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{{merge|Trehalose_dimycolate|discuss=Talk:Cord_factor#Merger proposal|date=August 2012}}
{{merge|Trehalose_dimycolate|discuss=Talk:Cord_factor#Merger proposal|date=August 2012}}
'''Cord factor''' refers to [[trehalose dimycolate]], a virulence factor and glycolipid cell-wall component of virulent strains of [[Mycobacterium tuberculosis]] and closely related species.<ref>{{MeshName|Cord+factor}}</ref><ref name="pmid18524936">{{cite journal |author=Welsh KJ, Abbott AN, Hwang SA, ''et al.'' |title=A role for tumour necrosis factor-alpha, complement C5 and interleukin-6 in the initiation and development of the mycobacterial cord factor trehalose 6,6'-dimycolate induced granulomatous response |journal=Microbiology (Reading, Engl.) |volume=154 |issue=Pt 6 |pages=1813–24 |year=2008 |month=June |pmid=18524936 |doi=10.1099/mic.0.2008/016923-0 |url=http://mic.sgmjournals.org/cgi/pmidlookup?view=long&pmid=18524936 |pmc=2556040}}</ref> It is a surface glycolipid which blocks macrophage activation by [[IFN-γ]], induces secretion of [[TNFα]] and causes Mycobacterium tuberculosis to form cords ''[[in vitro]]''. This is the main virulence factor for the mycobacterium tuberculosis that makes it resistance to anti-tuberculosis medications.
'''Cord factor''' refers to [[trehalose dimycolate]], a virulence factor and glycolipid cell-wall component of virulent strains of [[Mycobacterium tuberculosis]] and closely related species.<ref>{{MeshName|Cord+factor}}</ref><ref name="pmid18524936">{{cite journal |author=Welsh KJ, Abbott AN, Hwang SA, ''et al.'' |title=A role for tumour necrosis factor-alpha, complement C5 and interleukin-6 in the initiation and development of the mycobacterial cord factor trehalose 6,6'-dimycolate induced granulomatous response |journal=Microbiology (Reading, Engl.) |volume=154 |issue=Pt 6 |pages=1813–24 |year=2008 |month=June |pmid=18524936 |doi=10.1099/mic.0.2008/016923-0 |url=http://mic.sgmjournals.org/cgi/pmidlookup?view=long&pmid=18524936 |pmc=2556040}}</ref> It is a surface glycolipid which blocks macrophage activation by [[IFN-γ]], induces secretion of [[TNFα]] and causes Mycobacterium tuberculosis to form cords ''[[in vitro]]''. This is the main virulence factor for the mycobacterium tuberculosis that makes it resistance to anti-tuberculosis medications.



==Structure==
==Structure==
A cord factor molecule is composed of a trehalose sugar, a disaccharide, that is esterified to two mycolic acid residues, as shown in Figure 1.<ref>{{cite journal|last=NOLL|first=H|coauthors=BLOCH, H; ASSELINEAU, J; LEDERER, E|title=The chemical structure of the cord factor of Mycobacterium tuberculosis.|journal=Biochimica et biophysica acta|date=1956 May|volume=20|issue=2|pages=299-309|pmid=13328853}}</ref><ref>{{cite journal|last=Jonsson|first=B. E.|coauthors=Gilljam, M.; Lindblad, A.; Ridell, M.; Wold, A. E.; 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}}</ref> One of the two mycolic acid residues is attached to the sixth carbon of one mo nosaccharide, while the other mycolic acid residue is attached to the sixth carbon of the other monosaccharide.<ref>{{cite journal|last=NOLL|first=H|coauthors=BLOCH, H; ASSELINEAU, J; LEDERER, E|title=The chemical structure of the cord factor of Mycobacterium tuberculosis.|journal=Biochimica et biophysica acta|date=1956 May|volume=20|issue=2|pages=299-309|pmid=13328853}}</ref> Therefore, cord factor is also named trehalose-6,6'-dimycolate.<ref>{{cite journal|last=NOLL|first=H|coauthors=BLOCH, H; ASSELINEAU, J; LEDERER, E|title=The chemical structure of the cord factor of Mycobacterium tuberculosis.|journal=Biochimica et biophysica acta|date=1956 May|volume=20|issue=2|pages=299-309|pmid=13328853}}</ref> 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>{{cite journal|last=Rajni|coauthors=Rao, N; Meena, LS|title=Biosynthesis and Virulent Behavior of Lipids Produced by Mycobacterium tuberculosis: LAM and Cord Factor: An Overview.|journal=Biotechnology research international|date=2011|volume=2011|pages=274693|pmid=21350659}}</ref> Cord factor's amphiphilic nature leads to varying structures when many cord factor molecules are in close proximity.<ref>{{cite journal|last=Rajni|coauthors=Rao, N; Meena, LS|title=Biosynthesis and Virulent Behavior of Lipids Produced by Mycobacterium tuberculosis: LAM and Cord Factor: An Overview.|journal=Biotechnology research international|date=2011|volume=2011|pages=274693|pmid=21350659}}</ref> On a hydrophobic surface, they spontaneously form a crystalline monolayer.<ref>{{cite journal|last=Retzinger|first=GS|coauthors=Meredith, SC; Hunter, RL; Takayama, K; 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 (Baltimore, Md. : 1950)|date=1982 Aug|volume=129|issue=2|pages=735-44|pmid=6806381}}</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|coauthors=Venkataprasad, N; Olsen, MR|title=The role of trehalose dimycolate (cord factor) on morphology of virulent ''M. tuberculosis'' in vitro.|journal=Tuberculosis (Edinburgh, Scotland)|date=2006 Sep|volume=86|issue=5|pages=349-56|pmid=16343989}}</ref> This monolayer also forms in oil-water, plastic-water, and air-water surfaces.<ref>{{cite journal|last=Hunter|first=RL|coauthors=Olsen, MR; Jagannath, C; 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=2006 Autumn|volume=36|issue=4|pages=371-86|pmid=17127724}}</ref> In an aqueous environment free of hydrophobic surfaces, cord factor forms a micelle.<ref>{{cite journal|last=Retzinger|first=GS|coauthors=Meredith, SC; Takayama, K; Hunter, RL; 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=1981 Aug 10|volume=256|issue=15|pages=8208-16|pmid=7263645}}</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>{{cite journal|last=Hunter|first=RL|coauthors=Olsen, MR; Jagannath, C; 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=2006 Autumn|volume=36|issue=4|pages=371-86|pmid=17127724}}</ref><ref>{{cite journal|last=Brennan|first=PJ|title=Structure, function, and biogenesis of the cell wall of Mycobacterium tuberculosis.|journal=Tuberculosis (Edinburgh, Scotland)|date=2003|volume=83|issue=1-3|pages=91-7|pmid=12758196}}</ref>
Trehalose-6,6' dimycolate molecules comprises trehalose sugar esterified into two mycolic acid residues which range from 20–80 carbons in length.<ref>{{cite journal|last=Rajni|first=Nisha Rao|coauthors=Meena|title=Laxman S|journal=Biotechnol Res Int.|year=2011|month=December|doi=10.4061/2011/274693|pmc=3039431|pmid=21350659|volume=2011|pages=274693}}</ref>

