Ebola pathophysiology: Difference between revisions

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__NOTOC__
__NOTOC__
{{Ebola}}
{{Ebola}}
{{CMG}} {{MJM}}
{{CMG}}; {{AE}} {{MJM}}; {{GRN}}
==Overview==
==Overview==
Since the Ebola Hemorrhagic Fever is endemic in relatively inaccessible areas, it is difficult to study the [[pathophysiology]] of the [[disease]] in a human model, so almost all the information of the [[pathogenesis]] of the [[disease]] has been obtained from animal models, such as rodents and nonhuman primates. Mainly, the [[virus]] affects the mononuclear phagocyte system, but also [[hepatocytes]], spongiocytes, [[fibroblasts]] and [[endothelial]] cells, and makes severe changes in the [[hematological]], and [[coagulation]] systems.<ref name="pmid8678836">{{cite journal| author=Ryabchikova E, Kolesnikova L, Smolina M, Tkachev V, Pereboeva L, Baranova S et al.| title=Ebola virus infection in guinea pigs: presumable role of granulomatous inflammation in pathogenesis. | journal=Arch Virol | year= 1996 | volume= 141 | issue= 5 | pages= 909-21 | pmid=8678836 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8678836  }} </ref><ref name="pmid9728532">{{cite journal| author=Bray M, Davis K, Geisbert T, Schmaljohn C, Huggins J| title=A mouse model for evaluation of prophylaxis and therapy of Ebola hemorrhagic fever. | journal=J Infect Dis | year= 1998 | volume= 178 | issue= 3 | pages= 651-61 | pmid=9728532 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9728532  }} </ref><ref name="pmid9988186">{{cite journal| author=Connolly BM, Steele KE, Davis KJ, Geisbert TW, Kell WM, Jaax NK et al.| title=Pathogenesis of experimental Ebola virus infection in guinea pigs. | journal=J Infect Dis | year= 1999 | volume= 179 Suppl 1 | issue=  | pages= S203-17 | pmid=9988186 | doi=10.1086/514305 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9988186  }} </ref><ref name="pmid11798241">{{cite journal| author=Bray M, Hatfill S, Hensley L, Huggins JW| title=Haematological, biochemical and coagulation changes in mice, guinea-pigs and monkeys infected with a mouse-adapted variant of Ebola Zaire virus. | journal=J Comp Pathol | year= 2001 | volume= 125 | issue= 4 | pages= 243-53 | pmid=11798241 | doi=10.1053/jcpa.2001.0503 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11798241  }} </ref>  
The Ebola virus infects the [[mononuclear]] phagocyte system, but also other [[cells]] such as [[hepatocytes]], [[spongiocytes]], [[fibroblasts]] and [[endothelial]] cells, inducing tissue [[necrosis]] and disrupting the [[hematological]] and [[coagulation]] systems. The Ebola virus is transmitted by direct contact with [[infected]] patients or animals. The [[natural reservoir]] has not been identified.<ref name="pmid8678836">{{cite journal| author=Ryabchikova E, Kolesnikova L, Smolina M, Tkachev V, Pereboeva L, Baranova S et al.| title=Ebola virus infection in guinea pigs: presumable role of granulomatous inflammation in pathogenesis. | journal=Arch Virol | year= 1996 | volume= 141 | issue= 5 | pages= 909-21 | pmid=8678836 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8678836  }} </ref><ref name="pmid9728532">{{cite journal| author=Bray M, Davis K, Geisbert T, Schmaljohn C, Huggins J| title=A mouse model for evaluation of prophylaxis and therapy of Ebola hemorrhagic fever. | journal=J Infect Dis | year= 1998 | volume= 178 | issue= 3 | pages= 651-61 | pmid=9728532 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9728532  }} </ref><ref name="pmid9988186">{{cite journal| author=Connolly BM, Steele KE, Davis KJ, Geisbert TW, Kell WM, Jaax NK et al.| title=Pathogenesis of experimental Ebola virus infection in guinea pigs. | journal=J Infect Dis | year= 1999 | volume= 179 Suppl 1 | issue=  | pages= S203-17 | pmid=9988186 | doi=10.1086/514305 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9988186  }} </ref><ref name="pmid11798241">{{cite journal| author=Bray M, Hatfill S, Hensley L, Huggins JW| title=Haematological, biochemical and coagulation changes in mice, guinea-pigs and monkeys infected with a mouse-adapted variant of Ebola Zaire virus. | journal=J Comp Pathol | year= 2001 | volume= 125 | issue= 4 | pages= 243-53 | pmid=11798241 | doi=10.1053/jcpa.2001.0503 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11798241  }} </ref>
 
