Enterovirus 68 pathophysiology: Difference between revisions

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{{Enterovirus 68}}
{{Enterovirus 68}}


==Overview==
==Overview==
Unlike other enteroviruses, EV-D68 causes respiratory disease almost exclusively. Its cellular tropism, optimal growth at lower temperatures, and acid-lability are responsible for its infection of [[leukocytes]] and cells of the respiratory mucosa. The virus has the ability to replicate inside leukocytes, which allows it to infect the parenchymal tissue, to increase its viral load that will contribute to viral dissemination, and to activate [[endothelial cell]]s that attract more leukocytes to the infected site. Although viral transmission is not fully understood, the virus can be isolated in respiratory secretions and may be transmitted from person to person via aerosol or direct contact.


==Pathogenesis==
==Pathogenesis==
Enterovirus 68 belongs to the Human Enterovirus D species (HEV-D), along with EV-70 and EV-94.  Unlike the remaining, EV-69 is acid-labile, which reduces its ability to colonize the gastrointestinal mucosa.  It has therefore been implicated in respiratory infections, and in rare occasions in [[CNS infection]].  This characteristic of EV-68 sets it apart from other enteroviruses, in what deals with its [[pathogenesis]] and infected cells.<ref name="pmid20872722">{{cite journal| author=Smura T, Ylipaasto P, Klemola P, Kaijalainen S, Kyllönen L, Sordi V et al.| title=Cellular tropism of human enterovirus D species serotypes EV-94, EV-70, and EV-68 in vitro: implications for pathogenesis. | journal=J Med Virol | year= 2010 | volume= 82 | issue= 11 | pages= 1940-9 | pmid=20872722 | doi=10.1002/jmv.21894 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20872722  }} </ref>
EV-68 belongs to the Human Enterovirus D species (HEV-D), along with EV-70 and EV-94.  Unlike the remaining enteroviruses in its class, EV-68 is acid-labile, which reduces its ability to colonize the [[gastrointestinal]] mucosa.  It has been implicated in [[respiratory infections]] and in very rare occasions in [[CNS]] disease.  This property of EV-68 sets it apart from other [[enterovirus]]es.<ref name="pmid20872722">{{cite journal| author=Smura T, Ylipaasto P, Klemola P, Kaijalainen S, Kyllönen L, Sordi V et al.| title=Cellular tropism of human enterovirus D species serotypes EV-94, EV-70, and EV-68 in vitro: implications for pathogenesis. | journal=J Med Virol | year= 2010 | volume= 82 | issue= 11 | pages= 1940-9 | pmid=20872722 | doi=10.1002/jmv.21894 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20872722  }} </ref>
 
 
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HEV-D viruses have an unusually wide leukocyte tropism.


However, the role of leukocytes in enterovirus pathogenesis is somewhat obscure.  
=== Tropism ===
* The virus shows optimal growth at lower temperatures, making the [[respiratory tract]] an adequate host for [[viral replication]].  Besides the cells of the [[respiratory]] mucosa, EV-68 also shows [[tropism]] for [[leukocytes]]. The virus binds receptors on the [[lymphocyte]] surface containing sialic-acid in order to access the cytoplasm.<ref name="pmid15919894">{{cite journal| author=Vlasak M, Roivainen M, Reithmayer M, Goesler I, Laine P, Snyers L et al.| title=The minor receptor group of human rhinovirus (HRV) includes HRV23 and HRV25, but the presence of a lysine in the VP1 HI loop is not sufficient for receptor binding. | journal=J Virol | year= 2005 | volume= 79 | issue= 12 | pages= 7389-95 | pmid=15919894 | doi=10.1128/JVI.79.12.7389-7395.2005 | pmc=PMC1143622 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15919894  }} </ref>  Since [[leukocytes]] are capable of migrating to other tissues, by infecting these cells, the virus gains access to secondary sites.<ref name="pmid20872722">{{cite journal| author=Smura T, Ylipaasto P, Klemola P, Kaijalainen S, Kyllönen L, Sordi V et al.| title=Cellular tropism of human enterovirus D species serotypes EV-94, EV-70, and EV-68 in vitro: implications for pathogenesis. | journal=J Med Virol | year= 2010 | volume= 82 | issue= 11 | pages= 1940-9 | pmid=20872722 | doi=10.1002/jmv.21894 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20872722  }} </ref>  [[Viral replication]] inside [[leukocytes]] limits their function, thereby facilitating viral replication and spread.<ref name="pmid17298395">{{cite journal| author=Kramer M, Schulte BM, Toonen LW, de Bruijni MA, Galama JM, Adema GJ et al.| title=Echovirus infection causes rapid loss-of-function and cell death in human dendritic cells. | journal=Cell Microbiol | year= 2007 | volume= 9 | issue= 6 | pages= 1507-18 | pmid=17298395 | doi=10.1111/j.1462-5822.2007.00888.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17298395  }} </ref>