==Evidence of Virulence==
A large quantity of cord factor is found in virulent ''M. tuberculosis'', but not in avirulent ''M. tuberculosis''.<ref>{{cite journal|last=Hunter|first=RL|coauthors=Olsen, MR; Jagannath, C; 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=2006 Autumn|volume=36|issue=4|pages=371-86|pmid=17127724}}</ref> Furthermore, ''M. tuberculosis'' loses its virulence if its ability to produce cord factor molecules is compromised.<ref>{{cite journal|last=Hunter|first=RL|coauthors=Olsen, MR; Jagannath, C; 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=2006 Autumn|volume=36|issue=4|pages=371-86|pmid=17127724}}</ref> Consequently, when all lipids are removed from the exterior of ''M. tuberculosis'' cells, the survival of the bacteria is reduced within a host.<ref>{{cite journal|last=Indrigo|first=J|coauthors=Hunter RL, Jr; Actor, JK|title=Influence of trehalose 6,6'-dimycolate (TDM) during mycobacterial infection of bone marrow macrophages.|journal=Microbiology (Reading, England)|date=2002 Jul|volume=148|issue=Pt 7|pages=1991-8|pmid=12101287}}</ref> When cord factor is added back to those cells, ''M. tuberculosis'' survives at a rate similar to that of its original state.<ref>{{cite journal|last=Indrigo|first=J|coauthors=Hunter RL, Jr; Actor, JK|title=Influence of trehalose 6,6'-dimycolate (TDM) during mycobacterial infection of bone marrow macrophages.|journal=Microbiology (Reading, England)|date=2002 Jul|volume=148|issue=Pt 7|pages=1991-8|pmid=12101287}}</ref> Cord factor increases the virulence of tuberculosis in mice, but it has minimal effect on other infections.<ref>{{cite journal|last=Hunter|first=RL|coauthors=Olsen, MR; Jagannath, C; 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=2006 Autumn|volume=36|issue=4|pages=371-86|pmid=17127724}}</ref>


