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| __NOTOC__
| | #redirect [[Lassa virus]] |
| <div style="float: right;">
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| {{Taxobox
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| | name = ''Lassa Virus (LASV)''
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| | image = Lassa virus.JPG
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| | image_width = 200 px
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| | image_caption = [[Transmission electron microscopy|TEM]] [[micrograph]] of ''Lassa virus'' [[Virion#Structure|virions]].
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| | virus_group = v
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| | ordo = ''Unassigned''
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| | familia = ''[[Arenavirus|Arenaviridae]]''
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| | genus = ''[[Arenavirus]]''
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| | species = '''''Lassa virus'''''
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| }}</div>
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| {{Lassa fever}}
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| {{CMG}}; {{AE}} {{Ammu}}
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| ==Overview==
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| Lassa fever is caused by the ''[[Lassa virus]]'', a member of the [[Arenaviridae]] family. It is an [[enveloped virus|enveloped]], [[single-stranded]], bisegmented [[RNA]] virus. [[Viral replication|Replication]] for [[Lassa virus]] is very rapid, while also demonstrating temporal control in [[replication]].
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| ==Virus==
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| * Lassa virus belongs to Arenaviridae <ref name=NCCN>{{cite web | title = The Centers for Disease Control and Prevention | url =http://www.cdc.gov/vhf/virus-families/arenaviridae.html }}</ref>.
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| ===Taxonomy===
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| * [[Virus]]; [[ssRNA]] virus; [[ssRNA]] negative-strand virus; [[Arenaviridae]]; [[Arenavirus]]; Old world [[arenavirus]].
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| ===Arenaviridae===
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| * The Arenaviridae are a family of [[viruses]] whose members are generally associated with rodent-transmitted diseases in [[humans]]. Each [[virus]] usually is associated with a particular [[rodent]] host species in which it is maintained. [[Arenavirus]] infections are relatively common in humans in some areas of the world and can cause severe [[illnesses]].
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| * The virus particles are spherical and have an average diameter of 110-130 nanometers. All are enveloped in a [[lipid]] (fat) membrane. Viewed in cross-section, they show grainy particles that are [[ribosomes]] acquired from their [[host]] cells. It is this characteristic that gave them their name, derived from the Latin "arena", which means "sandy". Their genome, or genetic material, is composed of [[RNA]] only, and while their replication strategy is not completely understood, we know that new viral particles, called [[virions]], are created by budding from the surface of their [[hosts]]' cells.
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| [[File:Lassa fever micro.png|left|thumb|500px|Outbreak Distribution Map Lassa Fever CDC.png<SMALL><SMALL>''[http://www.cdc.gov/vhf/virus-families/arenaviridae.html]''<ref name="CDC">{{Cite web | title = Center for Disease Control and Prevention (CDC) | url = http://www.cdc.gov}}</ref></SMALL></SMALL>]]
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| ===History of Arenaviridae===
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| * The first [[Arenavirus]], [[Lymphocytic choriomeningitis virus]] (LCMV), was isolated in 1933 during a study of an epidemic of [[St. Louis encephalitis]]. Although not the cause of the outbreak, [[LCMV]] was found to be a cause of aseptic (nonbacterial) [[meningitis]]. By the 1960s, several similar [[viruses]] had been discovered and they were classified into the new family [[Arenaviridae]]. Since [[Tacaribe]] virus was found in 1956, new [[Arenavirus]] have been discovered on the average of every one to three years. A number of [[Arenavirus]] have been isolated in rodents only, but few cause [[hemorrhagic disease]]. [[Junin virus]], isolated in 1958, was the first of these to be recognized. This virus causes Argentine [[hemorrhagic fever]] in a limited agrigultural area of the pampas in Argentina. Several years later, in 1963, in the remote savannas of the Beni province of Bolivia, Machupo virus was isolated. The next member of the virus family to be associated with an outbreak of human illness was Lassa virus in Nigeria in 1969. The most recent additions to these human pathogenic viruses were Guanarito detected in Venezuela in 1989, Sabia in Brazil in 1993, Chapare in Bolivia in 2004, and Lujo in South Africa in 2008.
