| Revision as of 12:40, 12 May 2011 editCheMoBot (talk | contribs)Bots141,565 edits Updating {{chembox}} (no changed fields - added verified revid - updated 'UNII_Ref', 'ChemSpiderID_Ref', 'StdInChI_Ref', 'StdInChIKey_Ref', 'ChEMBL_Ref', 'KEGG_Ref') per Chem/Drugbox validation ( |
Latest revision as of 10:28, 2 December 2024 edit Graeme Bartlett (talk | contribs)Administrators249,716 edits more ids |
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'''Trehalose dimycolate''' is a molecule produced by ] and other mycobacteria. |
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'''Cord factor''', or '''trehalose dimycolate''' (TDM), is a ] molecule found in the cell wall of '']'' and similar species. It is the primary lipid found on the exterior of ''M. tuberculosis'' cells.<ref name="multipleroles">{{cite journal|last=Hunter|first=RL|author2=Olsen, MR |author3=Jagannath, C |author4= Actor, JK |title=Multiple roles of cord factor in the pathogenesis of primary, secondary, and cavitary tuberculosis, including a revised description of the pathology of secondary disease.|journal=Annals of Clinical and Laboratory Science|date=Autumn 2006|volume=36|issue=4|pages=371–86|pmid=17127724}}</ref> Cord factor influences the arrangement of ''M. tuberculosis'' cells into long and slender formations, giving its name.<ref>{{cite journal|last=Saita|first=N.|author2=Fujiwara, N. |author3=Yano, I. |author4=Soejima, K. |author5= Kobayashi, K. |title=Trehalose 6,6'-Dimycolate (Cord Factor) of Mycobacterium tuberculosis Induces Corneal Angiogenesis in Rats|journal=Infection and Immunity|date=1 October 2000|volume=68|issue=10|pages=5991–5997|doi=10.1128/IAI.68.10.5991-5997.2000|pmc=101563 |pmid=10992511}}</ref> Cord factor is virulent towards mammalian cells and critical for survival of ''M. tuberculosis'' in hosts, but not outside of hosts.<ref name="biosynth">{{cite journal|last=Rajni|author2=Rao, N |author3=Meena, LS |title=Biosynthesis and Virulent Behavior of Lipids Produced by Mycobacterium tuberculosis: LAM and Cord Factor: An Overview.|journal=Biotechnology Research International|year=2011|volume=2011|pages=274693|pmid=21350659|doi=10.4061/2011/274693|pmc=3039431 |doi-access=free }}</ref><ref>{{cite journal|last=Silva|first=CL|author2=Ekizlerian, SM |author3=Fazioli, RA |title=Role of cord factor in the modulation of infection caused by mycobacteria.|journal=The American Journal of Pathology|date=February 1985|volume=118|issue=2|pages=238–47|pmid=3881973|pmc=1887869}}</ref> Cord factor has been observed to influence ]s, induce the formation of ]s, and inhibit ] growth.<ref name="fusion">{{cite journal|last=Spargo|first=BJ|author2=Crowe, LM |author3=Ioneda, T |author4=Beaman, BL |author5= Crowe, JH |title=Cord factor (alpha,alpha-trehalose 6,6'-dimycolate) inhibits fusion between phospholipid vesicles.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=Feb 1, 1991|volume=88|issue=3|pages=737–40|pmid=1992465|doi=10.1073/pnas.88.3.737 |pmc=50888|bibcode=1991PNAS...88..737S|doi-access=free}}</ref> The antimycobacterial drug ] is thought to inhibit TDM production levels and in this way disrupts its cell wall assembly.<ref>TAHLAN, K., R. WILSON, D. B. KASTRINSKY, K. ARORA, V. NAIR, E. FISCHER, S. W. BARNES, J. R. WALKER, D. ALLAND, C. E. BARRY a H. I. BOSHOFF. SQ109 Targets MmpL3, a Membrane Transporter of Trehalose Monomycolate Involved in Mycolic Acid Donation to the Cell Wall Core of Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy. 2012-03-16, vol. 56, issue 4, s. 1797-1809. DOI: 10.1128/AAC.05708-11. http://aac.asm.org/cgi/doi/10.1128/AAC.05708-11</ref> |
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==Structure== |
