Yersinia pestis infection pathophysiology: Difference between revisions
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==Pathophysiology== | ==Pathophysiology== | ||
A person can get plague from flea bites or another individual when the other person has plague pneumonia and coughs droplets containing the plague bacteria into air that is breathed by a non-infected person. | |||
[[Pathogenesis]] due to ''Yersinia pestis'' infection of mammalian hosts is due to several factors including an ability of these bacteria to suppress and avoid normal [[immune system]] responses such as [[phagocytosis]] and [[antibody]] production. Flea bites allow for the bacteria to pass the skin barrier. ''Yersinia pestis'' expresses the ''yadBC'' gene, which is similar to [[Bacterial adhesin|adhesins]] in other ''Yersinia'' species, allowing for adherence and invasion of [[Epithelium|epithelial]] cells.<ref name="pmid18025093">{{cite journal |author=Forman S, Wulff CR, Myers-Morales T, Cowan C, Perry RD, Straley SC |title=yadBC of Yersinia pestis, a New Virulence Determinant for Bubonic Plague |journal=Infect. Immun. |volume=76 |issue=2 |pages=578–87 |year=2008 |pmid=18025093 |doi=10.1128/IAI.00219-07 |pmc=2223446}}</ref> ''Yersinia pestis'' expresses a [[plasminogen]] activator that is an important virulence factor for pneumonic plague and that might degrade on blood clots in order to facilitate systematic invasion.<ref name="pmid17255510">{{cite journal |author=Lathem WW, Price PA, Miller VL, Goldman WE |title=A plasminogen-activating protease specifically controls the development of primary pneumonic plague |journal=Science |volume=315 |issue=5811 |pages=509–13 |year=2007 |pmid=17255510 |doi=10.1126/science.1137195}}</ref> Many of the bacteria's [[virulence factor]]s are anti-[[phagocytosis|phagocytic]] in nature. Two important anti-phagocytic [[antigens]], named F1 (Fraction 1) and V or [[LcrV]], are both important for [[virulence]].<ref name=Baron/> These antigens are produced by the bacterium at normal human body temperature. Furthermore, ''Yersinia pestis'' survives and produces F1 and V antigens while it is residing within white blood cells such as [[monocyte]]s, but not in [[neutrophils]]. Natural or induced [[immunity (medical)|immunity]] is achieved by the production of specific [[opsonin|opsonic]] [[antibody|antibodies]] against F1 and V antigens; antibodies against F1 and V induce [[phagocytosis]] by neutrophils.<ref>{{cite book | author = Salyers AA, Whitt DD | title = Bacterial Pathogenesis: A Molecular Approach | edition = 2nd | publisher = ASM Press | year = 2002 | id = pp. 207-12}}</ref> | |||
In addition, the [[Type III secretion system]] (T3SS) allows ''Yersinia pestis'' to inject proteins into macrophages and other immune cells. These T3SS-injected proteins are called Yops (Yersinia Outer Proteins) and include Yop B/D, which form pores in the host cell membrane and have been linked to [[cytolysis]]. The YopO, [[YopH N|YopH]], YopM, YopT, YopJ, and YopE are injected into the [[cytoplasm]] of host cells via T3SS into the pore created in part by YopB and YopD.<ref>{{cite journal |author=Viboud GI, Bliska JB |title=Yersinia outer proteins: role in modulation of host cell signaling responses and pathogenesis |journal=Annu. Rev. Microbiol. |volume=59 |issue= |pages=69–89 |year=2005 |pmid=15847602 |doi=10.1146/annurev.micro.59.030804.121320}}</ref> The injected Yop proteins limit phagocytosis and cell signaling pathways important in the [[innate immune system]], as discussed below. In addition, some ''Yersinia pestis'' strains are capable of interfering with immune signaling (e.g., by preventing the release of some [[cytokines]]). | |||