==Pathophysiology==
==Pathophysiology==
=== Structure===
====Size and Shape====
[[Electron microscope|Electron micrographs]] of members of ''Ebola virus'' show them to have the characteristic thread-like structure of a [[Filoviridae|filovirus]].<ref name="Klenk2004">{{cite book |title=Ebola and Marburg Viruses, Molecular and Cellular Biology |last=Klenk |first=Hans-Dieter |authorlink= |coauthors=Feldmann, Heinz |year=2004 |publisher=Horizon Bioscience |location=Wymondham, Norfolk |isbn=0954523237 |pages= }}</ref> EBOV VP30 is around 288 amino acids long.<ref name="Klenk2004" />  The virions are tubular and variable in shape and may appear as a "U", "6", coiled, circular, or branched shape, however, laboratory purification techniques, such as [[centrifugation]], may contribute to the various shapes.<ref name="Klenk2004" /> Virions are generally 80 [[nanometer|nm]] in diameter.<ref name="Klenk2004" /> They are variable in length, and can be up to 1400 nm long. On average, however, the length of a typical [[virion|Ebola virus]] is closer to 1000 nm. In the center of the virion is a structure called nucleocapsid,  which is formed by the helically wound viral genomic RNA complexed with the proteins ''NP, VP35, VP30'' and ''L''. It has a diameter of 40 &ndash; 50 nm and contains a central channel of 20–30 nm in diameter. Virally encoded [[glycoprotein]] (GP) spikes 10 nm long and 10 nm apart are present on the outer [[viral envelope]] of the virion, which is derived from the host cell membrane. Between envelope and nucleocapsid, in the so-called matrix space, the viral proteins VP40 and VP24 are located.
====Genome====
Each virion contains one minor molecule of linear, single-stranded, [[Sense (molecular biology)|negative-sense]] RNA, totaling 18959 to 18961 nucleotides in length. The 3′ terminus is not polyadenylated and the 5′ end is not capped. It was found that 472 nucleotides from the 3' end and 731 nucleotides from the 5' end were sufficient for replication.<ref name="Klenk2004" /> It codes for seven structural proteins and one non-structural protein. The gene order is 3′ - leader - NP - VP35 - VP40 - GP/sGP - VP30 - VP24 - L - trailer - 5′; with the leader and trailer being non-transcribed regions which carry important signals to control transcription, replication and packaging of the viral genomes into new virions. The genomic material by itself is not infectious, because viral proteins, among them the RNA-dependent RNA polymerase, are necessary to transcribe the viral genome into mRNAs, as well as for replication of the viral genome.
===Transmission===
Among humans, the virus is transmitted by direct contact with infected [[body fluid]]s, or to a lesser extent, skin or [[mucous membrane]] contact. The [[incubation period]] can be anywhere from 2 to 21 days, but is generally between 5 and 10 days.
Although [[airborne transmission]] between monkeys has been demonstrated by an accidental outbreak in a laboratory located in Virginia, USA, there is very limited evidence for human-to-human airborne transmission in any reported epidemics. [[Mayinga N'Seka|Nurse Mayinga]] might represent the only possible case. The means by which she contracted the virus remains uncertain.
The infection of human cases with Ebola virus has been documented through the handling of infected chimpanzees, gorillas, and forest antelopes--both dead and alive--as was documented in Côte d'Ivoire, the Republic of Congo and Gabon. The transmission of the Ebola Reston strain through the handling of cynomolgus monkeys has also been reported.
So far, all epidemics of Ebola have occurred in sub-optimal hospital conditions, where practices of basic hygiene and sanitation are often either luxuries or unknown to caretakers and where disposable needles and [[autoclave]]s are unavailable or too expensive. In modern hospitals with disposable needles and knowledge of basic hygiene and [[Universal precautions|barrier nursing]] techniques, Ebola has never spread on such a large scale.
In the early stages, Ebola may not be highly contagious. Contact with someone in early stages may not even transmit the disease. As the illness progresses, bodily fluids from diarrhea, vomiting, and bleeding represent an extreme [[biohazard]]. Due to lack of proper equipment and hygienic practices, large scale epidemics occur mostly in poor, isolated areas without modern hospitals or well-educated medical staff. Many areas where the infectious reservoir exists have just these characteristics. In such environments, all that can be done is to immediately cease all needle-sharing or use without adequate [[Sterilization (microbiology)|sterilization]] procedures, to isolate patients, and to observe strict [[Universal precautions|barrier nursing]] procedures with the use of a medical rated disposable face mask, gloves, goggles, and a gown at all times. This should be strictly enforced for all medical personnel and visitors.
Ebola is unlikely to develop(sometimes) into a [[Pandemic|pandemic]], or world-wide infection, due to its difficulty in spreading by [[airborne transmission]] and the period of time that the virus can use a living and contagious victim to spread compared to other infectious diseases.  In isolated settings such as a quarantined hospital or a remote village, most victims are infected shortly after the first case of infection is present.  In addition, the quick onset of symptoms from the time the disease becomes contagious in an individual makes it easy to identify sick individuals and limits an individual's ability to spread the disease by traveling.  Because bodies of the deceased are still infectious, many doctors implemented measures to properly dispose of dead bodies in spite of some traditional local burial rituals.<ref name="nyt">{{cite news |first=Blaine |last=Harden |authorlink= |coauthors= |title=Dr. Matthew's Passion |url=http://www.nytimes.com/library/magazine/home/20010218mag%2debola.html |work=[[New York Times]] Magazine |publisher= |date=2001-02-18 |accessdate=2008-02-25 }}</ref>
===Life Cycle===
