Yersinia pestis infection pathophysiology: Difference between revisions

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* On the inoculation site there may be an [[ulcer]], [[papule]], [[vesicle]] or [[eschar]].
* On the inoculation site there may be an [[ulcer]], [[papule]], [[vesicle]] or [[eschar]].
* Local [[cutaneous]] proliferation, usually not clinically evident, occurs after inoculation.
* Local [[cutaneous]] proliferation, usually not clinically evident, occurs after inoculation.
*''Y. pestis'' can reproduce inside cells, so even if [[phagocytosis|phagocytosed]], they can still survive.Plague bacteria secrete several [[toxin]]s, one of which is known to cause dangerous [[beta blocker|beta-adrenergic blockade]].
* The [[infection]] spreads via the [[lymphatic]]s to the regional [[lymph node]]s causing [[inflammation]] and [[swelling]] in one or several nodes. This will cause regional [[lymphadenopathy]] and [[abscesses]]., often called ''buboes''. Buboes may occur in any regional [[lymph]] node sites including:<ref name=WHObook>Plague Manual: Epidemiology, Distribution, Surveillance. World Health Organization. Communicable Disease Surveillance and Response
* The [[infection]] spreads via the [[lymphatic]]s to the regional [[lymph node]]s causing [[inflammation]] and [[swelling]] in one or several nodes. This will cause regional [[lymphadenopathy]] and [[abscesses]]., often called ''buboes''. Buboes may occur in any regional [[lymph]] node sites including:<ref name=WHObook>Plague Manual: Epidemiology, Distribution, Surveillance. World Health Organization. Communicable Disease Surveillance and Response
and Control. WHO/CDS/CSR/EDC/99.2 </ref>
and Control. WHO/CDS/CSR/EDC/99.2 </ref>
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:: [[Bacterial]] spread, from an initial focus of [[infection]], such as the [[skin]] (bubonic plague) or the [[lungs]] (pulmonic plague).
:: [[Bacterial]] spread, from an initial focus of [[infection]], such as the [[skin]] (bubonic plague) or the [[lungs]] (pulmonic plague).
:: Simillar clinical presentation to other [[gram-negative]] [[septicemia]]s.
:: Simillar clinical presentation to other [[gram-negative]] [[septicemia]]s.
* Presence of rapidly replicating [[gram-negative]] [[bacilli]] in the [[bloodstream]] initiates a self-perpetuating [[immunological]] cascade, typically linked to the host response to the [[bacterial]] [[endotoxin]].
* Presence of rapidly replicating [[gram-negative]] [[bacilli]] in the [[bloodstream]] typically linked to the host response to the [[bacterial]] [[endotoxin]].
* The host response may result in a wide spectrum of pathological events including [[disseminated intravascular coagulopathy]] ([[DIC]]), [[multiple organ failure]], and [[adult respiratory distress syndrome]] ([[ARDS]]).
* Bacterial endotoxins cause [[disseminated intravascular coagulation]] (DIC), causing tiny clots throughout the body and possibly ischaemic necrosis (tissue death due to lack of circulation/perfusion to that tissue) from the clots. DIC results in depletion of the body's clotting resources, so that it can no longer control bleeding. Consequently, there is bleeding into the skin and other organs, which can cause red and/or black patchy rash and hemoptysis/haemoptysis (coughing up or [[vomiting]] of blood). There are bumps on the skin that look somewhat like insect bites; these are usually red, and sometimes white in the center.
* The host response may result in a wide spectrum of pathological events including [[disseminated intravascular coagulopathy]] ([[DIC]]), [[multiple organ failure]], and [[adult respiratory distress syndrome]] ([[ARDS]]).Untreated, septicemic plague is usually fatal.