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A cord factor molecule is composed of a ] molecule, ] (a ]), composed of two ] molecules linked together. Trehalose is ] to two ] residues.<ref name="chemstruct">{{cite journal|last=NOLL|first=H|author2=BLOCH, H |author3=ASSELINEAU, J |author4= LEDERER, E |title=The chemical structure of the cord factor of Mycobacterium tuberculosis.|journal=Biochimica et Biophysica Acta|date=May 1956|volume=20|issue=2|pages=299–309|pmid=13328853|doi=10.1016/0006-3002(56)90289-x}}</ref><ref>{{cite journal|last=Jonsson|first=B. E.|author2=Gilljam, M. |author3=Lindblad, A. |author4=Ridell, M. |author5=Wold, A. E. |author6= Welinder-Olsson, C. |title=Molecular Epidemiology of Mycobacterium abscessus, with Focus on Cystic Fibrosis|journal=Journal of Clinical Microbiology|date=21 March 2007|volume=45|issue=5|pages=1497–1504|doi=10.1128/JCM.02592-06 |pmid=17376883 |pmc=1865885}}</ref> One of the two mycolic acid residues is attached to the sixth carbon of one glucose, while the other mycolic acid residue is attached to the sixth carbon of the other glucose.<ref name="chemstruct" /> Therefore, cord factor is also named trehalose-6,6'-dimycolate.<ref name="chemstruct" /> The carbon chain of the mycolic acid residues vary in length depending on the species of bacteria it is found in, but the general range is 20 to 80 carbon atoms.<ref name="biosynth" /> Cord factor's ] nature leads to varying structures when many cord factor molecules are in close proximity.<ref name="biosynth" /> On a hydrophobic surface, they spontaneously form a crystalline monolayer.<ref>{{cite journal|last=Retzinger|first=GS|author2=Meredith, SC |author3=Hunter, RL |author4=Takayama, K |author5= Kézdy, FJ |title=Identification of the physiologically active state of the mycobacterial glycolipid trehalose 6,6'-dimycolate and the role of fibrinogen in the biologic activities of trehalose 6,6'-dimycolate monolayers.|journal=Journal of Immunology|date=August 1982|volume=129|issue=2|pages=735–44|doi=10.4049/jimmunol.129.2.735 |pmid=6806381|s2cid=45693526 |doi-access=free}}</ref> This crystalline monolayer is extremely durable and firm; it is stronger than any other amphiphile found in biology.<ref>{{cite journal|last=Hunter|first=RL|author2=Venkataprasad, N |author3=Olsen, MR |title=The role of trehalose dimycolate (cord factor) on morphology of virulent ''M. tuberculosis'' in vitro.|journal=Tuberculosis (Edinburgh, Scotland)|date=September 2006|volume=86|issue=5|pages=349–56|pmid=16343989|doi=10.1016/j.tube.2005.08.017}}</ref> This monolayer also forms in oil-water, plastic-water, and air-water surfaces.<ref name="multipleroles" /> In an aqueous environment free of hydrophobic surfaces, cord factor forms a micelle.<ref name="surfaceprop">{{cite journal|last=Retzinger|first=GS|author2=Meredith, SC |author3=Takayama, K |author4=Hunter, RL |author5= Kézdy, FJ |title=The role of surface in the biological activities of trehalose 6,6'-dimycolate. Surface properties and development of a model system.|journal=The Journal of Biological Chemistry|date=Aug 10, 1981|volume=256|issue=15|pages=8208–16|doi=10.1016/S0021-9258(18)43410-2|pmid=7263645|doi-access=free}}</ref> Furthermore, cord factor interlocks with lipoarabinomannan (LAM), which is found on the surface of ''M. tuberculosis'' cells as well, to form an asymmetrical bilayer.<ref name="multipleroles" /><ref>{{cite journal|last=Brennan|first=PJ|title=Structure, function, and biogenesis of the cell wall of Mycobacterium tuberculosis.|journal=Tuberculosis (Edinburgh, Scotland)|year=2003|volume=83|issue=1–3|pages=91–7|pmid=12758196|doi=10.1016/s1472-9792(02)00089-6}}</ref> These properties cause bacteria that produce cord factor to grow into long, intertwining filaments, giving them a rope- or cord-like appearance when stained and viewed through a microscope (hence the name).<ref>{{cite book | author = Bartelt, MA. | year = 2000 | title = Diagnostic Bacteriology: A Study Guide | publisher = F.A. Davis Company | location = Philadelphia, USA | pages = 500 | isbn = 978-0-8036-0301-1}}</ref> |
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==Evidence of virulence== |
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] of '']'']] |