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| ===Structure and genome===
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| * Lassa viruses are enveloped, [[single-stranded]], bisegmented, ambisense [[RNA viruses]]. Their genome<ref name="pmid10615121">{{cite journal| author=| title=Genome:The autobiography of a species in 23 chapters | journal=Nat Genet | year= 2000 | volume= 24 | issue= 1 | pages= 21 | pmid=10615121 | doi=10.1038/71638 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10615121 }} </ref> is contained in two RNA segments that code for two proteins each, one in each sense, for a total of four viral proteins.<ref name="pmid17143722">{{cite journal| author=Moshkoff DA, Salvato MS, Lukashevich IS| title=Molecular characterization of a reassortant virus derived from Lassa and Mopeia viruses. | journal=Virus Genes | year= 2007 | volume= 34 | issue= 2 | pages= 169-76 | pmid=17143722 | doi=10.1007/s11262-006-0050-3 | pmc=PMC1892610 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17143722 }} </ref> The large segment encodes a small zinc-binding protein (Z) that regulates transcription and replication,<ref name="pmid11533204">{{cite journal| author=Cornu TI, de la Torre JC| title=RING finger Z protein of lymphocytic choriomeningitis virus (LCMV) inhibits transcription and RNA replication of an LCMV S-segment minigenome. | journal=J Virol | year= 2001 | volume= 75 | issue= 19 | pages= 9415-26 | pmid=11533204 | doi=10.1128/JVI.75.19.9415-9426.2001 | pmc=PMC114509 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11533204 }} </ref><ref name="pmid9281522">{{cite journal| author=Djavani M, Lukashevich IS, Sanchez A, Nichol ST, Salvato MS| title=Completion of the Lassa fever virus sequence and identification of a RING finger open reading frame at the L RNA 5' End. | journal=Virology | year= 1997 | volume= 235 | issue= 2 | pages= 414-8 | pmid=9281522 | doi=10.1006/viro.1997.8722 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9281522 }} </ref> and the [[RNA polymerase]] (L). The small segment encodes the [[nucleoprotein]] (NP) and the surface [[glycoprotein precursor]] (GP, also known as the viral spike), which is proteolytically cleaved into the envelope [[glycoproteins]] GP1 and GP2 that bind to the alpha-dystroglycan receptor and mediate [[host]] cell entry.<ref name="pmid11119613">{{cite journal| author=Smelt SC, Borrow P, Kunz S, Cao W, Tishon A, Lewicki H et al.| title=Differences in affinity of binding of lymphocytic choriomeningitis virus strains to the cellular receptor alpha-dystroglycan correlate with viral tropism and disease kinetics. | journal=J Virol | year= 2001 | volume= 75 | issue= 1 | pages= 448-57 | pmid=11119613 | doi=10.1128/JVI.75.1.448-457.2001 | pmc=PMC113937 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11119613 }} </ref>
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| * Lassa fever causes hemorrhagic [[fever]] frequently shown by [[immunosuppression]]. Replication for Lassa virus is very rapid, while also demonstrating temporal control in replication.<ref name="pmid16629503">{{cite journal| author=Lashley FR| title=Emerging infectious diseases at the beginning of the 21st century. | journal=Online J Issues Nurs | year= 2006 | volume= 11 | issue= 1 | pages= 2 | pmid=16629503 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16629503 }} </ref> The first replication step is transcription of mRNA copies of the negative- or minus-sense genome. This ensures an adequate supply of viral proteins for subsequent steps of replication, as the NP and L proteins are translated from the [[mRNA]]. The positive- or plus-sense [[genome]], then makes viral complementary [[RNA]] (vcRNA)copies of itself. The [[RNA]] copies are a template for producing negative-sense progeny, but [[mRNA]] is also synthesized from it. The [[mRNA]] synthesized from [[vcRNA]] are translated to make the GP and Z proteins. This temporal control allows the spike proteins to be produced last, and therefore, delay recognition by the host immune system.
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| * [[Nucleotide]] studies of the genome have shown that Lassa has four lineages: three found in Nigeria and the fourth in Guinea, Liberia, and Sierra Leone. The Nigerian strains seem likely to have been ancestral to the others but additional work is required to confirm this.<ref name="pmid10888638">{{cite journal| author=Bowen MD, Rollin PE, Ksiazek TG, Hustad HL, Bausch DG, Demby AH et al.| title=Genetic diversity among Lassa virus strains. | journal=J Virol | year= 2000 | volume= 74 | issue= 15 | pages= 6992-7004 | pmid=10888638 | doi= | pmc=PMC112216 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10888638 }} </ref> One book that explains about this disease is The Lassa Ward by Ross I. Donaldson. He describes what it is like being a doctor and taking care of the Sierra Leone people who have contracted the virus.