==Biological Function==
==Biological Function==
The function of cord factor is highly dependent on what environment it is located, and therefore its conformation.<ref>{{cite journal|last=Hunter|first=Robert L.|coauthors=Olsen, Margaret; Jagannath, Chinnaswamy; 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|year=2006|month=April|volume=168|issue=4|pages=1249–1261|doi=10.2353/ajpath.2006.050848}}</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>{{cite journal|last=Hunter|first=Robert L.|coauthors=Olsen, Margaret; Jagannath, Chinnaswamy; 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|year=2006|month=April|volume=168|issue=4|pages=1249–1261|doi=10.2353/ajpath.2006.050848}}</ref> Cord factor protects ''M. tuberculosis'' from the defenses of the host.<ref>{{cite journal|last=Hunter|first=RL|coauthors=Olsen, MR; Jagannath, C; 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=2006 Autumn|volume=36|issue=4|pages=371-86|pmid=17127724}}</ref> Specifically, cord factor on the surface of ''M. tuberculosis'' cells prevents fusion between macrophages containing the ''M. tuberculosis'' cells and the lysosomes that would destroy them.<ref>{{cite journal|last=Spargo|first=BJ|coauthors=Crowe, LM; Ioneda, T; Beaman, BL; 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=1991 Feb 1|volume=88|issue=3|pages=737-40|pmid=1992465}}</ref><ref>{{cite journal|last=Indrigo|first=J|coauthors=Hunter RL, Jr; Actor, JK|title=Cord factor trehalose 6,6'-dimycolate (TDM) mediates trafficking events during mycobacterial infection of murine macrophages.|journal=Microbiology (Reading, England)|date=2003 Aug|volume=149|issue=Pt 8|pages=2049-59|pmid=12904545}}</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>{{cite journal|last=Spargo|first=BJ|coauthors=Crowe, LM; Ioneda, T; Beaman, BL; 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=1991 Feb 1|volume=88|issue=3|pages=737-40|pmid=1992465}}</ref> Esterase activity that targets cord factor results in the lysis of ''M. tuberculosis'' cells.<ref>{{cite journal|last=Yang|first=Y.|coauthors=Bhatti, A.; Ke, D.; Gonzalez-Juarrero, M.; Lenaerts, A.; Kremer, L.; Guerardel, Y.; Zhang, P.; 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}}</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>{{cite journal|last=Indrigo|first=J|coauthors=Hunter RL, Jr; Actor, JK|title=Cord factor trehalose 6,6'-dimycolate (TDM) mediates trafficking events during mycobacterial infection of murine macrophages.|journal=Microbiology (Reading, England)|date=2003 Aug|volume=149|issue=Pt 8|pages=2049-59|pmid=12904545}}</ref> This suggests an additional molecule from ''M. tuberculosis'' is required.<ref>{{cite journal|last=Indrigo|first=J|coauthors=Hunter RL, Jr; Actor, JK|title=Cord factor trehalose 6,6'-dimycolate (TDM) mediates trafficking events during mycobacterial infection of murine macrophages.|journal=Microbiology (Reading, England)|date=2003 Aug|volume=149|issue=Pt 8|pages=2049-59|pmid=12904545}}</ref> Regardless, cord factor's ability to prevent fusion is related to an increased hydration force or through steric hindrance.<ref>{{cite journal|last=Spargo|first=BJ|coauthors=Crowe, LM; Ioneda, T; Beaman, BL; 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=1991 Feb 1|volume=88|issue=3|pages=737-40|pmid=1992465}}</ref> Cord factor remains on the surface of ''M. tuberculosis'' cells until it associates with a lipid droplet, where it forms a monolayer.<ref>{{cite journal|last=Hunter|first=Robert L.|coauthors=Olsen, Margaret; Jagannath, Chinnaswamy; 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|year=2006|month=April|volume=168|issue=4|pages=1249–1261|doi=10.2353/ajpath.2006.050848}}</ref> 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|coauthors=Garcia, A; Hunter, RL|title=Characterization of the trehalose 6,6'-dimycolate surface monolayer by scanning tunneling microscopy.|journal=Infection and immunity|date=1994 Feb|volume=62|issue=2|pages=754-6|pmid=8300239}}</ref> Macrophages can die when in contact with monolayers of cord factor, but not when cord factor is in other configurations.<ref>{{cite journal|last=Hunter|first=RL|coauthors=Olsen, MR; Jagannath, C; 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=2006 Autumn|volume=36|issue=4|pages=371-86|pmid=17127724}}</ref> As the monolayer surface area of cord factor increases, so does its toxicity.<ref>{{cite journal|last=Geisel|first=RE|coauthors=Sakamoto, K; Russell, DG; 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 (Baltimore, Md. : 1950)|date=2005 Apr 15|volume=174|issue=8|pages=5007-15|pmid=15814731}}</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|coauthors=Okamoto, Y; Uenishi, Y; Sunagawa, M; Uchiyama, T; 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=2007 Jul|volume=43|issue=1|pages=10-21|pmid=17434713}}</ref> Furthermore, fibrinogen 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.|coauthors=Geisel, R. E.; Kim, M.-J.; Wyatt, B. T.; Sellers, L. B.; Smiley, S. T.; Cooper, A. M.; Russell, D. G.; 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}}</ref>

==Host Responses and Cytokines==

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>{{cite journal|last=Sakamoto|first=K.|coauthors=Kim, M. J.; Rhoades, E. R.; Allavena, R. E.; Ehrt, S.; Wainwright, H. C.; Russell, D. G.; 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}}</ref> After 24 hours, 503 genes are upregulated, and 162 genes are downregulated.<ref>{{cite journal|last=Sakamoto|first=K.|coauthors=Kim, M. J.; Rhoades, E. R.; Allavena, R. E.; Ehrt, S.; Wainwright, H. C.; Russell, D. G.; 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}}</ref> 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>{{cite journal|last=Rao|first=V|coauthors=Fujiwara, N; Porcelli, SA; 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=2005 Feb 21|volume=201|issue=4|pages=535-43|pmid=15710652}}</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=1970 Mar|volume=101|issue=3|pages=709-16|pmid=4314542}}</ref> There is evidence that cord factor is recognized by the Mincle receptor, which is found on macrophages.<ref>{{cite journal|last=Ishikawa|first=E|coauthors=Ishikawa, T; Morita, YS; Toyonaga, K; Yamada, H; Takeuchi, O; Kinoshita, T; Akira, S; Yoshikai, Y; Yamasaki, S|title=Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle.|journal=The Journal of experimental medicine|date=2009 Dec 21|volume=206|issue=13|pages=2879-88|pmid=20008526}}</ref> <ref>{{cite journal|last=Schoenen|first=H|coauthors=Bodendorfer, B; Hitchens, K; Manzanero, S; Werninghaus, K; Nimmerjahn, F; Agger, EM; Stenger, S; Andersen, P; Ruland, J; Brown, GD; Wells, C; 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 (Baltimore, Md. : 1950)|date=2010 Mar 15|volume=184|issue=6|pages=2756-60|pmid=20164423}}</ref> An activated Mincle receptor leads to a pathway that ultimately results in the production of several cytokines.<ref>{{cite journal|last=Werninghaus|first=K.|coauthors=Babiak, A.; Gross, O.; Holscher, C.; Dietrich, H.; Agger, E. M.; Mages, J.; Mocsai, A.; Schoenen, H.; Finger, K.; Nimmerjahn, F.; Brown, G. D.; Kirschning, C.; Heit, A.; Andersen, P.; Wagner, H.; Ruland, J.; 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}}</ref> <ref>{{cite journal|last=Yamasaki|first=S|coauthors=Ishikawa, E; Sakuma, M; Hara, H; Ogata, K; Saito, T|title=Mincle is an ITAM-coupled activating receptor that senses damaged cells.|journal=Nature immunology|date=2008 Oct|volume=9|issue=10|pages=1179-88|pmid=18776906}}</ref> These cytokines can lead to further cytokine production that promote inflammatory responses.<ref>{{cite journal|last=Welsh|first=K. J.|coauthors=Abbott, A. N.; Hwang, S.-A.; Indrigo, J.; Armitige, L. Y.; Blackburn, M. R.; Hunter, R. L.; 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}}</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|coauthors=Kang, JS; Yan, JJ; Lee, MS; Jeon, BY; Cho, SN; Kim, YJ|title=Neutrophils Promote Mycobacterial Trehalose Dimycolate-Induced Lung Inflammation via the Mincle Pathway.|journal=PLoS pathogens|date=2012|volume=8|issue=4|pages=e1002614|pmid=22496642}}</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>{{cite journal|last=Sakamoto|first=K.|coauthors=Kim, M. J.; Rhoades, E. R.; Allavena, R. E.; Ehrt, S.; Wainwright, H. C.; Russell, D. G.; 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}}</ref>