* Virus attaches to host receptors through the GP (glycoprotein) surface [[peplomer]] and is endocytosed into vesicles in the host cell.
* Fusion of virus membrane with the vesicle membrane occurs; nucleocapsid is released into the cytoplasm.
* The encapsidated, negative-sense genomic ssRNA is used as a template for the synthesis ( 3' - 5') of polyadenylated, monocistronic mRNAs.
* Translation of the mRNA into viral proteins occurs using the host cell's machinery.
* Post-translational processing of viral proteins occurs. GP0 (glycoprotein precursor) is cleaved to GP1 and GP2, which are heavily glycosylated. These    two molecules assemble, first into heterodimers, and then into trimers to give the surface peplomers. SGP (secreted glycoprotein) precursor is cleaved to SGP and delta peptide, both of which are released from the cell.
* As viral protein levels rise, a switch occurs from translation to replication. Using the negative-sense genomic RNA as a template, a complementary +ssRNA is synthesized; this is then used as a template for the synthesis of new genomic (-)ssRNA, which is rapidly encapsidated.
* The newly-formed nucleocapsides and envelope proteins associate at the host cell's plasma membrane; budding occurs, and the virions are released
Ebola hemorrhagic fever (Ebola fever) is caused by a virus belonging to the family called [[Filoviridae]]. Scientists have identified four types of the Ebola virus. Three have been reported to cause [[disease]] in humans: Ebola-Zaire virus, Ebola-Sudan virus, and Ebola-Ivory Coast virus. The human disease has so far been limited to parts of Africa.
A very small number of people in the United States who were infected with the fourth type of the virus, known as Ebola Reston, did not develop any signs of disease.
The disease can be passed to humans from infected animals and animal materials. Ebola can also be spread between humans by close contact with infected bodily fluids or through infected [[needles]] in the hospital.
===Tropism===
===Tropism===
* Ebola [[virus]] infects mainly the cells of the mononuclear phagocyte system, but also [[fibroblasts]], [[hepatocytes]], spongiocytes, adrenal cortical cells and [[endothelial cells]].<ref name="pmid8678836">{{cite journal| author=Ryabchikova E, Kolesnikova L, Smolina M, Tkachev V, Pereboeva L, Baranova S et al.| title=Ebola virus infection in guinea pigs: presumable role of granulomatous inflammation in pathogenesis. | journal=Arch Virol | year= 1996 | volume= 141 | issue= 5 | pages= 909-21 | pmid=8678836 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8678836  }} </ref>  
* Ebola [[virus]] infects mainly the cells of the mononuclear phagocyte system, but also [[fibroblasts]], [[hepatocytes]], spongiocytes, adrenal cortical cells and [[endothelial cells]].<ref name="pmid8678836">{{cite journal| author=Ryabchikova E, Kolesnikova L, Smolina M, Tkachev V, Pereboeva L, Baranova S et al.| title=Ebola virus infection in guinea pigs: presumable role of granulomatous inflammation in pathogenesis. | journal=Arch Virol | year= 1996 | volume= 141 | issue= 5 | pages= 909-21 | pmid=8678836 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8678836  }} </ref>  
* The [[infection]] of the mononuclear phagocyte system cells plays a key role in the pathogenesis and spread of the disease as they carry the virus from  of the initial [[infection]] site, through the [[lymphatic system]] and [[blood]], to the regional [[lymph nodes]],[[spleen]] and [[liver]].<ref name="pmid14633608">{{cite journal| author=Geisbert TW, Hensley LE, Larsen T, Young HA, Reed DS, Geisbert JB et al.| title=Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques: evidence that dendritic cells are early and sustained targets of infection. | journal=Am J Pathol | year= 2003 | volume= 163 | issue= 6 | pages= 2347-70 | pmid=14633608 | doi=10.1016/S0002-9440(10)63591-2 | pmc=PMC1892369 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14633608  }} </ref>  
* The [[infection]] of the mononuclear phagocyte system cells plays a key role in the pathogenesis and spread of the disease as they carry the virus from  of the initial [[infection]] site, through the [[lymphatic system]] and [[blood]], to the regional [[lymph nodes]],[[spleen]] and [[liver]].<ref name="pmid14633608">{{cite journal| author=Geisbert TW, Hensley LE, Larsen T, Young HA, Reed DS, Geisbert JB et al.| title=Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques: evidence that dendritic cells are early and sustained targets of infection. | journal=Am J Pathol | year= 2003 | volume= 163 | issue= 6 | pages= 2347-70 | pmid=14633608 | doi=10.1016/S0002-9440(10)63591-2 | pmc=PMC1892369 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14633608  }} </ref>  
* The next table summarizes the [[pathogenesis]] of the [[disease]] according to the [[virus]] [[tropism]].
* The next table summarizes the [[pathogenesis]] of the [[disease]] according to the [[virus]] [[tropism]].
{| style="font-size: 85%;"
{| style="border: 2px solid #DCDCDC; font-size: 90%; width: 60%;" align=center
|+ '''Pathogenesis'''
|-
! style="width: 80px; background: #4479BA; text-align: center;"|{{fontcolor|#FFF|Organ/Tissue}}
! style="width: 80px; background: #4479BA; text-align: center;"|{{fontcolor|#FFF|Organ/Tissue}}
! style="width: 720px; background: #4479BA; text-align: center;"| {{fontcolor|#FFF|Effect}}
! style="width: 720px; background: #4479BA; text-align: center;"| {{fontcolor|#FFF|Effect}}
|-
|-
| style="background: #F5F5F5; padding: 5px; text-align: center;"| '''[[Endothelial cells]]'''
| style="background: #F5F5F5; padding: 5px; text-align: center;"| '''[[Endothelial cells]]'''
| style="background: #DCDCDC; padding: 5px;"| There is no clear evidence of endovascular damage<ref name="pmid14633609">{{cite journal| author=Geisbert TW, Young HA, Jahrling PB, Davis KJ, Larsen T, Kagan E et al.| title=Pathogenesis of Ebola hemorrhagic fever in primate models: evidence that hemorrhage is not a direct effect of virus-induced cytolysis of endothelial cells. | journal=Am J Pathol | year= 2003 | volume= 163 | issue= 6 | pages= 2371-82 | pmid=14633609 | doi=10.1016/S0002-9440(10)63592-4 | pmc=PMC1892396 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14633609  }} </ref>