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| [[File:Lassa virus micro.png|left|thumb|500px|Lassa Fever wikipedia.png<SMALL><SMALL>''[http://phil.cdc.gov/phil/details.asp]''<ref name="CDC">{{Cite web | title =wikipedia | url = http://phil.cdc.gov/phil/details.asp}}</ref></SMALL></SMALL>]]
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| ===Receptors===
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| * The Lassa virus gains entry into the [[host]] cell by means of the [[cell-surface receptor]] the alpha-[[dystroglycan]] (alpha-DG),<ref name="pmid10888638">{{cite journal| author=Bowen MD, Rollin PE, Ksiazek TG, Hustad HL, Bausch DG, Demby AH et al.| title=Genetic diversity among Lassa virus strains. | journal=J Virol | year= 2000 | volume= 74 | issue= 15 | pages= 6992-7004 | pmid=10888638 | doi= | pmc=PMC112216 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10888638 }} </ref> a versatile [[receptor]] for [[protein]]s of the [[extracellular matrix]]. It shares this receptor with the prototypic Old World [[arenavirus]] [[lymphocytic choriomeningitis]] virus. [[Receptor]] recognition depends on a specific sugar modification of alpha-dystroglycan by a group of glycosyltransferases known as the LARGE proteins. Specific variants of the genes encoding these proteins appear to be under positive selection inWest Africa where Lassa is endemic. Alpha-dystroglycan is also used as a receptor by viruses of the New World clade C arenaviruses (Oliveros and Latino viruses). In contrast, the New World arenaviruses of clades A and B, which include the important viruses Machupo, Guanarito, Junin, and Sabia in addition to the non pathogenic Amapari virus, use the [[transferrin]] receptor 1. A small aliphatic amino acid at the GP1 [[glycoprotein]] [[amino acid]] position 260 is required for high-affinity binding to alpha-DG. In addition, GP1 amino acid position 259 also appears to be important, since all arenaviruses showing high-affinity alpha-DG binding possess a bulky aromatic amino acid ([[tyrosine]] or [[phenylalanine]]) at this position.
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| * Unlike most enveloped viruses which use [[clathrin]] coated pits for cellular entry and bind to their receptors in a pH dependent fashion, Lassa and [[lymphocytic choriomeningitis virus]] instead use an endocytotic pathway independent of [[clathrin]], caveolin, [[dynamin]] and [[actin]]. Once within the cell the viruses are rapidly delivered to [[endosomes]] via vesicular trafficking albeit one that is largely independent of the small GTPases Rab5 and Rab7. On contact with the [[endosome]] pH-dependent membrane fusion occurs mediated by the envelope [[glycoprotein]], which at the lower pH of the [[endosome]] binds the [[lysosome]] protein LAMP1 which results in [[membrane]] fusion and escape from the [[endosome]].
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| ===Life cycle===
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| * The life cycle of Lassa virus is similar to the Old World arenaviruses<ref name=Wikipedia>{{cite web | title = Wikipedia lassa virus | url =http://en.wikipedia.org/wiki/Lassa_virus }}</ref>. Lassa virus enters the cell by the receptor-mediated [[endocytosis]]. Which endocytotic pathway is used is not known yet, but at least the cellular entry is sensitive to [[cholesterol]] depletion. It was reported that virus internalization is limited upon [[cholesterol]] depletion. The receptor used for cell entry is alpha-dystroglycan, a highly conserved and ubiquitously expressed cell surface receptor for extracellular [[matrix proteins]].
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| * [[Dystroglycan]], which is later cleaved into alpha-dystroglycan and beta-dystroglycan is originally expressed in most cells to mature tissues, and it provides molecular link between the ECM and the actin-based [[cytoskeleton]]<ref name="pmid18182084">{{cite journal| author=Rojek JM, Kunz S| title=Cell entry by human pathogenic arenaviruses. | journal=Cell Microbiol | year= 2008 | volume= 10 | issue= 4 | pages= 828-35 | pmid=18182084 | doi=10.1111/j.1462-5822.2007.01113.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18182084 }} </ref>. After virus enters the cell by alpha-dystroglycan mediated endocytosis, low-pH environment triggers pH-dependent membrane fusion and releases RNP (viral ribonucleoprotein) complex into the [[cytoplasm]]. Viral RNA is unpacked, and replication and transcription initiate in the [[cytoplasm]].<ref name="pmid18182084">{{cite journal| author=Rojek JM, Kunz S| title=Cell entry by human pathogenic arenaviruses. | journal=Cell Microbiol | year= 2008 | volume= 10 | issue= 4 | pages= 828-35 | pmid=18182084 | doi=10.1111/j.1462-5822.2007.01113.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18182084 }} </ref> As the replication starts, both S and L RNA genomes synthesize the antigenomic S and L RNAs, and from the antigenomic [[RNA]]s, genomic S and L RNA are synthesized. Both genomic and antigenomic RNAs are needed for [[transcription]] and [[translation]]. S RNA encodes GP and NP (viral nucleocapsid protein) proteins, and L RNA encodes Z and L proteins. L protein most likely represents the viral RNA-dependent [[RNA polymerase]].