Cord factor presence increases the production of the cytokines interleukin-12 (IL-12), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor (TNFα), and macrophage inflammatory protein 2 (MIP-2), which are all pro-inflammatory cytokines important for granuloma formation.<ref>{{cite journal|last=Indrigo|first=J|coauthors=Hunter RL, Jr; Actor, JK|title=Cord factor trehalose 6,6'-dimycolate (TDM) mediates trafficking events during mycobacterial infection of murine macrophages.|journal=Microbiology (Reading, England)|date=2003 Aug|volume=149|issue=Pt 8|pages=2049-59|pmid=12904545}}</ref><ref>{{cite journal|last=Werninghaus|first=K.|coauthors=Babiak, A.; Gross, O.; Holscher, C.; Dietrich, H.; Agger, E. M.; Mages, J.; Mocsai, A.; Schoenen, H.; Finger, K.; Nimmerjahn, F.; Brown, G. D.; Kirschning, C.; Heit, A.; Andersen, P.; Wagner, H.; Ruland, J.; 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}}</ref><ref>{{cite journal|last=Roach|first=DR|coauthors=Bean, AG; Demangel, C; France, MP; Briscoe, H; Britton, WJ|title=TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection.|journal=Journal of immunology (Baltimore, Md. : 1950)|date=2002 May 1|volume=168|issue=9|pages=4620-7|pmid=11971010}}</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}}</ref><ref>{{cite journal|last=Cooper|first=AM|coauthors=Magram, J; Ferrante, J; 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=1997 Jul 7|volume=186|issue=1|pages=39-45|pmid=9206995}}</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|date=1995|volume=13|pages=251-76|pmid=7612223}}</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|coauthors=Connaughton, Suzanne E; Warrier, Rajeev R; Carvajal, Daisy M; Wu, Chang-you; Ferrante, Jessica; Stewart, Colin; Sarmiento, Ulla; Faherty, Denise A; Gately, Maurice K|title=IL-12-Deficient Mice Are Defective in IFNγ Production and Type 1 Cytokine Responses|journal=Immunity|year=1996|month=May|volume=4|issue=5|pages=471–481|doi=10.1016/S1074-7613(00)80413-6}}</ref> The IFN-γ molecules in turn activate macrophages.<ref>{{cite journal|last=Yamagami|first=H|coauthors=Matsumoto, T; Fujiwara, N; Arakawa, T; Kaneda, K; Yano, I; 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=2001 Feb|volume=69|issue=2|pages=810-5|pmid=11159972}}</ref>


When macrophages are activated by cord factor, they can arrange into granulomas around ''M. tuberculosis'' cells.<ref>{{cite journal|last=Hunter|first=Robert L.|coauthors=Olsen, Margaret; Jagannath, Chinnaswamy; 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|year=2006|month=April|volume=168|issue=4|pages=1249–1261|doi=10.2353/ajpath.2006.050848}}</ref><ref>{{cite journal|last=Bekierkunst|first=A|title=Acute granulomatous response produced in mice by trehalose-6,6-dimycolate.|journal=Journal of bacteriology|date=1968 Oct|volume=96|issue=4|pages=958-61|pmid=4971895}}</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|coauthors=Ikeda, N; Nakayama, M; Kato, Y; Yano, I; 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=2000 Apr|volume=68|issue=4|pages=2043-52|pmid=10722600}}</ref> The granulomas can be formed either with or without T-cells, indicating that they can be foreign-body-type or hypersensitivity-type.<ref>{{cite journal|last=Yamagami|first=H|coauthors=Matsumoto, T; Fujiwara, N; Arakawa, T; Kaneda, K; Yano, I; 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=2001 Feb|volume=69|issue=2|pages=810-5|pmid=11159972}}</ref> 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>{{cite journal|last=Yamagami|first=H|coauthors=Matsumoto, T; Fujiwara, N; Arakawa, T; Kaneda, K; Yano, I; 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=2001 Feb|volume=69|issue=2|pages=810-5|pmid=11159972}}</ref> Thus, cord factor can act as a nonspecific irritant or a T-cell dependent antigen.<ref>{{cite journal|last=Yamagami|first=H|coauthors=Matsumoto, T; Fujiwara, N; Arakawa, T; Kaneda, K; Yano, I; 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=2001 Feb|volume=69|issue=2|pages=810-5|pmid=11159972}}</ref> Granulomas enclose ''M. tuberculosis'' cells to halt the bacteria from spreading, but they also allow the bacteria to remain in the host.<ref>{{cite journal|last=Indrigo|first=J|coauthors=Hunter RL, Jr; Actor, JK|title=Cord factor trehalose 6,6'-dimycolate (TDM) mediates trafficking events during mycobacterial infection of murine macrophages.|journal=Microbiology (Reading, England)|date=2003 Aug|volume=149|issue=Pt 8|pages=2049-59|pmid=12904545}}</ref> From there, the tissue can become damaged and the disease can transmit further with cord factor. <ref>{{cite journal|last=Kobayashi|first=Kazuo|coauthors=Kaneda, Kenji; 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}}</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|coauthors=Xing, Y; Magliozzo, RS; Bloom, BR|title=Killing of virulent Mycobacterium tuberculosis by reactive nitrogen intermediates produced by activated murine macrophages.|journal=The Journal of experimental medicine|date=1992 Apr 1|volume=175|issue=4|pages=1111-22|pmid=1552282}}</ref>
{{Empty section|date=December 2012}}