After primary infection of the gastrointestinal tract, the viremia could be started via leukocytes if the virus was able to infect the dendritic cells and/or macrophages of Payer’s patches.  
* EV-68 also replicates inside [[endothelial cells]] that provide the required increase in viral load for the virus to infect [[parenchymal]] tissue, and gain access to secondary sites.<ref name="pmid17298395">{{cite journal| author=Kramer M, Schulte BM, Toonen LW, de Bruijni MA, Galama JM, Adema GJ et al.| title=Echovirus infection causes rapid loss-of-function and cell death in human dendritic cells. | journal=Cell Microbiol | year= 2007 | volume= 9 | issue= 6 | pages= 1507-18 | pmid=17298395 | doi=10.1111/j.1462-5822.2007.00888.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17298395  }} </ref> The virus also promotes the activation of [[endothelial cells]] leading to chemoattraction of further [[leukocytes]].


Leukocytes may also serve as an additional reservoir for virus replication, thereby lengthening the viremic phase and increasing the amount of virus in circulation. Accordingly, a correla- tion between poliovirus neurovirulence and replication efficiency in monocytes has been observed [Freistadt and Eberle, 1996]. Tissue migrating leukocytes may also provide a virus with an access to secondary target tissues. Viral replication in leukocytes is also likely to affect the host immune system [Kramer et al., 2007, 2008]. At least some enteroviruses (e.g., CBV-3, CBV-4, and PV-1) are able to induce proinflammatory cytokine expression in human leukocytes [Henke et al., 1992; Vreugdenhil et al., 2000]. This can cause and/or maintain local inflammation in the secondary target tissues, thus contributing to immune-mediated chronic diseases such as T1D.
* However, EV-68 shows less [[tropism]] for [[endothelial cells]] than EV-70 or EV-94, which makes [[infection]] of secondary sites less common.<ref name="pmid20872722">{{cite journal| author=Smura T, Ylipaasto P, Klemola P, Kaijalainen S, Kyllönen L, Sordi V et al.| title=Cellular tropism of human enterovirus D species serotypes EV-94, EV-70, and EV-68 in vitro: implications for pathogenesis. | journal=J Med Virol | year= 2010 | volume= 82 | issue= 11 | pages= 1940-9 | pmid=20872722 | doi=10.1002/jmv.21894 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20872722  }} </ref>


It seems there are considerable differences between the abilities of different enterovirus serotypes to infect and replicate in leukocytes. Poliovirus is able to infect the monocytic fraction of peripheral blood mononuclear cells [Eberle et al., 1995], monocytic and granulocytic cell lines [Fagreus et al., 1981; Kitamura et al., 1985; Okada et al., 1987; Roivainen and Hovi, 1989; Freistadt and Eberle, 1996; Vuorinen et al., 1999], and monocyte- derived dendritic cells and macrophages [Wahid et al., 2005]. However, both T and B cells seem to be resistant to poliovirus infection [Okada et al., 1987; Vuorinen
=== Transmission ===
Non-polio enteroviruses can be found in an infected person’s:<ref name="CDC">{{cite web | title = Enterovirus D68 | url = http://www.cdc.gov/non-polio-enterovirus/about/EV-D68.html }}</ref> <ref name="pmid24324030">{{cite journal| author=Lu QB, Wo Y, Wang HY, Wei MT, Zhang L, Yang H et al.| title=Detection of enterovirus 68 as one of the commonest types of enterovirus found in patients with acute respiratory tract infection in China. | journal=J Med Microbiol | year= 2014 | volume= 63 | issue= Pt 3 | pages= 408-14 | pmid=24324030 | doi=10.1099/jmm.0.068247-0 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24324030  }} </ref>


-->
* Feces (stool)
* Eye, nose, and mouth secretions (such as saliva, nasal mucus, or sputum)
* Blister fluid
Transmission occurs via the following routes:
* Close contact, such as touching or shaking hands, with an infected person
* Touching objects or surfaces that have the virus on them, then touching eyes, nose, or mouth before washing hands
* Changing diapers of an infected person, then touching the eyes, nose, or mouth before washing hands
* Drinking water that has the virus in it


===Transmission===
* Pregnant women who are infected with a non-polio enterovirus shortly before delivery can pass the virus to their babies.
Viral shedding from the respiratory tract, such as through coughing or sneezing, for 1 to 3 weeks or less. Infected people can shed the virus even if they do not have symptoms.