===Meningeal plague===
===Meningeal plague===
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===Evasion of the Immune System===
===Evasion of the Immune System===
====Anti-phagocytic Antigens====
====Anti-phagocytic Antigens====
Many of the [[bacteria]]'s [[virulence factor]]s are [[antiphagocytic]] in nature. Two important [[antiphagocytic]] [[antigens]], named F1 (Fraction 1) and V or LcrV, are important for the [[virulence]]. 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>
Many of the [[bacteria]]'s [[virulence factor]]s are [[antiphagocytic]] in nature. Two important [[antiphagocytic]] [[antigens]], named F1 (Fraction 1) and V or LcrV, are important for the [[virulence]]. These [[antigens]] are produced by the [[bacteria]] 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>


====Type III Secretion System (T3SS)====
====Type III Secretion System (T3SS)====
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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.<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 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.<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]]. In addition, some [[Yersinia pestis]] [[strains]] are capable of interfering with [[immune]] signaling (e.g., by preventing the release of some [[cytokines]]).
The injected Yop [[proteins]] limit [[phagocytosis]] and [[cell signaling pathways]], important in the [[innate immune system]]. In addition, some [[Yersinia pestis]] [[strains]] are capable of interfering with [[immune]] signaling (e.g., by preventing the release of some [[cytokines]]).


====Yersinia Outer Proteins====
====Yersinia Outer Proteins====
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:Responsible for [[acetylation]] of [[MAPK]] at [[serine]]s and [[threonine]] groups, which 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 cell]]s 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]].
:Responsible for [[acetylation]] of [[MAPK]] at [[serine]]s and [[threonine]] groups, which 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 cell]]s 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]].
:This mechanism has been proposed to play a role in the establishment of [[infection]], and evasion of the host [[immune response]], by the [[bacteria]].  
:This mechanism has been proposed to play a role in the establishment of [[infection]], and evasion of the host [[immune response]] by the [[bacteria]].  


* '''YopO''' - [[Protein kinase]], also known as ''Yersinia protein kinase A'' (YpkA), 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>
* '''YopO''' - [[Protein kinase]], also known as ''Yersinia protein kinase A'' (YpkA), 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>
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===Flea Bites===
===Flea Bites===
Plague [[bacteria]] are most often transmitted by the bite of an [[infected]] flea. During plague epizootics, many rodents die, causing hungry fleas to seek other sources of [[blood]]. People and animals that visit places where rodents have recently died from plague, are at risk of being [[infected]] from flea bites. Dogs and cats may also bring plague-infected fleas into the home. Flea bite exposure may result in primary bubonic plague or septicemic plague.
Plague [[bacteria]] are most often transmitted by the bite of an [[infected]] flea. [[Image:Scanning Electron Micrograph of a Flea.jpg|thumb|right|'''''[[Xenopsylla cheopis]]''''' primary vector of [[Bubonic plague]]]]
Bubonic plague is mainly a disease in [[rodent]]s and [[flea]]s (''[[Xenopsylla cheopis]]''). Infection in a human occurs when a person is bitten by a flea that has been infected by biting a rodent that itself has been infected by the bite of a flea carrying the disease. The bacteria multiply inside the flea, sticking together to form a plug that blocks its stomach and causes it to begin to starve. The flea then voraciously bites a host and continues to feed, even though it cannot quell its hunger, and consequently the flea vomits blood tainted with the bacteria back into the bite wound. The bubonic plague bacterium then infects a new victim, and the flea eventually dies from starvation. Serious outbreaks of plague are usually started by other disease outbreaks in rodents, or a rise in the rodent population.During plague epizootics, many rodents die, causing hungry fleas to seek other sources of [[blood]]. People and animals that visit places where rodents have recently died from plague, are at risk of being [[infected]] from flea bites. Dogs and cats may also bring plague-infected fleas into the home. Flea bite exposure may result in primary bubonic plague or septicemic plague.