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|coauthors=Dozois, CM; Petit, JF; Lemaire, G|title=Interleukin-12 synthesis is a required step in trehalose dimycolate-induced activation of mouse peritoneal macrophages.|journal=Infection and immunity|date=1997 Apr|volume=65|issue=4|pages=1364-9|pmid=9119475}}</ref> Furthermore, cord factor's production of TNF-α, also known as cachectin, is also able to induce cachexia, 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|year=1990|month=March|volume=61|issue=3|pages=354–361|doi=10.1038/bjc.1990.78}}</ref> <ref>{{cite journal|last=Silva|first=CL|coauthors=Faccioli, LH|title=Tumor necrosis factor (cachectin) mediates induction of cachexia by cord factor from mycobacteria.|journal=Infection and immunity|date=1988 Dec|volume=56|issue=12|pages=3067-71|pmid=3053451}}</ref> Cord factor also increases NADase activity in the host, and thus it lowers NAD; enzymes that require NAD decrease in activity accordingly.<ref>{{cite journal|last=Rajni|coauthors=Rao, N; Meena, LS|title=Biosynthesis and Virulent Behavior of Lipids Produced by Mycobacterium tuberculosis: LAM and Cord Factor: An Overview.|journal=Biotechnology research international|date=2011|volume=2011|pages=274693|pmid=21350659}}</ref> Cord factor is thus able to obstruct oxidative phosphorylation and the electron transport chain in mitochondrial membranes.<ref>{{cite journal|last=Rajni|coauthors=Rao, N; Meena, LS|title=Biosynthesis and Virulent Behavior of Lipids Produced by Mycobacterium tuberculosis: LAM and Cord Factor: An Overview.|journal=Biotechnology research international|date=2011|volume=2011|pages=274693|pmid=21350659}}</ref> In mice, cord factor has shown to cause atrophy in the thymus through apoptosis; similarly in rabbits, atrophy of the thymus and spleen occurred.<ref>{{cite journal|last=Hamasaki|first=N|coauthors=Isowa, K; Kamada, K; Terano, Y; Matsumoto, T; Arakawa, T; Kobayashi, K; 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=2000 Jun|volume=68|issue=6|pages=3704-9|pmid=10816531}}</ref><ref>{{cite journal|last=Ozeki|first=Y|coauthors=Kaneda, K; Fujiwara, N; Morimoto, M; Oka, S; 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=1997 May|volume=65|issue=5|pages=1793-9|pmid=9125563}}</ref> This atrophy occurs in conjunction with granuloma formation, and if granuloma formation is disturbed, so is the progression of atrophy.<ref>{{cite journal|last=Ozeki|first=Y|coauthors=Kaneda, K; Fujiwara, N; Morimoto, M; Oka, S; 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=1997 May|volume=65|issue=5|pages=1793-9|pmid=9125563}}</ref>
==Interaction with host immune system==


==Scientific Applications and Uses==
{{Empty section|date=December 2012}}
Infection by ''M. tuberculosis'' remains a serious problem in the world and knowledge of cord factor can be useful in controlling this disease.<ref>{{cite journal|last=Rao|first=V|coauthors=Fujiwara, N; Porcelli, SA; 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=2005 Feb 21|volume=201|issue=4|pages=535-43|pmid=15710652}}</ref> 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.|coauthors=Hwang, Shen-An; Hunter, Robert L.; Kruzel, Marian L.; Actor, Jeffrey K.|title=Lactoferrin modulation of mycobacterial cord factor trehalose 6-6'-dimycolate induced granulomatous response|journal=Translational Research|year=2010|month=October|volume=156|issue=4|pages=207–215|doi=10.1016/j.trsl.2010.06.001}}</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>{{cite journal|last=Retzinger|first=GS|coauthors=Meredith, SC; Takayama, K; Hunter, RL; 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=1981 Aug 10|volume=256|issue=15|pages=8208-16|pmid=7263645}}</ref><ref>{{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=1987 Apr|volume=46|issue=2|pages=190-8|pmid=3556532}}</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>{{cite journal|last=Retzinger|first=GS|coauthors=Meredith, SC; Takayama, K; Hunter, RL; 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=1981 Aug 10|volume=256|issue=15|pages=8208-16|pmid=7263645}}</ref><ref>{{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=1987 Apr|volume=46|issue=2|pages=190-8|pmid=3556532}}</ref> Cord factor beads are easily created and applied to organisms for study, and then easily recovered.<ref>{{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=1987 Apr|volume=46|issue=2|pages=190-8|pmid=3556532}}</ref>


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|coauthors=Tenu, JP; Lemaire, G; Petit, JF|title=Antitumor activity and hydrogen peroxide release by macrophages elicited by trehalose diesters.|journal=Journal of immunology (Baltimore, Md. : 1950)|date=1982 Aug|volume=129|issue=2|pages=860-6|pmid=6806386}}</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|coauthors=Afroun, S; Bray, D; Petit, JF; Lemaire, G|title=Low response of BALB/c macrophages to priming and activating signals.|journal=Journal of leukocyte biology|date=1992 Sep|volume=52|issue=3|pages=315-22|pmid=1381743}}</ref>
==See also==
==See also==
* [[Nocardia]]
* [[Nocardia]]

Revision as of 04:48, 30 November 2013

Cord factor refers to trehalose dimycolate, a virulence factor and glycolipid cell-wall component of virulent strains of Mycobacterium tuberculosis and closely related species.[1][2] It is a surface glycolipid which blocks macrophage activation by IFN-γ, induces secretion of TNFα and causes Mycobacterium tuberculosis to form cords in vitro. This is the main virulence factor for the mycobacterium tuberculosis that makes it resistance to anti-tuberculosis medications.