==Life Cycle==
===Immune Response===
The [[immune response]] towards EV-68 is not fully understood.  Viral clearance is achieved by an adequate [[T-cell|T]] and [[B-cell]] response that contain and eliminate the virus.  [[B lymphocytes]], along with tissue [[macrophages]] contain the [[pathogen]], while [[T lymphocytes]] penetrate the areas of [[infection]], causing tissue damage.  Tissue damage may lead to cell death of the affected areas.<ref name="pmid21631275">{{cite journal| author=Kreuter JD, Barnes A, McCarthy JE, Schwartzman JD, Oberste MS, Rhodes CH et al.| title=A fatal central nervous system enterovirus 68 infection. | journal=Arch Pathol Lab Med | year= 2011 | volume= 135 | issue= 6 | pages= 793-6 | pmid=21631275 | doi=10.1043/2010-0174-CR.1 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21631275  }} </ref>


==References==
==References==

Latest revision as of 15:07, 4 November 2018


Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

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Overview

Unlike other enteroviruses, EV-D68 causes respiratory disease almost exclusively. Its cellular tropism, optimal growth at lower temperatures, and acid-lability are responsible for its infection of leukocytes and cells of the respiratory mucosa. The virus has the ability to replicate inside leukocytes, which allows it to infect the parenchymal tissue, to increase its viral load that will contribute to viral dissemination, and to activate endothelial cells that attract more leukocytes to the infected site. Although viral transmission is not fully understood, the virus can be isolated in respiratory secretions and may be transmitted from person to person via aerosol or direct contact.

Pathogenesis

EV-68 belongs to the Human Enterovirus D species (HEV-D), along with EV-70 and EV-94. Unlike the remaining enteroviruses in its class, EV-68 is acid-labile, which reduces its ability to colonize the gastrointestinal mucosa. It has been implicated in respiratory infections and in very rare occasions in CNS disease. This property of EV-68 sets it apart from other enteroviruses.[1]

Tropism

Transmission

Non-polio enteroviruses can be found in an infected person’s:[4] [5]

  • Feces (stool)
  • Eye, nose, and mouth secretions (such as saliva, nasal mucus, or sputum)
  • Blister fluid

Transmission occurs via the following routes:

  • Close contact, such as touching or shaking hands, with an infected person
  • Touching objects or surfaces that have the virus on them, then touching eyes, nose, or mouth before washing hands
  • Changing diapers of an infected person, then touching the eyes, nose, or mouth before washing hands
  • Drinking water that has the virus in it
  • Pregnant women who are infected with a non-polio enterovirus shortly before delivery can pass the virus to their babies.

Viral shedding from the respiratory tract, such as through coughing or sneezing, for 1 to 3 weeks or less. Infected people can shed the virus even if they do not have symptoms.

Immune Response

The immune response towards EV-68 is not fully understood. Viral clearance is achieved by an adequate T and B-cell response that contain and eliminate the virus. B lymphocytes, along with tissue macrophages contain the pathogen, while T lymphocytes penetrate the areas of infection, causing tissue damage. Tissue damage may lead to cell death of the affected areas.[6]

References

  1. 1.0 1.1 1.2 Smura T, Ylipaasto P, Klemola P, Kaijalainen S, Kyllönen L, Sordi V; et al. (2010). "Cellular tropism of human enterovirus D species serotypes EV-94, EV-70, and EV-68 in vitro: implications for pathogenesis". J Med Virol. 82 (11): 1940–9. doi:10.1002/jmv.21894. PMID 20872722.
  2. Vlasak M, Roivainen M, Reithmayer M, Goesler I, Laine P, Snyers L; et al. (2005). "The minor receptor group of human rhinovirus (HRV) includes HRV23 and HRV25, but the presence of a lysine in the VP1 HI loop is not sufficient for receptor binding". J Virol. 79 (12): 7389–95. doi:10.1128/JVI.79.12.7389-7395.2005. PMC 1143622. PMID 15919894.
  3. 3.0 3.1 Kramer M, Schulte BM, Toonen LW, de Bruijni MA, Galama JM, Adema GJ; et al. (2007). "Echovirus infection causes rapid loss-of-function and cell death in human dendritic cells". Cell Microbiol. 9 (6): 1507–18. doi:10.1111/j.1462-5822.2007.00888.x. PMID 17298395.
  4. "Enterovirus D68".
  5. Lu QB, Wo Y, Wang HY, Wei MT, Zhang L, Yang H; et al. (2014). "Detection of enterovirus 68 as one of the commonest types of enterovirus found in patients with acute respiratory tract infection in China". J Med Microbiol. 63 (Pt 3): 408–14. doi:10.1099/jmm.0.068247-0. PMID 24324030.
  6. Kreuter JD, Barnes A, McCarthy JE, Schwartzman JD, Oberste MS, Rhodes CH; et al. (2011). "A fatal central nervous system enterovirus 68 infection". Arch Pathol Lab Med. 135 (6): 793–6. doi:10.1043/2010-0174-CR.1. PMID 21631275.