This way of [[transmission]] distinguishes [[Yersinia pestis]] from other [[enterobacteriaceae]] such as [[Yersinia pseudotuberculosis]].<ref name="Koirala2006">{{cite journal|last1=Koirala|first1=Janak|title=Plague: Disease, Management, and Recognition of Act of Terrorism|journal=Infectious Disease Clinics of North America|volume=20|issue=2|year=2006|pages=273–287|issn=08915520|doi=10.1016/j.idc.2006.02.004}}</ref>
This way of [[transmission]] distinguishes [[Yersinia pestis]] from other [[enterobacteriaceae]] such as [[Yersinia pseudotuberculosis]].<ref name="Koirala2006">{{cite journal|last1=Koirala|first1=Janak|title=Plague: Disease, Management, and Recognition of Act of Terrorism|journal=Infectious Disease Clinics of North America|volume=20|issue=2|year=2006|pages=273–287|issn=08915520|doi=10.1016/j.idc.2006.02.004}}</ref>
In 1894, two bacteriologists, [[Alexandre Emile John Yersin|Alexandre Yersin]] of [[France]] and [[Shibasaburo Kitasato]] of [[Japan]], independently isolated the bacterium in [[Hong Kong]] responsible for the [[Third Pandemic]]. Though both investigators reported their findings, a series of confusing and contradictory statements by Kitasato eventually led to the acceptance of Yersin as the primary discoverer of the organism. Yersin named it '''''Pasteurella pestis''''' in honor of the [[Pasteur Institute]], where he worked, but in 1967 it was moved to a new genus, renamed '''''[[Yersinia pestis]]''''' in honor of Yersin. Yersin also noted that rats were affected by plague not only during plague epidemics but also often preceding such epidemics in humans, and that plague was regarded by many locals as a disease of rats: villagers in China and India asserted that, when large numbers of rats were found dead, plague outbreaks in people soon followed.
In 1898, the French scientist [[Paul-Louis Simond]] (who had also come to China to battle the [[Third Pandemic]]) established the rat-flea [[Vector (biology)|vector]] that drives the disease. He had noted that persons who became ill did not have to be in close contact with each other to acquire the disease. In Yunnan, China, inhabitants would flee from their homes as soon as they saw dead rats, and on the island of Formosa (Taiwan), residents considered handling dead rats a risk for developing plague. These observations led him to suspect that the flea might be an intermediary factor in the transmission of plague, since people acquired plague only if they were in contact with recently dead rats, but not affected if they touched rats that had been dead for more than 24 hours. In a now classic experiment, Simond demonstrated how a healthy rat died of plague after infected fleas had jumped to it from a plague-dead rat.


===Contact with Contaminated Fluid or Tissue===
===Contact with Contaminated Fluid or Tissue===
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===Infectious Droplets===
===Infectious Droplets===
When a person has plague [[pneumonia]], they may [[cough]] droplets containing the [[Yersinia pestis|plague bacteria]] into air. If these [[bacteria]]-containing droplets are breathed in by another person, they can cause pneumonic plague.
When a person has plague [[pneumonia]], they may [[cough]] droplets containing the [[Yersinia pestis|plague bacteria]] into air. If these [[bacteria]]-containing droplets are breathed in by another person, they can cause pneumonic plague. Typically this requires direct and close contact with the person with pneumonic plague. [[Transmission]] of these droplets is the only way that plague can spread between people. This type of spread has not been documented in the United States since 1924, but still occurs with some frequency in developing countries.
 
Typically this requires direct and close contact with the person with pneumonic plague. [[Transmission]] of these droplets is the only way that plague can spread between people. This type of spread has not been documented in the United States since 1924, but still occurs with some frequency in developing countries.