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A large quantity of cord factor is found in virulent ''M. tuberculosis'', but not in avirulent ''M. tuberculosis''.<ref name="multipleroles" /> Furthermore, ''M. tuberculosis'' loses its virulence if its ability to produce cord factor molecules is compromised.<ref name="multipleroles" /> Consequently, when all lipids are removed from the exterior of ''M. tuberculosis'' cells, the survival of the bacteria is reduced within a host.<ref name="influenceof">{{cite journal|last=Indrigo|first=J |author2=Hunter RL, Jr |author3=Actor, JK|title=Influence of trehalose 6,6'-dimycolate (TDM) during mycobacterial infection of bone marrow macrophages.|journal=Microbiology|date=July 2002|volume=148|issue=Pt 7|pages=1991–8|pmid=12101287|doi=10.1099/00221287-148-7-1991|doi-access=free}}</ref> When cord factor is added back to those cells, ''M. tuberculosis'' survives at a rate similar to that of its original state.<ref name="influenceof" /> Cord factor increases the virulence of tuberculosis in mice, but it has minimal effect on other infections.<ref name="multipleroles" /> |
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==Biological function== |
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The function of cord factor is highly dependent on what environment it is located, and therefore its conformation.<ref name="caseating">{{cite journal|last=Hunter|first=Robert L.|author2=Olsen, Margaret |author3=Jagannath, Chinnaswamy |author4= Actor, Jeffrey K. |title=Trehalose 6,6′-Dimycolate and Lipid in the Pathogenesis of Caseating Granulomas of Tuberculosis in Mice|journal=The American Journal of Pathology|date=April 2006|volume=168|issue=4|pages=1249–1261|doi=10.2353/ajpath.2006.050848|pmid=16565499|pmc=1606544}}</ref> This is evident as cord factor is harmful when injected with an oil solution, but not when it is with a saline solution, even in very large amounts.<ref name="caseating" /> Cord factor protects ''M. tuberculosis'' from the defenses of the host.<ref name="multipleroles" /> Specifically, cord factor on the surface of ''M. tuberculosis'' cells prevents fusion between phagosomal vesicles containing the ''M. tuberculosis'' cells and the ]s that would destroy them.<ref name="fusion" /><ref name="trafficking">{{cite journal|last=Indrigo|first=J |author2=Hunter RL, Jr |author3=Actor, JK|title=Cord factor trehalose 6,6'-dimycolate (TDM) mediates trafficking events during mycobacterial infection of murine macrophages.|journal=Microbiology|date=August 2003|volume=149|issue=Pt 8|pages=2049–59|pmid=12904545|doi=10.1099/mic.0.26226-0|doi-access=free}}</ref> The individual components of cord factor, the trehalose sugars and mycolic acid residues, are not able to demonstrate this activity; the cord factor molecules must be fully intact.<ref name="fusion" /> Esterase activity that targets cord factor results in the lysis of ''M. tuberculosis'' cells.<ref>{{cite journal|last=Yang|first=Y.|author2=Bhatti, A. |author3=Ke, D. |author4=Gonzalez-Juarrero, M. |author5=Lenaerts, A. |author6=Kremer, L. |author7=Guerardel, Y. |author8=Zhang, P. |author9= Ojha, A. K. |title=Exposure to a Cutinase-like Serine Esterase Triggers Rapid Lysis of Multiple Mycobacterial Species|journal=Journal of Biological Chemistry|date=15 November 2012|volume=288|issue=1|pages=382–392|doi=10.1074/jbc.M112.419754 |pmid=23155047 |pmc=3537035|doi-access=free}}</ref> However, the ''M. tuberculosis'' cells must still be alive to prevent this fusion; heat-killed cells with cord factor are unable to prevent being digested.<ref name="trafficking" /> This suggests an additional molecule from ''M. tuberculosis'' is required.<ref name="trafficking" /> Regardless, cord factor's ability to prevent fusion is related to an increased hydration force or through steric hindrance.<ref name="fusion" /> Cord factor remains on the surface of ''M. tuberculosis'' cells until it associates with a ], where it forms a monolayer.