| style="background: #DCDCDC; padding: 5px;"| [[Glycoprotein|Glycoprotein (GP)]] on the [[virion]] [[viral envelope|envelope]] allows introduction of its content into the [[endothelial cell]]s, which induces a [[cytopathic effect]] and damage to the [[endothelial|endothelial]] barrier function that, together with effects of [[TNF-alpha|TNF-α]] released by infected [[mononuclear cell]]s, leads to the loss of vascular integrity and increased leakage.
|-
|-
| style="background: #F5F5F5; padding: 5px; text-align: center;"| '''[[Liver]]'''
| style="background: #F5F5F5; padding: 5px; text-align: center;"| '''[[Liver]]'''
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|-
|-
| style="background: #F5F5F5; padding: 5px; text-align: center;"| '''[[Lymphatic system]]'''
| style="background: #F5F5F5; padding: 5px; text-align: center;"| '''[[Lymphatic system]]'''
| style="background: #DCDCDC; padding: 5px;"| [[Necrosis of the [[spleen]], [[lymph nodes]] and [[thymus]]; [[Apoptosis]] of [[lymphocytes]] leading to [[lymphopenia]].<ref name="pmid14633608">{{cite journal| author=Geisbert TW, Hensley LE, Larsen T, Young HA, Reed DS, Geisbert JB et al.| title=Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques: evidence that dendritic cells are early and sustained targets of infection. | journal=Am J Pathol | year= 2003 | volume= 163 | issue= 6 | pages= 2347-70 | pmid=14633608 | doi=10.1016/S0002-9440(10)63591-2 | pmc=PMC1892369 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14633608  }} </ref><ref name="pmid9893381">{{cite journal| author=Zaki SR, Goldsmith CS| title=Pathologic features of filovirus infections in humans. | journal=Curr Top Microbiol Immunol | year= 1999 | volume= 235 | issue=  | pages= 97-116 | pmid=9893381 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9893381  }} </ref>  
| style="background: #DCDCDC; padding: 5px;"| [[Necrosis]] of the [[spleen]], [[lymph nodes]] and [[thymus]]; [[Apoptosis]] of [[lymphocytes]] leading to [[lymphopenia]].<ref name="pmid14633608">{{cite journal| author=Geisbert TW, Hensley LE, Larsen T, Young HA, Reed DS, Geisbert JB et al.| title=Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques: evidence that dendritic cells are early and sustained targets of infection. | journal=Am J Pathol | year= 2003 | volume= 163 | issue= 6 | pages= 2347-70 | pmid=14633608 | doi=10.1016/S0002-9440(10)63591-2 | pmc=PMC1892369 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14633608  }} </ref><ref name="pmid9893381">{{cite journal| author=Zaki SR, Goldsmith CS| title=Pathologic features of filovirus infections in humans. | journal=Curr Top Microbiol Immunol | year= 1999 | volume= 235 | issue=  | pages= 97-116 | pmid=9893381 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9893381  }} </ref>  
|}
|}
====Viral Reservoirs====
<br>
Despite numerous studies, the wildlife reservoir of ''Ebolavirus'' has not been identified. Between 1976 and 1998, from 30,000 mammals, birds, reptiles, amphibians, and arthropods sampled from outbreak regions, no ''Ebolavirus'' was detected <ref name="Pourrut2005">{{cite journal |last=Pourrut |first=Xavier|authorlink= |coauthors=''et al.'' |year=2005 |month= |title=The natural history of Ebola virus in Africa |journal=Microbes and Infection |volume=7 |issue=7-8|pages=1005-1014 |doi=10.1016/j.micinf.2005.04.006 |url= |accessdate= |quote= }}</ref> apart from some genetic material found in six rodents (''Mus setulosus''and  ''Praomys'' species) and a [[shrew]] (''Sylvisorex ollula'') collected from the [[Central African Republic]] in 1998.<ref name="Morvan1999">{{cite journal|last=Morvan |first=Jaques |authorlink= |coauthors=''et al.'' |year=1999 |month= |title=Identification of Ebola virus sequences present as RNA or DNA in organs of terrestrial small mammals of the Central African Republic |journal=Microbes and Infection |volume=1 |issue=14 |pages=1193-1201|doi=10.1016/S1286-4579(99)00242-7 |url= |accessdate= |quote= }}</ref> ''Ebolavirus'' was detected in the carcasses of [[gorilla]]s, chimpanzees and [[duiker]]s during outbreaks in 2001 and 2003 (the carcasses were the source of the initial human infections) but the high mortality from infection in these species precludes them from acting as reservoirs.<ref name="Pourrut2005" />
[[Plant]]s, [[arthropods]], and birds have also been considered as reservoirs, however bats are considered the most likely candidate<ref>{{cite news |first=|last= |authorlink= |coauthors= |title=Fruit bats may carry Ebola virus |url=http://news.bbc.co.uk/2/hi/health/4484494.stm |work=BBC News |publisher=|date=2005-12-11 |accessdate=2008-02-25 }}</ref>. Bats were known to reside in the cotton factory in which the index cases for the 1976 and 1979 outbreaks were employed and have also been implicated in Marburg infections in 1975 and 1980.<ref name="Pourrut2005" /> Of 24 plant species and 19 vertebrate species experimentally inoculated with  ''Ebolavirus'', only bats became infected.<ref>{{cite journal |last=Swanepoel |first=R |authorlink= |coauthors=''et al.''|year=1996 |month= |title=Experimental inoculation of plants and animals with Ebola virus |journal=Emerging Infectious Diseases |volume=2 |issue= |pages=321-325|doi= |url=http://www.cdc.gov/ncidod/eid/vol2no4/swanepo2.htm |accessdate= |quote= }}</ref> The absence of clinical signs in these bats is characteristic of a reservoir species. In 2002-03, a survey of 1,030 animals from [[Gabon]] and the [[Republic of the Congo]] including 679 bats found ''Ebolavirus'' RNA in 13[[fruit bats]] (''Hyspignathus monstrosus, Epomops franquetti and Myonycteris torquata'').<ref>{{cite journal |last=Leroy |first=Eric |authorlink=|coauthors=''et al.'' |year=2005 |month= |title=Fruit bats as reservoirs of Ebola virus |journal=Nature |volume=438 |issue= |pages=575-576 |doi=10.1038/438575a|url= |accessdate= |quote= }}</ref> Bats are also known to be the reservoirs for a number of related viruses including [[Nipah virus]], [[Hendra virus]] and[[lyssavirus]]es.