Cats are particularly susceptible to plague, and can be [[infected]] by eating [[infected]] rodents. Sick cats pose a risk of transmitting [[infectious]] plague droplets to their owners or to veterinarians. Several cases of human plague have occurred in the United States in recent decades as a result of contact with [[infected]] cats.
Cats are particularly susceptible to plague, and can be [[infected]] by eating [[infected]] rodents. Sick cats pose a risk of transmitting [[infectious]] plague droplets to their owners or to veterinarians. Several cases of human plague have occurred in the United States in recent decades as a result of contact with [[infected]] cats.
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==Gross Pathology==
==Gross Pathology==
===Bubonic Plague===
===Bubonic Plague===
Common presentation includes a [[skin lesion]], that may be a [[papule]], [[vesicle]], [[ulcer]] or [[eschar]] on the site of the bite, and enlarged regional [[lymph node]]s. The "buboes" may measure from 1 to 10 cm. There may also be deeper enlarged [[lymph node]]s.<ref name="Koirala2006">{{cite journal|last1=Koirala|first1=Janak|title=Plague: Disease, Management, and Recognition of Act of Terrorism|journal=Infectious Disease Clinics of North America|volume=20|issue=2|year=2006|pages=273–287|issn=08915520|doi=10.1016/j.idc.2006.02.004}}</ref>
Common presentation includes a [[skin lesion]] that may be a [[papule]], [[vesicle]], [[ulcer]] or [[eschar]] on the site of the bite, and enlarged regional [[lymph node]]s. The "buboes" may measure from 1 to 10 cm. There may also be deeper enlarged [[lymph node]]s.<ref name="Koirala2006">{{cite journal|last1=Koirala|first1=Janak|title=Plague: Disease, Management, and Recognition of Act of Terrorism|journal=Infectious Disease Clinics of North America|volume=20|issue=2|year=2006|pages=273–287|issn=08915520|doi=10.1016/j.idc.2006.02.004}}</ref>
===Pulmonic Plague===
===Pulmonic Plague===
Commonly occurs with [[pulmonary]] lobe involvement, progressing into bilateral [[pneumonia]], [[pleurisy]], [[cavitation]]s, potentially culminating in [[ARDS]].<ref name="Koirala2006">{{cite journal|last1=Koirala|first1=Janak|title=Plague: Disease, Management, and Recognition of Act of Terrorism|journal=Infectious Disease Clinics of North America|volume=20|issue=2|year=2006|pages=273–287|issn=08915520|doi=10.1016/j.idc.2006.02.004}}</ref>
Commonly occurs with [[pulmonary]] lobe involvement, progressing into bilateral [[pneumonia]], [[pleurisy]], [[cavitation]]s, potentially culminating in [[ARDS]].<ref name="Koirala2006">{{cite journal|last1=Koirala|first1=Janak|title=Plague: Disease, Management, and Recognition of Act of Terrorism|journal=Infectious Disease Clinics of North America|volume=20|issue=2|year=2006|pages=273–287|issn=08915520|doi=10.1016/j.idc.2006.02.004}}</ref>
===Septicemic Plague===
===Septicemic Plague===
This type of plague commonly leads to small vessel [[thrombosis]], which is responsible for the [[necrosis]] of extremities, such as fingers, toes and tip of the nose. These manifestations may occur in advanced disease.<ref name="Koirala2006">{{cite journal|last1=Koirala|first1=Janak|title=Plague: Disease, Management, and Recognition of Act of Terrorism|journal=Infectious Disease Clinics of North America|volume=20|issue=2|year=2006|pages=273–287|issn=08915520|doi=10.1016/j.idc.2006.02.004}}</ref>
This type of plague commonly leads to small vessel [[thrombosis]], which is responsible for the [[necrosis]] of extremities, such as fingers, toes and tip of the nose. These manifestations may occur in advanced stages of the disease.<ref name="Koirala2006">{{cite journal|last1=Koirala|first1=Janak|title=Plague: Disease, Management, and Recognition of Act of Terrorism|journal=Infectious Disease Clinics of North America|volume=20|issue=2|year=2006|pages=273–287|issn=08915520|doi=10.1016/j.idc.2006.02.004}}</ref>


==Microscopic Pathology==
==Microscopic Pathology==
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==Gallery==
==Gallery==
<gallery>
Image: Bubonic plague03.jpeg| Diagram depicts the modalities of transfer between various hosts of Yersinia pestis bacteria.<SMALL> <SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
</gallery>
===Gross Pathology===
===Gross Pathology===
<gallery>
<gallery>
Image:Plague5.jpg| Necropsy of a rock squirrel, Spermophilus variegatus, formerly known as Citellus variegatus, which was afflicted with the pneumonic hemorrhagic plague. Note the presence of hemorrhagic blood that had been expelled from the animal’s nares, which had been the result of pulmonic hemorrhage.<SMALL> <SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
Image:Plague5.jpg| Necropsy of a rock squirrel, Spermophilus variegatus afflicted with the pneumonic hemorrhagic plague. <SMALL> <SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>