<ref name="caseating" /> Then, as cord factor is in a monolayer configuration, it has a different function; it becomes fatal or harmful to the host organism.<ref>{{cite journal|last=Schabbing|first=RW|author2=Garcia, A |author3=Hunter, RL |title=Characterization of the trehalose 6,6'-dimycolate surface monolayer by scanning tunneling microscopy.|journal=Infection and Immunity|date=February 1994|volume=62|issue=2|pages=754–6|doi=10.1128/IAI.62.2.754-756.1994|pmid=8300239|pmc=186174}}</ref> ]s can die when in contact with monolayers of cord factor, but not when cord factor is in other configurations.<ref name="multipleroles" /> As the monolayer surface area of cord factor increases, so does its toxicity.<ref>{{cite journal|last=Geisel|first=RE|author2=Sakamoto, K |author3=Russell, DG |author4= Rhoades, ER |title=In vivo activity of released cell wall lipids of Mycobacterium bovis bacillus Calmette-Guérin is due principally to trehalose mycolates.|journal=Journal of Immunology|date=Apr 15, 2005|volume=174|issue=8|pages=5007–15|pmid=15814731|doi=10.4049/jimmunol.174.8.5007|doi-access=free}}</ref> The length of the carbon chain on cord factor has also shown to affect toxicity; a longer chain shows higher toxicity.<ref>{{cite journal|last=Fujita|first=Y|author2=Okamoto, Y |author3=Uenishi, Y |author4=Sunagawa, M |author5=Uchiyama, T |author6= Yano, I |title=Molecular and supra-molecular structure related differences in toxicity and granulomatogenic activity of mycobacterial cord factor in mice.|journal=Microbial Pathogenesis|date=July 2007|volume=43|issue=1|pages=10–21|pmid=17434713|doi=10.1016/j.micpath.2007.02.006}}</ref> Furthermore, ] has shown to adsorb to monolayers of cord factor and act as a cofactor for its biological effects.<ref>{{cite journal|last=Sakamoto|first=K.|author2=Geisel, R. E. |author3=Kim, M.-J. |author4=Wyatt, B. T. |author5=Sellers, L. B. |author6=Smiley, S. T. |author7=Cooper, A. M. |author8=Russell, D. G. |author9= Rhoades, E. R. |title=Fibrinogen Regulates the Cytotoxicity of Mycobacterial Trehalose Dimycolate but Is Not Required for Cell Recruitment, Cytokine Response, or Control of Mycobacterial Infection|journal=Infection and Immunity|date=22 December 2009|volume=78|issue=3|pages=1004–1011|doi=10.1128/IAI.00451-09|pmid=20028811|pmc=2825938}}</ref> |
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Cord factor isolated from species of '']'' has been shown to cause ] in mice. Severe muscle wasting occurred within 48 hours of the toxin being administered.<ref>{{Cite journal |last1=Silva |first1=C. L. |last2=Tincani |first2=I. |last3=Filho |first3=S. L. B. |last4=Faccioli |first4=L. H. |date=1988-06-01 |title=Mouse Cachexia Induced by Trehalose Dimycolate from Nocardia asteroides |journal=Microbiology |volume=134 |issue=6 |pages=1629–1633 |doi=10.1099/00221287-134-6-1629 |doi-access=free |pmid=3065451 |issn=1350-0872}}</ref> |
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==Host responses and cytokines== |
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Numerous responses that vary in effect result from cord factor's presence in host cells. After exposure to cord factor for 2 hours, 125 genes in the mouse genome are upregulated.<ref name="reprograms">{{cite journal|last=Sakamoto|first=K.|author2=Kim, M. J. |author3=Rhoades, E. R. |author4=Allavena, R. E. |author5=Ehrt, S. |author6=Wainwright, H. C. |author7=Russell, D. G. |author8= Rohde, K. H. |title=Mycobacterial Trehalose Dimycolate Reprograms Macrophage Global Gene Expression and Activates Matrix Metalloproteinases|journal=Infection and Immunity|date=21 December 2012|volume=81|issue=3|pages=764–776|doi=10.1128/IAI.00906-12 |pmid=23264051 |pmc=3584883}}</ref> After 24 hours, 503 genes are upregulated, and 162 genes are downregulated.<ref name="reprograms" /> The exact chemical mechanisms by which cord factor acts is not completely known. However, it is likely that the mycolic acids of cord factor must undergo a cyclopropyl modification to lead to a response from the host's immune system for initial infection.