<ref name="pmid12615304">{{cite journal| author=Drosten C, Kümmerer BM, Schmitz H, Günther S| title=Molecular diagnostics of viral hemorrhagic fevers. | journal=Antiviral Res | year= 2003 | volume= 57 | issue= 1-2 | pages= 61-87 | pmid=12615304 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12615304 }} </ref> When the cell is infected by the virus, [[L polymerase]] is associated with the viral RNP and initiates the transcription of the genomic RNA. The 5’ and 3’ terminal 19 nt viral promoter regions of both [[RNA]] segments are necessary for recognition and binding of the [[viral polymerase]]. The primary transcription first transcribesmRNAs from the genomic S and L RNAs, which code NP and L proteins, respectively. [[Transcription]] terminates at the [[stem-loop]] (SL) structure within the intergenomic region. [[Arenaviruses]] use a cap snatching strategy to gain the cap structures from the cellular [[mRNAs]], and it is mediated by the [[endonuclease]] activity of the [[L polymerase]] and the cap binding activity of NP. Antigenomic RNA transcribes viral genes GPC and Z, encoded in genomic orientation, from S and L segments respectively. The [[antigenomic RNA]] also serves as the template for the replication.<ref name="pmid23202452">{{cite journal| author=Yun NE, Walker DH| title=Pathogenesis of Lassa fever. | journal=Viruses | year= 2012 | volume= 4 | issue= 10 | pages= 2031-48 | pmid=23202452 | doi=10.3390/v4102031 | pmc=PMC3497040 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23202452 }} </ref> After translation of GPC, it is posttranslationally modified in the endoplasmic reticulum. GPC is cleaved into [[GP1]] and [[GP2]] at the later stage of the secretory pathway. It is reported the cellular protease [[SKI-1]]/[[S1P]] was responsible for the cleavage. Cleaved [[glycoproteins]] are incorporated into the [[virion]] envelope when the [[virus]] buds and release from the [[cell membrane]].<ref name="pmid12615304">{{cite journal| author=Drosten C, Kümmerer BM, Schmitz H, Günther S| title=Molecular diagnostics of viral hemorrhagic fevers. | journal=Antiviral Res | year= 2003 | volume= 57 | issue= 1-2 | pages= 61-87 | pmid=12615304 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12615304 }} </ref>
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| ==Vector==
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| * The reservoir, or host, of Lassa virus is a rodent known as the "multimammate rat" (Mastomys natalensis). Once infected, this rodent is able to excrete [[virus]] in [[urine]] for an extended time period, maybe for the rest of its life. Mastomys rodents breed frequently, produce large numbers of offspring, and are numerous in the savannas and forests of west, central, and east Africa. In addition, Mastomys readily colonize human homes and areas where food is stored. All of these factors contribute to the relatively efficient spread of Lassa virus from infected rodents to humans.
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| * Transmission of Lassa virus to humans occurs most commonly through [[ingestion]] or [[inhalation]]. Mastomysrodents shed the [[virus]] in [[urine]] and droppings and direct contact with these materials, through touching soiled objects, eating contaminated food, or exposure to open cuts or sores, can lead to [[infection]].
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| * Because Mastomys rodents often live in and around homes and scavenge on leftover human food items or poorly stored food, direct contact transmission is common. Mastomys rodents are sometimes consumed as a food source and infection may occur when rodents are caught and prepared. Contact with the [[virus]] may also occur when a person inhales tiny particles in the air contaminated with infected rodent excretions. This aerosol or airborne transmission may occur during cleaning activities, such as sweeping.
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| * Direct contact with infected rodents is not the only way in which people are infected; person-to-person transmission may occur after exposure to [[virus]] in the [[blood]], [[tissue]], secretions, or excretions of a Lassa virus-infected individual. Casual contact (including [[skin]]-to-[[skin]] contact without exchange of [[body fluids]]) does not spread Lassa virus. Person-to-person transmission is common in health care settings (called [[nosocomial transmission]]) where proper personal protective equipment (PPE) is not available or not used. Lassa virus may be spread in contaminated medical equipment, such as reused needles.
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| ==Microscopic Pathology==
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| The images below display key features of the Lassa virus.
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| <!--<gallery>-->
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| ==References==
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| {{Reflist|2}}
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| [[Category:Disease]]
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| [[Category:Viral diseases]]
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| [[Category:Viruses]]
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| [[Category:Zoonoses]]
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| [[Category:Hemorrhagic fevers]]
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| [[Category:Tropical disease]]
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| [[Category:Biological weapons]]
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| [[Category:Infectious disease]]
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