Image:Plague6.jpg| Necropsy of a rock squirrel, Spermophilus variegatus, exposure of the animal’s abdominal viscera revealed the presence of a massive hemorrhagic reaction, which was due to a Yersinia pestis infection, the bacteria responsible for causing plague <SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
Image:Plague6.jpg| Necropsy of a rock squirrel, Spermophilus variegatus, exposure of the animal’s abdominal viscera revealed the presence of a massive hemorrhagic reaction, due to a Yersinia pestis infection. <SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>


Image:Plague7.jpg| Necropsy of a rock squirrel, Spermophilus variegatus, exposure of the animal’s abdominal viscera revealed the presence of a massive hemorrhagic reaction, which was due to a Yersinia pestis infection, the bacteria responsible for causing plague. <SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
Image:Plague7.jpg| Necropsy of a rock squirrel revealed presence of a massive hemorrhagic reaction, due to a Yersinia pestis infection. <SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>


Image:Plague8.jpg| Necropsy of a rock squirrel, Spermophilus variegatus, exposure of the animal’s abdominal viscera revealed the presence of a massive hemorrhagic reaction, which was due to a Yersinia pestis infection, the bacteria responsible for causing plague. <SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
Image:Plague8.jpg| Necropsy of a rock squirrel, Spermophilus variegatus, exposure of the animal’s abdominal viscera revealed the presence of a massive hemorrhagic reaction, which was due to a Yersinia pestis infection, the bacteria responsible for causing plague. <SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
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Image:Plague12.jpg| High magnification of 1200X, this Brown and Brenn-stained lung tissue sample revealing the histopathologic changes indicative of what was diagnosed as a case of fatal human plague from the country of Nepal. <SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
Image:Plague12.jpg| High magnification of 1200X, this Brown and Brenn-stained lung tissue sample revealing the histopathologic changes indicative of what was diagnosed as a case of fatal human plague from the country of Nepal. <SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
Image: Bubonic plague16.jpeg| Histopathologic changes in a lymph node tissue sample in a case of fatal human plague. <SMALL><SMALL>''[http://phil.cdc.gov/phil/home.asp From Public Health Image Library (PHIL).] ''<ref name=PHIL> {{Cite web | title = Public Health Image Library (PHIL) | url = http://phil.cdc.gov/phil/home.asp}}</ref></SMALL></SMALL>
Image: Bubonic plague04.jpeg| Lung tissue sample revealed the histopathologic changes indicative of fatal human plague (125x mag). <SMALL><SMALL>''[http://phil.cdc.gov/phil/home.asp From Public Health Image Library (PHIL).] ''<ref name=PHIL> {{Cite web | title = Public Health Image Library (PHIL) | url = http://phil.cdc.gov/phil/home.asp}}</ref></SMALL></SMALL>
Image: Bubonic plague05.jpeg| Hematoxylin-eosin stained lung tissue sample revealed the histopathologic changes indicative of what was diagnosed as a case of fatal human plague from the country of Nepal (125x mag). <SMALL><SMALL>''[http://phil.cdc.gov/phil/home.asp From Public Health Image Library (PHIL).] ''<ref name=PHIL> {{Cite web | title = Public Health Image Library (PHIL) | url = http://phil.cdc.gov/phil/home.asp}}</ref></SMALL></SMALL>


Image:Plague14.jpg| Magnification of 500X, this hematoxylin and eosin-stained splenic tissue sample revealing the histopathologic changes indicative of what was diagnosed as a case of fatal human plague from the country of Nepal <SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
Image:Plague14.jpg| Magnification of 500X, this hematoxylin and eosin-stained splenic tissue sample revealing the histopathologic changes indicative of what was diagnosed as a case of fatal human plague from the country of Nepal <SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
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Latest revision as of 00:46, 30 July 2020