====Bats====
===Immune response===
Even though [[rabies]] and [[histoplasmosis]] can be found all over the world, some diseases associated with bats are found exclusively in certain regions of the world. Notably, research suggests that bats might be the source of several [[hemorrhagic]] fevers, which affect multiple [[organ systems]] in the body and often lead to life-threatening diseases.
* The virus activates the [[macrophages]] synthesis of [[interleukins]] (IL), which leads the [[Th1]]/[[Th2]] balance towards a more pronounced [[Th1]]-[[cell]] mediated response.<ref name="pmid24284388">{{cite journal| author=Qiu X, Audet J, Wong G, Fernando L, Bello A, Pillet S et al.| title=Sustained protection against Ebola virus infection following treatment of infected nonhuman primates with ZMAb. | journal=Sci Rep | year= 2013 | volume= 3 | issue= | pages= 3365 | pmid=24284388 | doi=10.1038/srep03365 | pmc=PMC3842534 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24284388  }} </ref>
* Some inflammatory mediators produced during the [[ebola virus]] infection include: [[interferon]] (IFN)-alpha, [[IFN]]-beta, [[IL-2]], [[IL-6]], [[IL-8]], [[IL-10]], [[interferon]]-inducible protein 10; monocyte chemoattractant protein 1; regulated upon activation normal T cell expressed and secreted ([[RANTES]]); [[TNF-alpha]]; and [[reactive oxygen]] and [[nitrogen species]].<ref name="pmid9988183">{{cite journal| author=Villinger F, Rollin PE, Brar SS, Chikkala NF, Winter J, Sundstrom JB et al.| title=Markedly elevated levels of interferon (IFN)-gamma, IFN-alpha, interleukin (IL)-2, IL-10, and tumor necrosis factor-alpha associated with fatal Ebola virus infection. | journal=J Infect Dis | year= 1999 | volume= 179 Suppl 1 | issue=  | pages= S188-91 | pmid=9988183 | doi=10.1086/514283 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9988183  }} </ref><ref name="pmid11803049">{{cite journal| author=Hensley LE, Young HA, Jahrling PB, Geisbert TW| title=Proinflammatory response during Ebola virus infection of primate models: possible involvement of the tumor necrosis factor receptor superfamily. | journal=Immunol Lett | year= 2002 | volume= 80 | issue= 3 | pages= 169-79 | pmid=11803049 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11803049  }} </ref><ref name="pmid11982604">{{cite journal| author=Baize S, Leroy EM, Georges AJ, Georges-Courbot MC, Capron M, Bedjabaga I et al.| title=Inflammatory responses in Ebola virus-infected patients. | journal=Clin Exp Immunol | year= 2002 | volume= 128 | issue= 1 | pages= 163-8 | pmid=11982604 | doi= | pmc=PMC1906357 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11982604  }} </ref>
* Some viral proteins, such as [[VP35]] and [[VP24]], block the type I [[interferon]] response, which plays a key role of the [[pathogenesis]] of the [[disease]].<ref name="pmid12829834">{{cite journal| author=Basler CF, Mikulasova A, Martinez-Sobrido L, Paragas J, Mühlberger E, Bray M et al.| title=The Ebola virus VP35 protein inhibits activation of interferon regulatory factor 3. | journal=J Virol | year= 2003 | volume= 77 | issue= 14 | pages= 7945-56 | pmid=12829834 | doi= | pmc=PMC161945 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12829834  }} </ref>
* The [[reactive oxygen]] and [[nitrogen species]] contribute to the [[cell]] and [[tissue]] damage, and therefore [[vascular]] and [[organ]] damage.<ref name="pmid15367603">{{cite journal| author=Sanchez A, Lukwiya M, Bausch D, Mahanty S, Sanchez AJ, Wagoner KD et al.| title=Analysis of human peripheral blood samples from fatal and nonfatal cases of Ebola (Sudan) hemorrhagic fever: cellular responses, virus load, and nitric oxide levels. | journal=J Virol | year= 2004 | volume= 78 | issue= 19 | pages= 10370-7 | pmid=15367603 | doi=10.1128/JVI.78.19.10370-10377.2004 | pmc=PMC516433 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15367603  }} </ref>
* The [[nitric oxide]] is known to be an important [[vasodilator]], therefore it plays and important role in the development of hypotension and shock.


