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dmm.biologists.org CLINICAL PUZZLEResearch problemEbola virus (EBOV) and Marburg virus(MARV) infections cause a severe form ofviral hemorrhagic fever (VHF) with lethal-ity in humans ranging from 23-90% depend-ing on the virus species and strain (Sanchezet al., 2007). Given the high virulence inhumans and the classification of theseviruses as biosafety level 4 and category Alist pathogens, animal models are crucial forunderstanding the underlying mechanismsof disease, as well as for the development oftherapeutics and vaccines. Furthermore, for Special Pathogens Program, Laboratory for Zoonotic Diseases and Special Pathogens, National MicrobiologyLaboratory, Public Health Agency of Canada, Winnipeg, Manitoba, R3E 3R2 CanadaDepartment of Medical Microbiology and Department of Pediatrics and Child Health, University of Manitoba,Winnipeg, Manitoba, R2H 2A6 CanadaLaboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases,National Institutes of Health, Hamilton, MT 59840, USA Disease modeling for Ebola and Marburg virusesDennis Bente, Jason Gren, James E. Strongand Heinz Feldmann The filoviruses Ebola and Marburg are zoonotic agents that are classified as bothbiosafety level 4 and category A list pathogens. These viruses are pathogenic inhumans and cause isolated infections or epidemics of viral hemorrhagic fever,mainly in Central Africa. Their natural reservoir has not been definitely identified,but certain species of African bat have been associated with Ebola and Marburginfections. Currently, there are no licensed options available for either treatment initial screening tools for pathophysiology, treatment and vaccine studies. Filovirus disease modeling CLINICAL PUZZLEthe antibody response is noted (days 7-11).Convalescence is prolonged and sometimesassociated with myelitis, recurrent hepati-tis, psychosis or uveitis (for reviews, seeMartini and Siegert, 1971; Pattyn, 1978;Peters and LeDuc, 1999; Feldmann et al.,2003; Sanchez et al., 2007).PathogenesisIn general terms, human VHF resultingfrom EBOV and MARV infections is asso-ciated with fluid distribution problems,hypotension and coagulation disorders, andoften leads to fulminant shock and subse-quent multiorgan system failure (Fig. 1).Viralreplication, in conjunction withimmune and vascular dysregulation, isthought to play a role in disease develop-ment. Specific organ involvement includesextensive disruption of the parafollicularregions in the spleen and lymph nodes, andproliferation of the virus in mononuclearphagocytic cells has been demonstrated. Adramatic lymphopenia is thought to be theresult of ‘bystander apoptosis’, most likelytriggered through either mediators releasedfrom virus-activated primary target cells orby as yet unidentified interactions betweenhost and viral products. In contrast to theactivation of monocytes/macrophages,infected dendritic cells were impaired in thesecretion of pro-inflammatory cytokines,the production of co-stimulatory moleculesand the stimulation of T cells. The abilityof filoviruses to interfere with the hostinnate immune system, especially the inter-feron (IFN) response, has been attributedto the virion proteins (VP) 35 and VP24.Overall, EBOV and MARV infectionsclearly affect the innate immune responsebut with obvious varying outcomes. In par-ticular, the presence of IL-1and elevatedlevels of IL-6 during the early symptomaticphase of the disease have been suggested asblood markers for survival, whereas therelease of IL-10 and high levels of neopterinand IL-1 receptor antagonist (IL-1RA) dur-ing the early stage of disease are moreindicative of fatal outcomes (for reviews, seeFeldmann et al., 2003; Sullivan et al., 2003;Geisbert and Hensley, 2004; Geisbert andJahrling, 2004; Mohamadzadeh et al., 2007;Sanchez et al., 2007).The disturbance of the blood-tissue bar-rier, which is controlled primarily byendothelial cells, is another important factorin pathogenesis (Fig. 1). The endotheliumseems to be affected directly by virus acti-vation and lytic replication, as well as indi-rectly by an inflammatory response throughmediators derived from primary target cellsor viral expression products. These processesmight explain the imbalance of fluid betweenthe intravascular and extravascular tissuespace that is observed in patients. Clinicaland laboratory data also indicate distur-bances in hemostasis during infection.Although thrombocytopenia is observedwith severe infections in primates, studies onthe role of disseminated intravascular coag-ulation (DIC) and consumption coagulopa-thy, as well as platelet and endothelial dys-functions, are still incomplete. DIC can beobserved regularly in primates and seems tobe triggered by widespread endothelial cellinjury as well as the release of tissue factoror thromboplastic substances (for reviews,see Feldmann et al., 2003; Sanchez et al.,2007; Aleksandrowicz et al., 2008).Animal modelsImmunocompetent adult mice are resistantto infection with wild-type filoviruses,which is thought to be the result of theirstrong innate immune response, particu-larly the type I IFN response (Bray et al.,2001) (Tables 1 and 2). Newborn mice,however, succumb to lethal infection fol-lowing intraperitoneal or intracerebralinfection (van der Groen et al., 1979), whichmight be explained by an incompletelydeveloped type I IFN response in these mice(Pfeifer et al., 1993). Filovirus infection isalso lethal for adult immunodeficient micesuch as the seve