<ref name="hostinnate">{{cite journal|last=Rao|first=V|author2=Fujiwara, N |author3=Porcelli, SA |author4= Glickman, MS |title=Mycobacterium tuberculosis controls host innate immune activation through cyclopropane modification of a glycolipid effector molecule.|journal=The Journal of Experimental Medicine|date=Feb 21, 2005|volume=201|issue=4|pages=535–43|pmid=15710652|doi=10.1084/jem.20041668 |pmc=2213067}}</ref> Furthermore, the ester linkages in cord factor are important for its toxic effects.<ref>{{cite journal|last=Kato|first=M|title=Action of a toxic glycolipid of Corynebacterium diphtheriae on mitochondrial structure and function.|journal=Journal of Bacteriology|date=March 1970|volume=101|issue=3|pages=709–16|doi=10.1128/JB.101.3.709-716.1970|pmid=4314542|pmc=250382}}</ref> There is evidence that cord factor is recognized by the ], which is found on macrophages.<ref>{{cite journal|last=Ishikawa|first=E|author2=Ishikawa, T |author3=Morita, YS |author4=Toyonaga, K |author5=Yamada, H |author6=Takeuchi, O |author7=Kinoshita, T |author8=Akira, S |author9=Yoshikai, Y |author10= Yamasaki, S |title=Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle.|journal=The Journal of Experimental Medicine|date=Dec 21, 2009|volume=206|issue=13|pages=2879–88|pmid=20008526|doi=10.1084/jem.20091750 |pmc=2806462}}</ref><ref>{{cite journal|last=Schoenen|first=H |author2=Bodendorfer, B |author3=Hitchens, K |author4=Manzanero, S |author5=Werninghaus, K |author6=Nimmerjahn, F |author7=Agger, EM |author8=Stenger, S |author9=Andersen, P |author10=Ruland, J |author11=Brown, GD |author12=Wells, C |author13=Lang, R|title=Cutting edge: Mincle is essential for recognition and adjuvanticity of the mycobacterial cord factor and its synthetic analog trehalose-dibehenate.|journal=Journal of Immunology|date=Mar 15, 2010|volume=184|issue=6|pages=2756–60|pmid=20164423|doi=10.4049/jimmunol.0904013 |pmc=3442336}}</ref> An activated Mincle receptor leads to a pathway that ultimately results in the production of several ].<ref name="analogue">{{cite journal|last=Werninghaus|first=K.|author2=Babiak, A. |author3=Gross, O. |author4=Holscher, C. |author5=Dietrich, H. |author6=Agger, E. M. |author7=Mages, J. |author8=Mocsai, A. |author9=Schoenen, H. |author10=Finger, K. |author11=Nimmerjahn, F. |author12=Brown, G. D. |author13=Kirschning, C. |author14=Heit, A. |author15=Andersen, P. |author16=Wagner, H. |author17=Ruland, J. |author18=Lang, R. |title=Adjuvanticity of a synthetic cord factor analogue for subunit Mycobacterium tuberculosis vaccination requires FcR -Syk-Card9-dependent innate immune activation|journal=Journal of Experimental Medicine|date=12 January 2009|volume=206|issue=1|pages=89–97|doi=10.1084/jem.20081445 |pmid=19139169 |pmc=2626670}}</ref><ref>{{cite journal|last=Yamasaki|first=S|author2=Ishikawa, E |author3=Sakuma, M |author4=Hara, H |author5=Ogata, K |author6= Saito, T |title=Mincle is an ITAM-coupled activating receptor that senses damaged cells.|journal=Nature Immunology|date=October 2008|volume=9|issue=10|pages=1179–88|pmid=18776906|doi=10.1038/ni.1651|s2cid=205361789}}</ref> These cytokines can lead to further cytokine production that promote inflammatory responses.<ref>{{cite journal|last=Welsh|first=K. J.|author2=Abbott, A. N. |author3=Hwang, S.-A. |author4=Indrigo, J. |author5=Armitige, L. Y. |author6=Blackburn, M. R. |author7=Hunter, R. L. |author8= Actor, J. K. |title=A role for tumour necrosis factor- , complement C5 and interleukin-6 in the initiation and development of the mycobacterial cord factor trehalose 6,6'-dimycolate induced granulomatous response|journal=Microbiology|date=1 June 2008|volume=154|issue=6|pages=1813–1824|doi=10.1099/mic.0.2008/016923-0 |doi-access=free |pmid=18524936 |pmc=2556040}}</ref> Cord factor, through the Mincle receptor, also causes the recruitment of neutrophils, which lead to pro-inflammatory cytokines as well.<ref>{{cite journal|last=Lee|first=WB|author2=Kang, JS |author3=Yan, JJ |author4=Lee, MS |author5=Jeon, BY |author6=Cho, SN |author7= Kim, YJ |title=Neutrophils Promote Mycobacterial Trehalose Dimycolate-Induced Lung Inflammation via the Mincle Pathway.|journal=PLOS Pathogens|year=2012|volume=8|issue=4|pages=e1002614|pmid=22496642|doi=10.1371/journal.ppat.1002614 |pmc=3320589 |doi-access=free }}</ref> However, there is also evidence that toll-like receptor 2 (TLR2) in conjunction with the protein MyD-88 is responsible for cytokine production rather than the Mincle receptor.<ref name="reprograms" /> |