One of these diseases is Marburg hemorrhagic fever, which is found exclusively in Africa. Past outbreaks have shown that Marburg Hemorrhagic Fever kills up to 90% of those infected.
===Coagulation system===
* Ebola infection is associated with hemorrhage in 50% of patients.
* Alterations of the [[coagulation]] system are induced by the [[ebola virus]], and are thought to be mediated by the production of [[tissue factor]]:<ref name="pmid14639531">{{cite journal| author=Geisbert TW, Young HA, Jahrling PB, Davis KJ, Kagan E, Hensley LE| title=Mechanisms underlying coagulation abnormalities in ebola hemorrhagic fever: overexpression of tissue factor in primate monocytes/macrophages is a key event. | journal=J Infect Dis | year= 2003 | volume= 188 | issue= 11 | pages= 1618-29 | pmid=14639531 | doi=10.1086/379724 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14639531  }} </ref>
:*Consumption of [[clotting factors]]
:*Increased concentrations of [[fibrin]] degradation products
:*[[Disseminated intravascular coagulopathy]]
===Understanding the immune response to the disease===
In one case study performed on an individual who had severe [[Ebola|Ebola virus infection]] in Sierra Leone to further understand the [[immune response]] during all the stages of the disease.<ref name="urlLongitudinal peripheral blood transcriptional analysis of a patient with severe Ebola virus disease | Science Translational Medicine">{{cite web |url=http://stm.sciencemag.org/content/9/385/eaai9321 |title=Longitudinal peripheral blood transcriptional analysis of a patient with severe Ebola virus disease &#124; Science Translational Medicine |format= |work= |accessdate=}}</ref>
The individual was provided with supportive care only without any other experimental therapies.
Daily global [[gene expression]] in peripheral [[white blood cells]] was recorded and correlated with many clinical and laboratory aspects during the course of disease ([[Viral load]], [[Multiple organ ACdysfunction syndrome|multiple organ dysfunction]], [[Coagulopathy|coagulopathy,]] etc) till complete recovery after 33 days.