== | ''Yersinia pestis'' [[Cell growth|proliferates]] inside [[lymph nodes]] where it is able to avoid destruction by cells of the [[immune system]] such as [[macrophages]]. The ability of ''Yersinia pestis'' to inhibit [[phagocytosis]] allows it to grow in lymph nodes and cause [[lymphadenopathy]]. YopH is a [[protein tyrosine phosphatase]] that contributes to the ability of ''Yersinia pestis'' to evade immune system cells.<ref name="pmid19221593">{{cite journal | author = de la Puerta ML, Trinidad AG, del Carmen Rodríguez M, Bogetz J, Sánchez Crespo M, Mustelin T, Alonso A, Bayón Y | title = Characterization of New Substrates Targeted By Yersinia Tyrosine Phosphatase YopH | journal = PLoS ONE | volume = 4 | issue = 2 | pages = e4431 | year = 2009 | month = February | pmid = 19221593 | pmc = 2637541| doi = 10.1371/journal.pone.0004431 | url = http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0004431 | editor1-last = Bozza | editor1-first = Patricia }}</ref> In macrophages, YopH has been shown to [[Dephosphorylation|dephosphorylate]] [[BCAR1|p130Cas]], [[FYB|Fyb]] ([[Fyn]] binding protein) [[SKAP2|SKAP-HOM]] and [[PTK2B|Pyk]], a [[tyrosine kinase]] homologous to [[PTK2|FAK]]. YopH also binds the p85 subunit of [[phosphoinositide 3-kinase]], the [[GAB1|Gab1]], the [[GAB1|Gab2]] adapter proteins, and the [[VAV1|Vav]] [[guanine nucleotide exchange factor]]. | ||
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YopE functions as a [[GTPase activating protein]] for members of the [[Rho family of GTPases]] such as [[RAC1]]. YopT is a [[cysteine protease]] that inhibits [[RHOA|RhoA]] by removing the [[Prenylation|isoprenyl group]], which is important for localizing the protein to the [[cell membrane]]. It has been proposed that YopE and YopT may function to limit YopB/D-induced cytolysis.<ref name="pmid18193942">{{cite journal| author = Mejía E, Bliska JB, Viboud GI | title = Yersinia Controls Type III Effector Delivery into Host Cells by Modulating Rho Activity | journal = PLoS ONE | volume = 4 | issue = 2 | pages = e4431 | year = 2009 | month = February | pmid = 18193942 | pmc = 2186360| doi = 10.1371/journal.ppat.0040003 | url = http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0004431 }}</ref> This might limit the function of YopB/D to create the pores used for Yop insertion into host cells and prevent YopB/D-induced rupture of host cells and release of cell contents that would attract and stimulate immune system responses. | |||
YopJ is an [[acetyltransferase]] that binds to a conserved [[Alpha helix|α-helix]] of [[Mitogen-activated protein kinase kinase|MAPK kinases]].<ref name="pmid18167536">{{cite journal | author = Hao YH, Wang Y, Burdette D, Mukherjee S, Keitany G, Goldsmith E, Orth K | title = Structural Requirements for Yersinia YopJ Inhibition of MAP Kinase Pathways | journal = PLoS ONE | volume = 2 | issue = 3 | pages = e1375 | year = 2008 | month = January | pmid = 18167536 | pmc = 2147050| doi = 10.1371/journal.pone.0001375 | url = http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001375 | editor1-last = Kobe | editor1-first = Bostjan }}</ref> YopJ acetylates MAPK kinases at [[serine]]s and [[threonine]]s that are normally phosphorylated during activation of the [[MAPK/ERK pathway|MAP kinase cascade]].<ref name="PMID16728640">{{cite journal | author = Mukherjee S, Keitany G, Li Y, Wang Y, Ball HL, Goldsmith EJ, Orth K | title = Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation | journal = Science | volume = 312 | issue = 5777 | pages = 1211–1214 | year = 2006 | month = May | pmid = 16728640 | pmc = | doi = 10.1126/science.1126867 | url = http://www.sciencemag.org/cgi/content/full/312/5777/1211 }}</ref><ref name="PMID17116858">{{cite journal | author = Mittal R, Peak-Chew S-Y, McMahon HT | title = Acetylation of MEK2 and IκB kinase (IKK) activation loop residues by YopJ inhibits signaling | journal = Proc. Natl. Acad. Sci. USA | volume = 103 | issue = 49 | pages = 18574–18579 | year = 2006 | month = December | pmid = 17116858 | pmc = 1654131| doi = 10.1073/pnas.0608995103 | url = http://www.pnas.org/content/103/49/18574.long }}</ref> YopJ is activated in eukaryotic cells by interaction with target cell [[Phytic acid]] (IP6).<ref name="PMID20430892">{{cite journal | author = Mittal R, Peak-Chew SY, Sade RS, Vallis Y, McMahon HT | title = The Acetyltransferase Activity of the Bacterial Toxin YopJ of Yersinia Is Activated by Eukaryotic Host Cell Inositol Hexakisphosphate | journal = J Biol Chem | volume = 285| issue = 26| pages = 19927–34| year = 2010 | month = | pmid = 20430892 | pmc = 2888404| doi = 10.1074/jbc.M110.126581 | url = http://www.jbc.org/content/early/2010/04/29/jbc.M110.126581.long }}</ref> This disruption of host cell protein kinase activity causes [[apoptosis]] of macrophages, and it has been proposed that this is important for the establishment of infection and for evasion of the host immune response. YopO is a protein kinase also known as Yersinia protein kinase A (YpkA). YopO is a potent inducer of human macrophage apoptosis.