Yersinia pestis infection Microchapters

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editors-In-Chief: Esther Lee, M.A.; Rim Halaby, M.D. [2]; João André Alves Silva, M.D. [3]

Overview

The route of infection (fleabite or aerosolized particles) classifies plague into: bubonic, pulmonic or septicemic. Yersinia pestis produces several virulence factors which are responsible for: evasion of the immune system, survival of the bacteria inside host cells, and infectious mechanisms, such as: degradation of extracellular proteins, production of endotoxins and inhibition of platelet aggregation. Y. pestis aggregates in different tissues, causing inflammation and necrosis, that are responsible for some of the clinical findings of plague: lymphadenopathy and abscesses (bubonic); bacteremia and sepsis (septicemic) and pneumonia and ARDS (pulmonic).

Pathogenesis

According to the route of infection, the plague may be divided into:[1]

Bubonic plague

Pulmonic Plague

Septicemic plague

  • May be classified in primary or secondary septicemic plague:[1]
  • Primary Septicemic Plague:
Cutaneous exposure to the bacteria, without lymphadenopathy, followed by systemic bacteremia.
Althought it affects all age groups, elderly are more commonly affected.
  • Secondary Septicemic Plague:
Bacterial spread, from an initial focus of infection, such as the skin (bubonic plague) or the lungs (pulmonic plague).
Simillar clinical presentation to other gram-negative septicemias.
  • Presence of rapidly replicating gram-negative bacilli in the bloodstream typically linked to the host response to the bacterial endotoxin.
  • Bacterial endotoxins cause disseminated intravascular coagulation (DIC), causing tiny clots throughout the body and possibly ischaemic necrosis (tissue death due to lack of circulation/perfusion to that tissue) from the clots. DIC results in depletion of the body's clotting resources, so that it can no longer control bleeding. Consequently, there is bleeding into the skin and other organs, which can cause red and/or black patchy rash and hemoptysis/haemoptysis (coughing up or vomiting of blood). There are bumps on the skin that look somewhat like insect bites; these are usually red, and sometimes white in the center.
  • The host response may result in a wide spectrum of pathological events including disseminated intravascular coagulopathy (DIC), multiple organ failure, and adult respiratory distress syndrome (ARDS).Untreated, septicemic plague is usually fatal.

Meningeal plague

Virulence Factors

Yersinia pestis produces several virulence factors that allow it to evade the host's immune system and cause infection. These virulence factors include:[1]

Phospholipase D

  • Survival inside the flea

V antigen and W antigen

Low-calcium-response plasmid

Hemin storage system

Plasminogen activator

Lipopolysaccharide endotoxin

Yersinia outer proteins (Yops)

  • Inhibitor of:

F1 antigen

Evasion of the Immune System

Anti-phagocytic Antigens

Many of the bacteria's virulence factors are antiphagocytic in nature. Two important antiphagocytic antigens, named F1 (Fraction 1) and V or LcrV, are important for the virulence. These antigens are produced by the bacteria 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.[7]

Type III Secretion System (T3SS)

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.[8]

The injected Yop proteins limit phagocytosis and cell signaling pathways, important in the innate immune system. In addition, some Yersinia pestis strains are capable of interfering with immune signaling (e.g., by preventing the release of some cytokines).

Yersinia Outer Proteins

YopH also binds the p85 subunit of phosphoinositide 3-kinase, the Gab1, the Gab2 adapter proteins, and the Vav guanine nucleotide exchange factor.
  • YopT - Cysteine protease that inhibits RhoA by removing the isoprenyl group. It has been proposed that YopE and YopT may function to limit YopB/D-induced cytolysis.[10] This might limit the function of YopB/D to create the pores used for Yop insertion into host cells. It may also prevent YopB/D-induced rupture of host cells, and the release of cell contents that would attract and stimulate immune system responses.
Responsible for acetylation of MAPK at serines and threonine groups, which are normally phosphorylated during activation of the MAP kinase cascade.[12][13] YopJ is activated in eukaryotic cells by interaction with target cell Phytic acid (IP6).[14] This disruption of host cell protein kinase activity causes apoptosis of macrophages.
This mechanism has been proposed to play a role in the establishment of infection, and evasion of the host immune response by the bacteria.