Structure

A cord factor molecule is composed of a trehalose sugar, a disaccharide, that is esterified to two mycolic acid residues, as shown in Figure 1.[3][4] One of the two mycolic acid residues is attached to the sixth carbon of one mo nosaccharide, while the other mycolic acid residue is attached to the sixth carbon of the other monosaccharide.[5] Therefore, cord factor is also named trehalose-6,6'-dimycolate.[6] 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.[7] Cord factor's amphiphilic nature leads to varying structures when many cord factor molecules are in close proximity.[8] On a hydrophobic surface, they spontaneously form a crystalline monolayer.[9] This crystalline monolayer is extremely durable and firm; it is stronger than any other amphiphile found in biology.[10] This monolayer also forms in oil-water, plastic-water, and air-water surfaces.[11] In an aqueous environment free of hydrophobic surfaces, cord factor forms a micelle.[12] Furthermore, cord factor interlocks with lipoarabinomannan (LAM), which is found on the surface of M. tuberculosis cells as well, to form an asymmetrical bilayer.[13][14]

Evidence of Virulence

A large quantity of cord factor is found in virulent M. tuberculosis, but not in avirulent M. tuberculosis.[15] Furthermore, M. tuberculosis loses its virulence if its ability to produce cord factor molecules is compromised.[16] Consequently, when all lipids are removed from the exterior of M. tuberculosis cells, the survival of the bacteria is reduced within a host.[17] When cord factor is added back to those cells, M. tuberculosis survives at a rate similar to that of its original state.[18] Cord factor increases the virulence of tuberculosis in mice, but it has minimal effect on other infections.[19]

Biological Function

The function of cord factor is highly dependent on what environment it is located, and therefore its conformation.[20] 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.[21] Cord factor protects M. tuberculosis from the defenses of the host.[22] Specifically, cord factor on the surface of M. tuberculosis cells prevents fusion between macrophages containing the M. tuberculosis cells and the lysosomes that would destroy them.[23][24] 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.[25] Esterase activity that targets cord factor results in the lysis of M. tuberculosis cells.[26] 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.[27] This suggests an additional molecule from M. tuberculosis is required.[28] Regardless, cord factor's ability to prevent fusion is related to an increased hydration force or through steric hindrance.[29] Cord factor remains on the surface of M. tuberculosis cells until it associates with a lipid droplet, where it forms a monolayer.[30] Then, as cord factor is in a monolayer configuration, it has a different function; it becomes fatal or harmful to the host organism.[31] Macrophages can die when in contact with monolayers of cord factor, but not when cord factor is in other configurations.[32] As the monolayer surface area of cord factor increases, so does its toxicity.[33] The length of the carbon chain on cord factor has also shown to affect toxicity; a longer chain shows higher toxicity.[34] Furthermore, fibrinogen has shown to adsorb to monolayers of cord factor and act as a cofactor for its biological effects.[35]

Host Responses and Cytokines

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.[36] After 24 hours, 503 genes are upregulated, and 162 genes are downregulated.[37] 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.[38] Furthermore, the ester linkages in cord factor are important for its toxic effects.[39] There is evidence that cord factor is recognized by the Mincle receptor, which is found on macrophages.[40] [41] An activated Mincle receptor leads to a pathway that ultimately results in the production of several cytokines.[42] [43] These cytokines can lead to further cytokine production that promote inflammatory responses.[44] Cord factor, through the Mincle receptor, also causes the recruitment of neutrophils, which lead to pro-inflammatory cytokines as well.[45] 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.[46]

Cord factor presence increases the production of the cytokines interleukin-12 (IL-12), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor (TNFα), and macrophage inflammatory protein 2 (MIP-2), which are all pro-inflammatory cytokines important for granuloma formation.[47][48][49] IL-12 is particularly important in the defense against M. tuberculosis; without it, M. tuberculosis spreads unhampered.[50][51] 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.[52] Then, with IL-12 available, Th1 cells and NK cells produce interferon gamma (IFN-γ) molecules and subsequently release them.[53] The IFN-γ molecules in turn activate macrophages.[54]

When macrophages are activated by cord factor, they can arrange into granulomas around M. tuberculosis cells.[55][56] Activated macrophages and neutrophils also cause an increase in vascular endothelial growth factor (VEGF), which is important for angiogenesis, a step in granuloma formation.[57] The granulomas can be formed either with or without T-cells, indicating that they can be foreign-body-type or hypersensitivity-type.[58] 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.[59] Thus, cord factor can act as a nonspecific irritant or a T-cell dependent antigen.[60] Granulomas enclose M. tuberculosis cells to halt the bacteria from spreading, but they also allow the bacteria to remain in the host.[61] From there, the tissue can become damaged and the disease can transmit further with cord factor. [62] Alternatively, the activated macrophages can kill the M. tuberculosis cells through reactive nitrogen intermediates to remove the infection.[63]

Besides inducing granuloma formation, activated macrophages that result from IL-12 and IFN-γ are able to limit tumor growth.[64] Furthermore, cord factor's production of TNF-α, also known as cachectin, is also able to induce cachexia, or loss of weight, within hosts.[65] [66] Cord factor also increases NADase activity in the host, and thus it lowers NAD; enzymes that require NAD decrease in activity accordingly.[67] Cord factor is thus able to obstruct oxidative phosphorylation and the electron transport chain in mitochondrial membranes.[68] In mice, cord factor has shown to cause atrophy in the thymus through apoptosis; similarly in rabbits, atrophy of the thymus and spleen occurred.[69][70] This atrophy occurs in conjunction with granuloma formation, and if granuloma formation is disturbed, so is the progression of atrophy.[71]