While the natural host had for years been unknown, new research suggests that fruit bats are a natural source of this virus, and the virus has been isolated repetitively from fruit bats in Uganda.
The study enabled us to identify the host responses (the genomic shift between increased [[Gene expression|expression of genes]] involved in [[inflammation]] and [[Cell death|cell destruction]] to increased [[Gene expression|expression of genes]] promoting cell repair) that correlate with the viral clearance and recovery.


The same may be true for Ebola [[hemorraghic fever]]. The virus that causes this disease is often referred to as the "cousin" of [[Marburg virus]], since they are the only distinct viruses that belong to a group of viruses known as [[filovirus]]es. Like Marburg, Ebola is highly fatal and is found mostly in Africa. Recent studies indicate that, as with Marburg, bats are likely to be a natural source of this virus, although no Ebola virus has been isolated from bats.
The study revealed that many changes in [[gene expression]] precede the change in the clinical status of the patient emphasizing the role of viral clearance in the cure of systemic illness.
 
===Microscopic Pathology===
These are that display some of the key features of the ebola virus.
<gallery>
Image:Ebola 1.jpg|Created by CDC microbiologist Frederick A. Murphy, this transmission electron micrograph (TEM) revealed some of the ultrastructural morphology displayed by an Ebola virus virion.
Image:Ebola 2.jpg|This 1995 transmission electron micrograph (TEM) revealed some of the ultrastructural morphologic changes in this tissue sample isolate brought on due to an Ebola hemorrhagic fever infection, including the presence of numbers of Ebola virions.
Image:Ebola 3.jpg|Created by CDC microbiologist Charles Humphrey, this scanning electron micrograph (SEM) revealed some of the ultrastructural morphologic features displayed by the Ebola virus discovered from the Ivory Coast of Africa.
Image:Ebola 4.jpg|Created by CDC microbiologist Charles Humphrey, this negatively-stained transmission electron micrograph (TEM) revealed some of the ultrastructural curvilinear morphologic features displayed by the Ebola virus discovered from the Ivory Coast of Africa.
</gallery>


==References==
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==References==
==References==
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{{Reflist|2}}
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Latest revision as of 17:38, 18 September 2017

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Michael Maddaleni, B.S.; Guillermo Rodriguez Nava, M.D. [2]

Overview

The Ebola virus infects the mononuclear phagocyte system, but also other cells such as hepatocytes, spongiocytes, fibroblasts and endothelial cells, inducing tissue necrosis and disrupting the hematological and coagulation systems. The Ebola virus is transmitted by direct contact with infected patients or animals. The natural reservoir has not been identified.[1][2][3][4]

Pathophysiology

Tropism

Pathogenesis
Organ/Tissue Effect
Endothelial cells Glycoprotein (GP) on the virion envelope allows introduction of its content into the endothelial cells, which induces a cytopathic effect and damage to the endothelial barrier function that, together with effects of TNF-α released by infected mononuclear cells, leads to the loss of vascular integrity and increased leakage.
Liver Causes hepatocellular necrosis which could impair the synthesis of proteins of the coagulation system[5]
Adrenal cortex Affects the synthesis of enzymes responsible for the synthesis of steroids, leading to hypotension, and fluid and electrolytes disturbances.[5]
Lymphatic system Necrosis of the spleen, lymph nodes and thymus; Apoptosis of lymphocytes leading to lymphopenia.[5][6]


Immune response

Coagulation system

  • Ebola infection is associated with hemorrhage in 50% of patients.
  • Alterations of the coagulation system are induced by the ebola virus, and are thought to be mediated by the production of tissue factor:[13]

Understanding the immune response to the disease

In one case study performed on an individual who had severe Ebola virus infection in Sierra Leone to further understand the immune response during all the stages of the disease.[14] The individual was provided with supportive care only without any other experimental therapies. Daily global gene expression in peripheral white blood cells was recorded and correlated with many clinical and laboratory aspects during the course of disease (Viral load, multiple organ dysfunction, coagulopathy, etc) till complete recovery after 33 days.