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Cord factor presence increases the production of the cytokines ] (IL-12), ] (IL-1β), ] (IL-6), ] (TNFα), and ] (MIP-2), which are all pro-inflammatory cytokines important for granuloma formation.<ref name="trafficking" /><ref name="analogue" /><ref>{{cite journal|last=Roach|first=DR|author2=Bean, AG |author3=Demangel, C |author4=France, MP |author5=Briscoe, H |author6= Britton, WJ |title=TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection.|journal=Journal of Immunology|date=May 1, 2002|volume=168|issue=9|pages=4620–7|pmid=11971010|doi=10.4049/jimmunol.168.9.4620|doi-access=free}}</ref> IL-12 is particularly important in the defense against ''M. tuberculosis''; without it, ''M. tuberculosis'' spreads unhampered.<ref>{{cite journal|last=Cooper|first=A. M.|title=Disseminated tuberculosis in interferon gamma gene-disrupted mice|journal=Journal of Experimental Medicine|date=1 December 1993|volume=178|issue=6|pages=2243–2247|doi=10.1084/jem.178.6.2243|pmid=8245795|pmc=2191280}}</ref><ref>{{cite journal|last=Cooper|first=AM|author2=Magram, J |author3=Ferrante, J |author4= Orme, IM |title=Interleukin 12 (IL-12) is crucial to the development of protective immunity in mice intravenously infected with mycobacterium tuberculosis.|journal=The Journal of Experimental Medicine|date=Jul 7, 1997|volume=186|issue=1|pages=39–45|pmid=9206995|doi=10.1084/jem.186.1.39 |pmc=2198958}}</ref> IL-12 triggers production of more cytokines through T cells and natural killer (NK) cells, while also leading to mature Th1 cells, and thus leading to immunity.<ref>{{cite journal|last=Trinchieri|first=G|title=Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity.|journal=Annual Review of Immunology|year=1995|volume=13|pages=251–76|pmid=7612223|doi=10.1146/annurev.iy.13.040195.001343|issue=1}}</ref> Then, with IL-12 available, Th1 cells and NK cells produce interferon gamma (IFN-γ) molecules and subsequently release them.<ref>{{cite journal|last=Magram|first=Jeanne|author2=Connaughton, Suzanne E |author3=Warrier, Rajeev R |author4=Carvajal, Daisy M |author5=Wu, Chang-you |author6=Ferrante, Jessica |author7=Stewart, Colin |author8=Sarmiento, Ulla |author9=Faherty, Denise A |author10= Gately, Maurice K |title=IL-12-Deficient Mice Are Defective in IFNγ Production and Type 1 Cytokine Responses|journal=Immunity|date=May 1996|volume=4|issue=5|pages=471–481|doi=10.1016/S1074-7613(00)80413-6|pmid=8630732|doi-access=free}}</ref> The IFN-γ molecules in turn activate macrophages.<ref name="foreignbody">{{cite journal|last=Yamagami|first=H|author2=Matsumoto, T |author3=Fujiwara, N |author4=Arakawa, T |author5=Kaneda, K |author6=Yano, I |author7= Kobayashi, K |title=Trehalose 6,6'-dimycolate (cord factor) of Mycobacterium tuberculosis induces foreign-body- and hypersensitivity-type granulomas in mice.|journal=Infection and Immunity|date=February 2001|volume=69|issue=2|pages=810–5|pmid=11159972|doi=10.1128/IAI.69.2.810-815.2001 |pmc=97956}}</ref> |