Scientific Applications and Uses

Infection by M. tuberculosis remains a serious problem in the world and knowledge of cord factor can be useful in controlling this disease.[72] For example, the glycoprotein known as lactoferrin is able to mitigate cytokine production and granuloma formation brought on by cord factor.[73] 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.[74][75] 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.[76][77] Cord factor beads are easily created and applied to organisms for study, and then easily recovered.[78]

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.[79] 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.[80]

See also

Technical Note In vitro stimulation of macrophages Purified cord factor was used to stimulate either mouse RAW 264.7 cells or bone marrow-derived macrophages. Cord factor was suspended at a concentration of 1 mg/ml in isopropanol and sonicated in a bath sonicator (model 3510; Branson Ultrasonic Corporation) for 5 min. This suspension was then incubated at 60°C for 10 min. and sonication repeated. The resulting solution was layered onto 24-well tissue culture plates at the indicated concentrations and incubated at 37°C in order to ensure complete evaporation of the solvent. Control wells were layered with solvent without cord factor and incubated at 37°C. To this layer of cord factor, either RAW 264.7 cells or bone marrow- derived macrophages were added at a concentration of 106 cells in 100 μl of medium and incubated at 37°C for 24 hours before activation e.g. TNF-α production was measured in the supernatant. Alternatively, cord factor was suspended at a concentration of 0.2 or 2 mg/ml in hexane. Of the resulting solution 50 μl was layered onto 96-well tissue culture plates at the indicated concentrations of 1 or 10 μg/well, respectively and the solvent completely evaporated. Control wells were layered with solvent without cord factor and incubated at 37°C. To this layer of cord factor, either RAW 264.7 cells or bone marrow-derived macrophages were added at a concentration of 106 cells in 100 μl of medium and incubated at 37°C for 24 hours before activation e.g. TNF-α production was measured in the supernatant. In vivo pulmonary granuloma formation in mice For in vivo experiments 10 μg cord factor per mouse was applied i.v. in a water/ oil/water emulsion. LIT: Interferon-gamma independent formation of pulmonary granuloma in mice by injections with trehalose dimycolate (cord factor), lipoarabinomannan and phosphatidylinositol mannosides isolated from Mycobacterium tuberculosis: H. Takimoto, et al.; Clin. Exp. Immunol. 144, 134 (2006) 􀂃 Macrophage scavenger receptor downregulates mycobacterial cord factor-induced proinflammatory cytokine production by alveolar and hepatic macrophages: Y. Ozeki, et al.; Microb. Pathog. 40, 171 (2006)

