14 26. keratinov cytes lymphocytes epithelial Induction and maturation of auotphagy Ref 17. cells and bronchoalveolar lavage fluids Inhibition of apoptosis Ref 16. Regulation of chemoattraction Ref 16,Release of cytokines chemokines Ref 16. Wound healing angiogenesis Ref 16, Up regulation of Th1 cytokine e g IFN down refulation of Ref 37. Th2 cytokine e g IL 4,Defensin Eosinophils PBMCs DCs T cells. monocytes macrophages airway,epithelial cells,defensin Up regulation in TB patients Ref 41. Protective effects against mycobacteria in eosinophils Ref 19. defensin Mycobactericidal and Mycobacteristatic activity Ref 20. Regulation of Inflammation e g TNF Ref 44,Activation of NF B Ref 24. Chemotatic effects in immature DCs and T cells Ref 21. defensin Still unknown yet, Hepcidin hepatocytes macrophages Homeostatic regulation of iron absorption iron recycling and Ref 55 56. iron mobilization, Inhibition of invasion of microbes and tumor cells Ref 59. Direct antimicrobial activity Ref 10,bacterial proliferation 49 HEPCIDIN. Similar to hCAP 18 LL 37 HBD 2 plays roles other than di. rect antimicrobial action These include chemotactic roles for Hepcidin is a cationic amphipathic bactericidal peptide pri. immature dendritic cells and memory T cells through a che marily produced in the liver and acts as a homeostatic regu. mokine receptor CCR6 dependent mechanism This mecha lator of iron absorption recycling and mobilization Its ex. nism promotes adaptive immune responses by recruiting im pression is markedly induced during infectious and in. mune cells to sites of microbial invasion 21 Unlike and flammatory conditions 57 58 Hepcidin is synthesized by iron. defensins defensins are found in some non human pri loading and cytokine IL 6 and decreased by anemia and. mates but not in humans gorillas bonobos or chimpanzees hypoxia The major mechanism of hepcidin function is. 50 Tang et al first isolated a trisulfide containing anti thought to be related to regulation of transmembrane iron. microbial peptide termed rhesus theta defensin 1 RTD 1 transport through binding with ferroportin an iron exporter. from granules of neutrophils and monocytes of the rhesus expressed in hepatocytes and macrophages 59 60 The re. macaque 51 Although defensins have antimicrobial ac sulting decrease in extracellular iron concentrations probably. tivity against diverse pathogens 51 53 especially viruses makes less available for invading microorganisms and tumor. 54 56 there is as yet no evidence that defensins are cells thereby contributing to host defense and controlling. involved in defense against mycobacterial infection The roles chronic diseases 57 58 61 As a novel mediator of innate im. of antimicrobial peptides in mycobacterial infection are sum munity hepcidin and related therapeutics are promising candi. marized in Table I Future studies will reveal the multiple dates for the treatment of various diseases such as hemochro. roles of various human defensins in the regulation of immune matosis and anemia from chronic inflammation 57 58 61. responses and host defense against mycobacterial infection Hepcidin is expressed in macrophages after infection with. the intracellular pathogens M avium and M tuberculosis. IMMUNE NETWORK http www ksimm or kr Volume 11 Number 5 October 2011 249. Antimicrobial Peptides in Mycobacterial Infection,Dong Min Shin and Eun Kyeong Jo. Stimulation of macrophages with mycobacteria and IFN CONFLICTS OF INTEREST. synergistically induced hepcidin mRNA and protein which lo. calized to the mycobacteria containing phagosomes 10 The author have no financial conflict of interest. Additionally hepcidin possesses direct antimicrobial activity. and causes damage to M tuberculosis 10 Further inves REFERENCES. tigation of the signaling mechanisms responsible for hepcidin. 1 WHO Global Tubercalosis Control 2010 Geneva WHO, mRNA expression showed that STAT1 and NF B activation. and induction of C EBP were involved in IFN and M 2 Pieters J Mycobacterium tuberculosis and the macrophage. tuberculosis induced hepcidin expression by macrophages maintaining a balance Cell Host Microbe 3 399 407 2008. 62 These data strongly suggest that M tuberculosis induced 3 Flynn JL Chan J Tuberculosis latency and reactivation. 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Antimicrobial Peptides in Mycobacterial Infection,Dong Min Shin and Eun Kyeong Jo. uginosa TNF alpha and IL 1beta but not IL 6 induce hu cytes isolation synthesis antimicrobial activities and bac. man beta defensin 2 in respiratory epithelia Am J Respir terial binding properties of the cyclic peptides J Biol Chem. Cell Mol Biol 22 714 721 2000 277 3079 3084 2002, 46 M ndez Samperio P Miranda E Trejo A Mycobacterium 54 Brandt CR Akkarawongsa R Altmann S Jose G Kolb AW. bovis Bacillus Calmette Gu rin BCG stimulates human be Waring AJ Lehrer RI Evaluation of a theta defensin in a. ta defensin 2 gene transcription in human epithelial cells Murine model of herpes simplex virus type 1 keratitis. Cell Immunol 239 61 66 2006 Invest Ophthalmol Vis Sci 48 5118 5124 2007. 47 Rivas Santiago CE Rivas Santiago B Le n DA Casta eda 55 Wang W Cole AM Hong T Waring AJ Lehrer RI Retrocy. 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T Zhao C Waring AJ Lehrer RI Circular minidefensins and 62 Sow FB Alvarez GR Gross RP Satoskar AR Schlesinger. posttranslational generation of molecular diversity J LS Zwilling BS Lafuse WP Role of STAT1 NF kappaB. Leukoc Biol 70 461 464 2001 and C EBPbeta in the macrophage transcriptional regu. 53 Tran D Tran PA Tang YQ Yuan J Cole T Selsted ME lation of hepcidin by mycobacterial infection and IFN. Homodimeric theta defensins from rhesus macaque leuko gamma J Leukoc Biol 86 1247 258 2009. 252 IMMUNE NETWORK http www ksimm or kr Volume 11 Number 5 October 2011.
Rhetorical Reading Strategies and the Construction of Meaning Christina Haas and Linda Flower There is a growing consensus in our field that reading should be thought of as a constructive rather than as a receptive process: that "meaning" does not exist in a text but in readers and the representations they build. This constructive
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exploitation of new knowledge, through small steps and transcendent leaps, has built a solid foundation for the future. Through its stewardship of the National Science Foundation and its advice to the President and Congress on science and engineering policy, the National Science Board has been a vital contributor to the astounding
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