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When macrophages are activated by cord factor, they can arrange into ] around ''M. tuberculosis'' cells.<ref name="caseating" /><ref>{{cite journal|last=Bekierkunst|first=A|title=Acute granulomatous response produced in mice by trehalose-6,6-dimycolate.|journal=Journal of Bacteriology|date=October 1968|volume=96|issue=4|pages=958–61|doi=10.1128/JB.96.4.958-961.1968|pmid=4971895|pmc=252404}}</ref> Activated macrophages and neutrophils also cause an increase in vascular endothelial growth factor (VEGF), which is important for angiogenesis, a step in granuloma formation.<ref>{{cite journal|last=Sakaguchi|first=I|author2=Ikeda, N |author3=Nakayama, M |author4=Kato, Y |author5=Yano, I |author6= Kaneda, K |title=Trehalose 6,6'-dimycolate (Cord factor) enhances neovascularization through vascular endothelial growth factor production by neutrophils and macrophages.|journal=Infection and Immunity|date=April 2000|volume=68|issue=4|pages=2043–52|pmid=10722600|doi=10.1128/iai.68.4.2043-2052.2000 |pmc=97384}}</ref> The granulomas can be formed either with or without T-cells, indicating that they can be foreign-body-type or hypersensitivity-type.<ref name="foreignbody" /> This means cord factor can stimulate a response by acting as a foreign molecule or by causing harmful reactions from the immune system if the host is already immunized.<ref name="foreignbody" /> Thus, cord factor can act as a nonspecific irritant or a T-cell dependent antigen.<ref name="foreignbody" /> Granulomas enclose ''M. tuberculosis'' cells to halt the bacteria from spreading, but they also allow the bacteria to remain in the host.<ref name="trafficking" /> From there, the tissue can become damaged and the disease can transmit further with cord factor.<ref>{{cite journal|last=Kobayashi|first=Kazuo|author2=Kaneda, Kenji |author3=Kasama, Tsuyoshi |title=Immunopathogenesis of delayed-type hypersensitivity|journal=Microscopy Research and Technique|date=15 May 2001|volume=53|issue=4|pages=241–245|doi=10.1002/jemt.1090|pmid=11340669|s2cid=1851137|doi-access=free}}</ref> Alternatively, the activated macrophages can kill the ''M. tuberculosis'' cells through reactive nitrogen intermediates to remove the infection.<ref>{{cite journal|last=Chan|first=J|author2=Xing, Y |author3=Magliozzo, RS |author4= Bloom, BR |title=Killing of virulent Mycobacterium tuberculosis by reactive nitrogen intermediates produced by activated murine macrophages.|journal=The Journal of Experimental Medicine|date=Apr 1, 1992|volume=175|issue=4|pages=1111–22|pmid=1552282|doi=10.1084/jem.175.4.1111 |pmc=2119182}}</ref> |
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Besides inducing granuloma formation, activated macrophages that result from IL-12 and IFN-γ are able to limit tumor growth.<ref>{{cite journal|last=Oswald|first=IP|author2=Dozois, CM |author3=Petit, JF |author4= Lemaire, G |title=Interleukin-12 synthesis is a required step in trehalose dimycolate-induced activation of mouse peritoneal macrophages.|journal=Infection and Immunity|date=April 1997|volume=65|issue=4|pages=1364–9|doi=10.1128/IAI.65.4.1364-1369.1997|pmid=9119475 |pmc=175141}}</ref> Furthermore, cord factor's stimulation of TNF-α production, also known as cachectin, is also able to induce ], or loss of weight, within hosts.<ref>{{cite journal|last=Semenzato|first=G|title=Tumour necrosis factor: a cytokine with multiple biological activities|journal=British Journal of Cancer|date=March 1990|volume=61|issue=3|pages=354–361|doi=10.1038/bjc.1990.78|pmid=2183871|pmc=1971301}}</ref><ref>{{cite journal|last=Silva|first=CL|author2=Faccioli, LH|title=Tumor necrosis factor (cachectin) mediates induction of cachexia by cord factor from mycobacteria.|journal=Infection and Immunity|date=December 1988|volume=56|issue=12|pages=3067–71|doi=10.1128/IAI.56.12.3067-3071.1988|pmid=3053451|pmc=259702}}</ref> Cord factor also increases NADase activity in the host, and thus it lowers NAD; enzymes that require NAD decrease in activity accordingly.<ref name="biosynth" /> Cord factor is thus able to obstruct ] and the ] in mitochondrial membranes.<ref name="biosynth" /> In mice, cord factor has shown to cause atrophy in the ] through apoptosis; similarly in rabbits, atrophy of the thymus and ] occurred.