Genetics

Yersinia pestis expresses the yadBC gene, which is similar to adhesins in other Yersinia species, allowing for adherence and invasion of epithelial cells.[16]

Transmission

Transmission of Y. pestis may occur through:[17]

  • Droplet contact – coughing or sneezing on another person
  • Direct physical contact – touching an infected person, including sexual contact
  • Indirect contact – usually by touching soil contamination or a contaminated surface
  • Airborne transmission – if the microorganism can remain in the air for long periods
  • Fecal-oral transmission – usually from contaminated food or water sources
  • Vector borne transmission – carried by insects or other animals

Unlike other types of plague, the pneumonic type can be transmitted from person to person. Pneumonic plague affects the lungs and is transmitted when a person breathes in Y. pestis particles in the air.

Bubonic plague is transmitted through the bite of an infected flea or exposure to infected material through a break in the skin.

Flea Bites

Plague bacteria are most often transmitted by the bite of an infected flea.

File:Scanning Electron Micrograph of a Flea.jpg
Xenopsylla cheopis primary vector of Bubonic plague

Bubonic plague is mainly a disease in rodents and fleas (Xenopsylla cheopis). Infection in a human occurs when a person is bitten by a flea that has been infected by biting a rodent that itself has been infected by the bite of a flea carrying the disease. The bacteria multiply inside the flea, sticking together to form a plug that blocks its stomach and causes it to begin to starve. The flea then voraciously bites a host and continues to feed, even though it cannot quell its hunger, and consequently the flea vomits blood tainted with the bacteria back into the bite wound. The bubonic plague bacterium then infects a new victim, and the flea eventually dies from starvation. Serious outbreaks of plague are usually started by other disease outbreaks in rodents, or a rise in the rodent population.During plague epizootics, many rodents die, causing hungry fleas to seek other sources of blood. People and animals that visit places where rodents have recently died from plague, are at risk of being infected from flea bites. Dogs and cats may also bring plague-infected fleas into the home. Flea bite exposure may result in primary bubonic plague or septicemic plague.

This way of transmission distinguishes Yersinia pestis from other enterobacteriaceae such as Yersinia pseudotuberculosis.[1]

In 1894, two bacteriologists, Alexandre Yersin of France and Shibasaburo Kitasato of Japan, independently isolated the bacterium in Hong Kong responsible for the Third Pandemic. Though both investigators reported their findings, a series of confusing and contradictory statements by Kitasato eventually led to the acceptance of Yersin as the primary discoverer of the organism. Yersin named it Pasteurella pestis in honor of the Pasteur Institute, where he worked, but in 1967 it was moved to a new genus, renamed Yersinia pestis in honor of Yersin. Yersin also noted that rats were affected by plague not only during plague epidemics but also often preceding such epidemics in humans, and that plague was regarded by many locals as a disease of rats: villagers in China and India asserted that, when large numbers of rats were found dead, plague outbreaks in people soon followed.

In 1898, the French scientist Paul-Louis Simond (who had also come to China to battle the Third Pandemic) established the rat-flea vector that drives the disease. He had noted that persons who became ill did not have to be in close contact with each other to acquire the disease. In Yunnan, China, inhabitants would flee from their homes as soon as they saw dead rats, and on the island of Formosa (Taiwan), residents considered handling dead rats a risk for developing plague. These observations led him to suspect that the flea might be an intermediary factor in the transmission of plague, since people acquired plague only if they were in contact with recently dead rats, but not affected if they touched rats that had been dead for more than 24 hours. In a now classic experiment, Simond demonstrated how a healthy rat died of plague after infected fleas had jumped to it from a plague-dead rat.

Contact with Contaminated Fluid or Tissue

Humans can become infected when handling tissue or body fluids of a plague-infected animal. For example, a hunter skinning a rabbit or other infected animal without using proper precautions could become infected with plague bacteria. This form of exposure most commonly results in bubonic plague or septicemic plague.