<ref name="pmid17475872">{{cite journal | author = Park H, Teja K, O'Shea JJ, Siegel RM | title = The Yersinia effector protein YpkA induces apoptosis independently of actin depolymerization | journal = J Immunol. | volume = 178 | issue = 10 | pages = 6426–6434 | year = 2007 | month = May | pmid = 17475872 | pmc = | doi = | url = http://www.jimmunol.org/cgi/content/full/178/10/6426 }}</ref> | |||
==References== | ==References== | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
A person can get plague from flea bites or another individual when the other person has plague pneumonia and coughs droplets containing the plague bacteria into air that is breathed by a non-infected person.
Pathogenesis due to Yersinia pestis infection of mammalian hosts is due to several factors including an ability of these bacteria to suppress and avoid normal immune system responses such as phagocytosis and antibody production. Flea bites allow for the bacteria to pass the skin barrier. Yersinia pestis expresses the yadBC gene, which is similar to adhesins in other Yersinia species, allowing for adherence and invasion of epithelial cells.[1] Yersinia pestis expresses a plasminogen activator that is an important virulence factor for pneumonic plague and that might degrade on blood clots in order to facilitate systematic invasion.[2] Many of the bacteria's virulence factors are anti-phagocytic in nature. Two important anti-phagocytic antigens, named F1 (Fraction 1) and V or LcrV, are both important for virulence.[3] These antigens are produced by the bacterium at normal human body temperature. Furthermore, Yersinia pestis survives and produces F1 and V antigens while it is residing within white blood cells such as monocytes, but not in neutrophils. Natural or induced immunity is achieved by the production of specific opsonic antibodies against F1 and V antigens; antibodies against F1 and V induce phagocytosis by neutrophils.[4]
In addition, the Type III secretion system (T3SS) allows Yersinia pestis to inject proteins into macrophages and other immune cells. These T3SS-injected proteins are called Yops (Yersinia Outer Proteins) and include Yop B/D, which form pores in the host cell membrane and have been linked to cytolysis. The YopO, YopH, YopM, YopT, YopJ, and YopE are injected into the cytoplasm of host cells via T3SS into the pore created in part by YopB and YopD.[5] The injected Yop proteins limit phagocytosis and cell signaling pathways important in the innate immune system, as discussed below. In addition, some Yersinia pestis strains are capable of interfering with immune signaling (e.g., by preventing the release of some cytokines).
Yersinia pestis proliferates inside lymph nodes where it is able to avoid destruction by cells of the immune system such as macrophages. The ability of Yersinia pestis to inhibit phagocytosis allows it to grow in lymph nodes and cause lymphadenopathy. YopH is a protein tyrosine phosphatase that contributes to the ability of Yersinia pestis to evade immune system cells.[6] In macrophages, YopH has been shown to dephosphorylate p130Cas, Fyb (Fyn binding protein) SKAP-HOM and Pyk, a tyrosine kinase homologous to FAK. YopH also binds the p85 subunit of phosphoinositide 3-kinase, the Gab1, the Gab2 adapter proteins, and the Vav guanine nucleotide exchange factor.
YopE functions as a GTPase activating protein for members of the Rho family of GTPases such as RAC1. YopT is a cysteine protease that inhibits RhoA by removing the isoprenyl group, which is important for localizing the protein to the cell membrane. It has been proposed that YopE and YopT may function to limit YopB/D-induced cytolysis.[7] This might limit the function of YopB/D to create the pores used for Yop insertion into host cells and prevent YopB/D-induced rupture of host cells and release of cell contents that would attract and stimulate immune system responses.