<ref>{{cite journal|last=Hamasaki|first=N|author2=Isowa, K |author3=Kamada, K |author4=Terano, Y |author5=Matsumoto, T |author6=Arakawa, T |author7=Kobayashi, K |author8= Yano, I |title=In vivo administration of mycobacterial cord factor (Trehalose 6, 6'-dimycolate) can induce lung and liver granulomas and thymic atrophy in rabbits.|journal=Infection and Immunity|date=June 2000|volume=68|issue=6|pages=3704–9|pmid=10816531|doi=10.1128/iai.68.6.3704-3709.2000 |pmc=97662}}</ref><ref name="apopt">{{cite journal|last=Ozeki|first=Y|author2=Kaneda, K |author3=Fujiwara, N |author4=Morimoto, M |author5=Oka, S |author6= Yano, I |title=In vivo induction of apoptosis in the thymus by administration of mycobacterial cord factor (trehalose 6,6'-dimycolate).|journal=Infection and Immunity|date=May 1997|volume=65|issue=5|pages=1793–9|doi=10.1128/IAI.65.5.1793-1799.1997|pmid=9125563 |pmc=175219}}</ref> This atrophy occurs in conjunction with granuloma formation, and if granuloma formation is disturbed, so is the progression of atrophy.<ref name="apopt" /> |
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==Scientific applications and uses== |
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Infection by ''M. tuberculosis'' remains a serious problem in the world and knowledge of cord factor can be useful in controlling this disease.<ref name="hostinnate" /> For example, the glycoprotein known as lactoferrin is able to mitigate cytokine production and granuloma formation brought on by cord factor.<ref>{{cite journal|last=Welsh|first=Kerry J.|author2=Hwang, Shen-An |author3=Hunter, Robert L. |author4=Kruzel, Marian L. |author5= Actor, Jeffrey K. |title=Lactoferrin modulation of mycobacterial cord factor trehalose 6-6'-dimycolate induced granulomatous response|journal=Translational Research|date=October 2010|volume=156|issue=4|pages=207–215|doi=10.1016/j.trsl.2010.06.001|pmid=20875896|pmc=2948024}}</ref> However, cord factor can serve as a useful model for all pathogenic glycolipids and therefore it can provide insight for more than just itself as a virulence factor.<ref name="surfaceprop" /><ref name="dissemination">{{cite journal|last=Retzinger|first=GS|title=Dissemination of beads coated with trehalose 6,6'-dimycolate: a possible role for coagulation in the dissemination process.|journal=Experimental and Molecular Pathology|date=April 1987|volume=46|issue=2|pages=190–8|pmid=3556532|doi=10.1016/0014-4800(87)90065-7}}</ref> Hydrophobic beads covered with cord factor are an effective tool for such research; they are able to reproduce an organism's response to cord factor from ''M. tuberculosis'' cells.<ref name="surfaceprop" /><ref name="dissemination" /> Cord factor beads are easily created and applied to organisms for study, and then easily recovered.<ref name="dissemination" /> |
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It is possible to form cord factor liposomes through water emulsion; these liposomes are nontoxic and can be used to maintain a steady supply of activated macrophages.<ref>{{cite journal|last=Lepoivre|first=M|author2=Tenu, JP |author3=Lemaire, G |author4= Petit, JF |title=Antitumor activity and hydrogen peroxide release by macrophages elicited by trehalose diesters.|journal=Journal of Immunology|date=August 1982|volume=129|issue=2|pages=860–6|doi=10.4049/jimmunol.129.2.860|pmid=6806386|doi-access=free}}</ref> Cord factor under proper control can potentially be useful in fighting cancer because IL-12 and IFN-γ are able to limit the growth of tumors.<ref>{{cite journal|last=Oswald|first=IP|author2=Afroun, S |author3=Bray, D |author4=Petit, JF |author5= Lemaire, G |title=Low response of BALB/c macrophages to priming and activating signals.|journal=Journal of Leukocyte Biology|date=September 1992|volume=52|issue=3|pages=315–22|pmid=1381743|doi=10.1002/jlb.52.3.315|s2cid=2190434}}</ref> |
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==See also== |
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==See also== |
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==References== |
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