re combined immunodefi-cient (SCID) mouse, which lacks functionalB- and T-cell responses (Table 2). Unlikehumans or other animal models, SCID miceremain healthy for several weeks, thendevelop gradual, progressive weight lossand slowing of activity, and then die 20-25or 50-70 days after ZEBOV or MARV chal-lenge, respectively (Bray, 2001; Warfield etal., 2007). Mice lacking a complete type IIFN response (innate immune response),such as knockout mice that do not expressSTAT or the IFN receptor , uniformlydie within a week of subcutaneous challengewith a variety of filovirus strains (Bray,2001)(Table 2).An immunocompetent murine modelwas developed by passaging ZEBOV ninetimes in progressively older suckling mice(Bray et al., 1998) (Tables 1 and 2). In miceinfected with this mouse-adapted strain, theonset of illness was 3 days after inoculationand death occurred after 5-7 days. Highvirus titers [up to 10plaque-forming units(PFU)/gram] could be detected in the liverand spleen (Bray et al., 1998). The patho-logical changes in the liver and spleen, aswell as the levels of serum transaminases(aspartate transaminase, AST; alaninetransaminase, ALT), in infected miceresembled those in ZEBOV-infected pri-mates (Bray et al., 2001). However, in con-trast to primate infections, only a few fib-rin deposits were found in mouse tissuesand infection was only lethal when the viruswas inoculated intraperitoneally. Further-more, mice were resistant to large doses ofthe same virus when inoculated by otherroutes.At this time, no immunocompetentmouse model for MARV has been reported(Table 1). A recent report has described aSCID mouse model, which uses liverhomogenates from MARV-infected SCIDmice that have been serially passaged tentimes, that reduces the time to death frombetween 50-70 days to 7-10 days(Warfieldet al., 2007). At 3-4 days post-inoculation,infected mice showed weight loss, ahunched appearance and exhibiteddecreased grooming; some mice appearedto have hemorrhages and some developedhind-leg paralysis. The viremia peaked ataround 10PFU/ml in serum at days 6-8.MARV was present at high titers in the Case study Marburg hemorrhagic fever: a 42-year-old man fell ill with fever, headache and conjunctivitis whichlasted 10, 5 and 4 days, respectively. Beginning on day 4, mild diarrhea occurred and he startedtodevelop a slightly clouded awareness. The patient was admitted to hospital on day 7 post onsetof symptoms, when he showed the beginning of a scarlatinoid rash, hepatitis (elevatedtransaminases), bloody diarrhea and encephalitis. His condition deteriorated over the next 4 dayswith increasingly severe bloody diarrhea, hematemesis, hematuria and cutaneous hemorrhages. Theinitial leucopenia converted into a leucocytosis. The fever remained throughout the disease courseand ranged from 39-40.8C. Finally the patient developed kidney failure and congestive heart failure.He succumbed to the infection on day 10 post onset of symptoms (summarized from Stille andBoehle, 1971). dmm.biologists.orgFilovirus disease modeling CLINICAL PUZZLEblood, liver, spleen, kidney and other organs.After infection, profound thrombocytope-nia, as well as notable alterations in serumchemistry levels (especially liver enzymes),occurred with progressively increasingseverity (Warfield et al., 2007).Guinea pigs inoculated with wild-typeEBOV develop only a short-lived, nonlethalfebrile illness (Bowen et al., 1978; Bowen etal., 1980; Ryabchikova et al., 1996). A lethalguinea pig model for EBOV infection wasdeveloped eventually by infecting inbredand outbred guinea pig strains with ZEBOV,followed by sequential passages (4-8 times)of virus in naïve guinea pigs (Bowen et al.,1978; Bowen et al., 1980; Conolly et al.,1999; Ryabchikova et al., 1996)(Table 1).The resulting guinea-pig-adapted strains ofvirus were uniformly lethal, typically result-ing in death after 8-11 days. Infected guineapigs exhibit few clinical signs of infectionuntil around day 5 when they cease eatingand become febrile and dehydrated. In theseguinea pigs, death was not accompanied byvisible signs of hemorrhage (Ryabchikova etal., 1996). The virus was first detected in thespleen and liver on day 2, and by day 3 itcould also be detected in the kidney, adrenalgland, lung and pancreas. Mean organ titersrose progressively and reached their high-est levels (4.8-6.4 logPFU/g) on day 9, andviremia peaked on day 7 with ~10PFU/ml(Connolly et al., 