YopJ is an acetyltransferase that binds to a conserved α-helix of MAPK kinases.[8] YopJ acetylates MAPK kinases at serines and threonines that are normally phosphorylated during activation of the MAP kinase cascade.[9][10] YopJ is activated in eukaryotic cells by interaction with target cell Phytic acid (IP6).[11] This disruption of host cell protein kinase activity causes apoptosis of macrophages, and it has been proposed that this is important for the establishment of infection and for evasion of the host immune response. YopO is a protein kinase also known as Yersinia protein kinase A (YpkA). YopO is a potent inducer of human macrophage apoptosis.[12]
References
- ↑ Forman S, Wulff CR, Myers-Morales T, Cowan C, Perry RD, Straley SC (2008). "yadBC of Yersinia pestis, a New Virulence Determinant for Bubonic Plague". Infect. Immun. 76 (2): 578–87. doi:10.1128/IAI.00219-07. PMC 2223446. PMID 18025093.
- ↑ Lathem WW, Price PA, Miller VL, Goldman WE (2007). "A plasminogen-activating protease specifically controls the development of primary pneumonic plague". Science. 315 (5811): 509–13. doi:10.1126/science.1137195. PMID 17255510.
- ↑
- ↑ Salyers AA, Whitt DD (2002). Bacterial Pathogenesis: A Molecular Approach (2nd ed.). ASM Press. pp. 207-12.
- ↑ Viboud GI, Bliska JB (2005). "Yersinia outer proteins: role in modulation of host cell signaling responses and pathogenesis". Annu. Rev. Microbiol. 59: 69–89. doi:10.1146/annurev.micro.59.030804.121320. PMID 15847602.
- ↑ de la Puerta ML, Trinidad AG, del Carmen Rodríguez M, Bogetz J, Sánchez Crespo M, Mustelin T, Alonso A, Bayón Y (2009). Bozza, Patricia, ed. "Characterization of New Substrates Targeted By Yersinia Tyrosine Phosphatase YopH". PLoS ONE. 4 (2): e4431. doi:10.1371/journal.pone.0004431. PMC 2637541. PMID 19221593. Unknown parameter
|month=ignored (help) - ↑ Mejía E, Bliska JB, Viboud GI (2009). "Yersinia Controls Type III Effector Delivery into Host Cells by Modulating Rho Activity". PLoS ONE. 4 (2): e4431. doi:10.1371/journal.ppat.0040003. PMC 2186360. PMID 18193942. Unknown parameter
|month=ignored (help) - ↑ Hao YH, Wang Y, Burdette D, Mukherjee S, Keitany G, Goldsmith E, Orth K (2008). Kobe, Bostjan, ed. "Structural Requirements for Yersinia YopJ Inhibition of MAP Kinase Pathways". PLoS ONE. 2 (3): e1375. doi:10.1371/journal.pone.0001375. PMC 2147050. PMID 18167536. Unknown parameter
|month=ignored (help) - ↑ Mukherjee S, Keitany G, Li Y, Wang Y, Ball HL, Goldsmith EJ, Orth K (2006). "Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation". Science. 312 (5777): 1211–1214. doi:10.1126/science.1126867. PMID 16728640. Unknown parameter
|month=ignored (help) - ↑ Mittal R, Peak-Chew S-Y, McMahon HT (2006). "Acetylation of MEK2 and IκB kinase (IKK) activation loop residues by YopJ inhibits signaling". Proc. Natl. Acad. Sci. USA. 103 (49): 18574–18579. doi:10.1073/pnas.0608995103. PMC 1654131. PMID 17116858. Unknown parameter
|month=ignored (help) - ↑ Mittal R, Peak-Chew SY, Sade RS, Vallis Y, McMahon HT (2010). "The Acetyltransferase Activity of the Bacterial Toxin YopJ of Yersinia Is Activated by Eukaryotic Host Cell Inositol Hexakisphosphate". J Biol Chem. 285 (26): 19927–34. doi:10.1074/jbc.M110.126581. PMC 2888404. PMID 20430892.
- ↑ Park H, Teja K, O'Shea JJ, Siegel RM (2007). "The Yersinia effector protein YpkA induces apoptosis independently of actin depolymerization". J Immunol. 178 (10): 6426–6434. PMID 17475872. Unknown parameter
|month=ignored (help)