Infectious Droplets

When a person has plague pneumonia, they may cough droplets containing the plague bacteria into air. If these bacteria-containing droplets are breathed in by another person, they can cause pneumonic plague. Typically this requires direct and close contact with the person with pneumonic plague. Transmission of these droplets is the only way that plague can spread between people. This type of spread has not been documented in the United States since 1924, but still occurs with some frequency in developing countries.

Cats are particularly susceptible to plague, and can be infected by eating infected rodents. Sick cats pose a risk of transmitting infectious plague droplets to their owners or to veterinarians. Several cases of human plague have occurred in the United States in recent decades as a result of contact with infected cats.

Gross Pathology

Bubonic Plague

Common presentation includes a skin lesion that may be a papule, vesicle, ulcer or eschar on the site of the bite, and enlarged regional lymph nodes. The "buboes" may measure from 1 to 10 cm. There may also be deeper enlarged lymph nodes.[1]

Pulmonic Plague

Commonly occurs with pulmonary lobe involvement, progressing into bilateral pneumonia, pleurisy, cavitations, potentially culminating in ARDS.[1]

Septicemic Plague

This type of plague commonly leads to small vessel thrombosis, which is responsible for the necrosis of extremities, such as fingers, toes and tip of the nose. These manifestations may occur in advanced stages of the disease.[1]

Microscopic Pathology

Studies in Y. pestis-infected cats revealed similar histological changes to those verified in humans. Common microscopic findings include:[18]

Gallery

Gross Pathology

Microscopic Pathology

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 Koirala, Janak (2006). "Plague: Disease, Management, and Recognition of Act of Terrorism". Infectious Disease Clinics of North America. 20 (2): 273–287. doi:10.1016/j.idc.2006.02.004. ISSN 0891-5520.
  2. ↑ 2.0 2.1 Plague Manual: Epidemiology, Distribution, Surveillance. World Health Organization. Communicable Disease Surveillance and Response and Control. WHO/CDS/CSR/EDC/99.2
  3. ↑ 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.
  4. ↑ "Plague manual--epidemiology, distribution, surveillance and control". Wkly Epidemiol Rec. 74 (51–52): 447. 1999. PMID 10635759.
  5. ↑ Bossi P, Tegnell A, Baka A, Van Loock F, Hendriks J, Werner A; et al. (2004). "Bichat guidelines for the clinical management of plague and bioterrorism-related plague". Euro Surveill. 9 (12): E5–6. PMID 15677847.
  6. ↑ Cleri DJ, Vernaleo JR, Lombardi LJ, Rabbat MS, Mathew A, Marton R; et al. (1997). "Plague pneumonia disease caused by Yersinia pestis". Semin Respir Infect. 12 (1): 12–23. PMID 9097371.
  7. ↑ Salyers AA, Whitt DD (2002). Bacterial Pathogenesis: A Molecular Approach (2nd ed.). ASM Press. pp. 207-12.
  8. ↑ 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.
  9. ↑ 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)
  10. ↑ 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)
  11. ↑ 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)
  12. ↑ 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)
  13. ↑ 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)
  14. ↑ 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.
  15. ↑ 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)
  16. ↑ 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.
  17. ↑ Plague Manual: Epidemiology, Distribution, Surveillance and Control, pp. 9 and 11. WHO/CDS/CSR/EDC/99.2
  18. ↑ Watson RP, Blanchard TW, Mense MG, Gasper PW (2001). "Histopathology of experimental plague in cats". Vet Pathol. 38 (2): 165–72. PMID 11280372.
  19. ↑ 19.00 19.01 19.02 19.03 19.04 19.05 19.06 19.07 19.08 19.09 19.10 19.11 19.12 19.13 19.14 19.15 19.16 19.17 19.18 19.19 19.20 19.21 19.22 19.23 19.24 19.25 19.26 19.27 19.28 19.29 19.30 19.31 "Public Health Image Library (PHIL), Centers for Disease Control and Prevention".

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