References

  1. ^ Cord+factor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  2. ^ Welsh KJ, Abbott AN, Hwang SA; et al. (2008). "A role for tumour necrosis factor-alpha, complement C5 and interleukin-6 in the initiation and development of the mycobacterial cord factor trehalose 6,6'-dimycolate induced granulomatous response". Microbiology (Reading, Engl.). 154 (Pt 6): 1813–24. doi:10.1099/mic.0.2008/016923-0. PMC 2556040. PMID 18524936. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ NOLL, H (1956 May). "The chemical structure of the cord factor of Mycobacterium tuberculosis". Biochimica et biophysica acta. 20 (2): 299–309. PMID 13328853. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  4. ^ Jonsson, B. E. (21 March 2007). "Molecular Epidemiology of Mycobacterium abscessus, with Focus on Cystic Fibrosis". Journal of Clinical Microbiology. 45 (5): 1497–1504. doi:10.1128/JCM.02592-06. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  5. ^ NOLL, H (1956 May). "The chemical structure of the cord factor of Mycobacterium tuberculosis". Biochimica et biophysica acta. 20 (2): 299–309. PMID 13328853. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  6. ^ NOLL, H (1956 May). "The chemical structure of the cord factor of Mycobacterium tuberculosis". Biochimica et biophysica acta. 20 (2): 299–309. PMID 13328853. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  7. ^ Rajni (2011). "Biosynthesis and Virulent Behavior of Lipids Produced by Mycobacterium tuberculosis: LAM and Cord Factor: An Overview". Biotechnology research international. 2011: 274693. PMID 21350659. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  8. ^ Rajni (2011). "Biosynthesis and Virulent Behavior of Lipids Produced by Mycobacterium tuberculosis: LAM and Cord Factor: An Overview". Biotechnology research international. 2011: 274693. PMID 21350659. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  9. ^ Retzinger, GS (1982 Aug). "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 of immunology (Baltimore, Md. : 1950). 129 (2): 735–44. PMID 6806381. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  10. ^ Hunter, RL (2006 Sep). "The role of trehalose dimycolate (cord factor) on morphology of virulent M. tuberculosis in vitro". Tuberculosis (Edinburgh, Scotland). 86 (5): 349–56. PMID 16343989. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  11. ^ Hunter, RL (2006 Autumn). "Multiple roles of cord factor in the pathogenesis of primary, secondary, and cavitary tuberculosis, including a revised description of the pathology of secondary disease". Annals of clinical and laboratory science. 36 (4): 371–86. PMID 17127724. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  12. ^ Retzinger, GS (1981 Aug 10). "The role of surface in the biological activities of trehalose 6,6'-dimycolate. Surface properties and development of a model system". The Journal of biological chemistry. 256 (15): 8208–16. PMID 7263645. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  13. ^ Hunter, RL (2006 Autumn). "Multiple roles of cord factor in the pathogenesis of primary, secondary, and cavitary tuberculosis, including a revised description of the pathology of secondary disease". Annals of clinical and laboratory science. 36 (4): 371–86. PMID 17127724. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  14. ^ Brennan, PJ (2003). "Structure, function, and biogenesis of the cell wall of Mycobacterium tuberculosis". Tuberculosis (Edinburgh, Scotland). 83 (1–3): 91–7. PMID 12758196.
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  16. ^ Hunter, RL (2006 Autumn). "Multiple roles of cord factor in the pathogenesis of primary, secondary, and cavitary tuberculosis, including a revised description of the pathology of secondary disease". Annals of clinical and laboratory science. 36 (4): 371–86. PMID 17127724. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
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  19. ^ Hunter, RL (2006 Autumn). "Multiple roles of cord factor in the pathogenesis of primary, secondary, and cavitary tuberculosis, including a revised description of the pathology of secondary disease". Annals of clinical and laboratory science. 36 (4): 371–86. PMID 17127724. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  20. ^ Hunter, Robert L. (2006). "Trehalose 6,6′-Dimycolate and Lipid in the Pathogenesis of Caseating Granulomas of Tuberculosis in Mice". The American Journal of Pathology. 168 (4): 1249–1261. doi:10.2353/ajpath.2006.050848. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  21. ^ Hunter, Robert L. (2006). "Trehalose 6,6′-Dimycolate and Lipid in the Pathogenesis of Caseating Granulomas of Tuberculosis in Mice". The American Journal of Pathology. 168 (4): 1249–1261. doi:10.2353/ajpath.2006.050848. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  22. ^ Hunter, RL (2006 Autumn). "Multiple roles of cord factor in the pathogenesis of primary, secondary, and cavitary tuberculosis, including a revised description of the pathology of secondary disease". Annals of clinical and laboratory science. 36 (4): 371–86. PMID 17127724. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  23. ^ Spargo, BJ (1991 Feb 1). "Cord factor (alpha,alpha-trehalose 6,6'-dimycolate) inhibits fusion between phospholipid vesicles". Proceedings of the National Academy of Sciences of the United States of America. 88 (3): 737–40. PMID 1992465. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  24. ^ Indrigo, J (2003 Aug). "Cord factor trehalose 6,6'-dimycolate (TDM) mediates trafficking events during mycobacterial infection of murine macrophages". Microbiology (Reading, England). 149 (Pt 8): 2049–59. PMID 12904545. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
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  28. ^ Indrigo, J (2003 Aug). "Cord factor trehalose 6,6'-dimycolate (TDM) mediates trafficking events during mycobacterial infection of murine macrophages". Microbiology (Reading, England). 149 (Pt 8): 2049–59. PMID 12904545. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  29. ^ Spargo, BJ (1991 Feb 1). "Cord factor (alpha,alpha-trehalose 6,6'-dimycolate) inhibits fusion between phospholipid vesicles". Proceedings of the National Academy of Sciences of the United States of America. 88 (3): 737–40. PMID 1992465. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  30. ^ Hunter, Robert L. (2006). "Trehalose 6,6′-Dimycolate and Lipid in the Pathogenesis of Caseating Granulomas of Tuberculosis in Mice". The American Journal of Pathology. 168 (4): 1249–1261. doi:10.2353/ajpath.2006.050848. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
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  40. ^ Ishikawa, E (2009 Dec 21). "Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle". The Journal of experimental medicine. 206 (13): 2879–88. PMID 20008526. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
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  47. ^ Indrigo, J (2003 Aug). "Cord factor trehalose 6,6'-dimycolate (TDM) mediates trafficking events during mycobacterial infection of murine macrophages". Microbiology (Reading, England). 149 (Pt 8): 2049–59. PMID 12904545. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  48. ^ Werninghaus, K. (12 January 2009). "Adjuvanticity of a synthetic cord factor analogue for subunit Mycobacterium tuberculosis vaccination requires FcR -Syk-Card9-dependent innate immune activation". Journal of Experimental Medicine. 206 (1): 89–97. doi:10.1084/jem.20081445. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
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  55. ^ Hunter, Robert L. (2006). "Trehalose 6,6′-Dimycolate and Lipid in the Pathogenesis of Caseating Granulomas of Tuberculosis in Mice". The American Journal of Pathology. 168 (4): 1249–1261. doi:10.2353/ajpath.2006.050848. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
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  72. ^ Rao, V (2005 Feb 21). "Mycobacterium tuberculosis controls host innate immune activation through cyclopropane modification of a glycolipid effector molecule". The Journal of experimental medicine. 201 (4): 535–43. PMID 15710652. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  73. ^ Welsh, Kerry J. (2010). "Lactoferrin modulation of mycobacterial cord factor trehalose 6-6'-dimycolate induced granulomatous response". Translational Research. 156 (4): 207–215. doi:10.1016/j.trsl.2010.06.001. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
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  76. ^ Retzinger, GS (1981 Aug 10). "The role of surface in the biological activities of trehalose 6,6'-dimycolate. Surface properties and development of a model system". The Journal of biological chemistry. 256 (15): 8208–16. PMID 7263645. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  77. ^ Retzinger, GS (1987 Apr). "Dissemination of beads coated with trehalose 6,6'-dimycolate: a possible role for coagulation in the dissemination process". Experimental and molecular pathology. 46 (2): 190–8. PMID 3556532. {{cite journal}}: Check date values in: |date= (help)
  78. ^ Retzinger, GS (1987 Apr). "Dissemination of beads coated with trehalose 6,6'-dimycolate: a possible role for coagulation in the dissemination process". Experimental and molecular pathology. 46 (2): 190–8. PMID 3556532. {{cite journal}}: Check date values in: |date= (help)
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