The study enabled us to identify the host responses (the genomic shift between increased expression of genes involved in inflammation and cell destruction to increased expression of genes promoting cell repair) that correlate with the viral clearance and recovery.

The study revealed that many changes in gene expression precede the change in the clinical status of the patient emphasizing the role of viral clearance in the cure of systemic illness.

References

  1. ↑ 1.0 1.1 Ryabchikova E, Kolesnikova L, Smolina M, Tkachev V, Pereboeva L, Baranova S; et al. (1996). "Ebola virus infection in guinea pigs: presumable role of granulomatous inflammation in pathogenesis". Arch Virol. 141 (5): 909–21. PMID 8678836.
  2. ↑ Bray M, Davis K, Geisbert T, Schmaljohn C, Huggins J (1998). "A mouse model for evaluation of prophylaxis and therapy of Ebola hemorrhagic fever". J Infect Dis. 178 (3): 651–61. PMID 9728532.
  3. ↑ Connolly BM, Steele KE, Davis KJ, Geisbert TW, Kell WM, Jaax NK; et al. (1999). "Pathogenesis of experimental Ebola virus infection in guinea pigs". J Infect Dis. 179 Suppl 1: S203–17. doi:10.1086/514305. PMID 9988186.
  4. ↑ Bray M, Hatfill S, Hensley L, Huggins JW (2001). "Haematological, biochemical and coagulation changes in mice, guinea-pigs and monkeys infected with a mouse-adapted variant of Ebola Zaire virus". J Comp Pathol. 125 (4): 243–53. doi:10.1053/jcpa.2001.0503. PMID 11798241.
  5. ↑ 5.0 5.1 5.2 5.3 Geisbert TW, Hensley LE, Larsen T, Young HA, Reed DS, Geisbert JB; et al. (2003). "Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques: evidence that dendritic cells are early and sustained targets of infection". Am J Pathol. 163 (6): 2347–70. doi:10.1016/S0002-9440(10)63591-2. PMC 1892369. PMID 14633608.
  6. ↑ Zaki SR, Goldsmith CS (1999). "Pathologic features of filovirus infections in humans". Curr Top Microbiol Immunol. 235: 97–116. PMID 9893381.
  7. ↑ Qiu X, Audet J, Wong G, Fernando L, Bello A, Pillet S; et al. (2013). "Sustained protection against Ebola virus infection following treatment of infected nonhuman primates with ZMAb". Sci Rep. 3: 3365. doi:10.1038/srep03365. PMC 3842534. PMID 24284388.
  8. ↑ Villinger F, Rollin PE, Brar SS, Chikkala NF, Winter J, Sundstrom JB; et al. (1999). "Markedly elevated levels of interferon (IFN)-gamma, IFN-alpha, interleukin (IL)-2, IL-10, and tumor necrosis factor-alpha associated with fatal Ebola virus infection". J Infect Dis. 179 Suppl 1: S188–91. doi:10.1086/514283. PMID 9988183.
  9. ↑ Hensley LE, Young HA, Jahrling PB, Geisbert TW (2002). "Proinflammatory response during Ebola virus infection of primate models: possible involvement of the tumor necrosis factor receptor superfamily". Immunol Lett. 80 (3): 169–79. PMID 11803049.
  10. ↑ Baize S, Leroy EM, Georges AJ, Georges-Courbot MC, Capron M, Bedjabaga I; et al. (2002). "Inflammatory responses in Ebola virus-infected patients". Clin Exp Immunol. 128 (1): 163–8. PMC 1906357. PMID 11982604.
  11. ↑ Basler CF, Mikulasova A, Martinez-Sobrido L, Paragas J, Mühlberger E, Bray M; et al. (2003). "The Ebola virus VP35 protein inhibits activation of interferon regulatory factor 3". J Virol. 77 (14): 7945–56. PMC 161945. PMID 12829834.
  12. ↑ Sanchez A, Lukwiya M, Bausch D, Mahanty S, Sanchez AJ, Wagoner KD; et al. (2004). "Analysis of human peripheral blood samples from fatal and nonfatal cases of Ebola (Sudan) hemorrhagic fever: cellular responses, virus load, and nitric oxide levels". J Virol. 78 (19): 10370–7. doi:10.1128/JVI.78.19.10370-10377.2004. PMC 516433. PMID 15367603.
  13. ↑ Geisbert TW, Young HA, Jahrling PB, Davis KJ, Kagan E, Hensley LE (2003). "Mechanisms underlying coagulation abnormalities in ebola hemorrhagic fever: overexpression of tissue factor in primate monocytes/macrophages is a key event". J Infect Dis. 188 (11): 1618–29. doi:10.1086/379724. PMID 14639531.
  14. ↑ "Longitudinal peripheral blood transcriptional analysis of a patient with severe Ebola virus disease | Science Translational Medicine".

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