1999). Infected guinea pigsalso showed progressive prolongation ofthe prothrombin time (PT) and the partialthromboplastin time (aPTT).As seen in ZEBOV infection, guinea pigsthat were experimentally infected with wild-type MARV developed only a mild febriledisease and most of them survived theinfection (Table 1). The virulence of thevirus was increased by serial passage inguinea pigs. Four to eight passages were suf-ficient to produce a virus that was lethal forall animals by 7-17 days after infection(Simpson et al., 1968). Infected animalsshowed weight loss, elevated temperatureand edematous faces, and the blood fromsome animals failed to clot. As seen inNHPs, a sudden decrease in temperatureoccurred shortly before death.Nonhuman primatesFilovirus infections have been intensivelyinvestigated in various species of NHP, butmainly in cynomolgus (Macaca fascicularisand rhesus macaques (Macaca mulattaAfrican green monkeys (Chlorocebusaethiops) are resistant to REBOV andbaboons (Papio hamadryas) appear to besomewhat more resistant to all EBOVspecies (Fisher-

Hoch et al., 1992; Fisher-Hoch and McCormick, 1999; Gonchar et al.,1991; Ryabchikova et al., 1999a; Ryabchikovaet al., 1999b). The viral dose and strain, theroute of infection and the species of NHPused all appear to influence the onset, dura-tion and severity of the clinical signs.Several NHP species have been used asmodels to study ZEBOV infection, namelythe African green monkey (Bowen et al.,1978; Fisher-Hoch et al., 1992; Davis et al.,1997; Ryabchikova et al., 1999a; Ryabchikovaet al., 1999b), hamadryad baboon (Jones,1980; Mikhailov et al., 1994; Borisevich et al.,1995; Ryabchikova et al., 1996; Kudoyarova-Zubavichene et al., 1999; Ryabchikova et al.,1999a; Ryabchikova et al., 1999b), rhesusmacaque (Bowen et al., 1978; Fisher-Hoch etal., 1985; P’iankov et al., 1995; Jaax et al., 1996;Johnson et al., 1996; Geisbert et al., 2002) andcynomolgus macaque (Jones, 1980; Fisher-Hoch et al., 1992; Geisbert et al., 2003). Forcynomolgus macaques infected withZEBOV, the onset of clinical signs is fairlyrapid, occurring within 4-5 days. In otherNHP models, the onset of symptoms isslower and thus more similar to thatobserved in humans. Usually macaquesbecome febrile and lethargic between 2-3days after infection and fever persiststhroughout the course of the disease. A dropin body temperature usually precedes death.Animals also show weight loss of up to 10%of their body weight, which is probably pri-marily related to dehydration rather thanmobilization of fat reserves and catabolism– although all of these factors probably con- Fig. 1. Ebola virus pathogenesis.The final event in severe/lethal cases of Ebola infection is shock, whichis caused by several processes that influence each other: systemic viral replication, immune suppression,an increase in vascular permeability and coagulopathy. Infection of primary target cells such asmonocytes/macrophages and dendritic cells results in the systemic spread of the virus and differentialactivation. Monocytes/macrophages are activated to produce pro-inflammatory cytokines and tissuefactor, whereas dendritic cell activation is impaired, leading to poor protective immune responses.Although the virus does not infect lymphocytes and natural killer (NK) cells, there is extensive apoptosis insubsets of these cell types. Endothelial cells are activated by pro-inflammatory cytokines and virusparticles, leading to increased permeability. Tissue factor expression in monocytes/macrophages induces coagulopathy, which is also able to increase inflammation. Filovirus disease modeling CLINICAL PUZZLEtribute. In addition, some animals developdiarrhea and intermittent melena. As soonas day 4 after infection, NHPs generallydevelop a maculopapular rash that remainsprominent until death. Lymphadenopathy ofperipheral lymph nodes develops early in thedisease course and an enlarged liver withrounded capsular borders is seen at mid- tolate-stages of the disease (Geisbert and Hens-ley, 2004). Virus can normally be detected inthe blood on day 2 after infection and usu-ally peaks 2-3 days later. Throughout thecourse of the disease, a rise in both absoluteand relative neutrophil counts develops,coinciding with severe lymphopenia in whichneutrophils account for over 90% of all leuko-cytes. In addition, a marked thrombocy-topenia is uniformly seen in these infectedanimals. Prolongation of the aPTT has beenreported as early as day 6 after infection andby day 10-12 blood samples often lose theirability to clot (Fisher-Hoch et al., 1983).Plasma levels of sodium, potassium and cal-cium all fall during disease progression,whereas urea and creatinine levels increase.Further, the levels of the liver transaminases(AST, ALT) start to increase, usually ataround day 5, and remain high until death(Fisher-Hoch et al., 1983; Fisher-Hoch et al.,Only a few studies have evaluated thepathogenesis of SEBOV in NHPs. In rhesusand cynomolgus macaques, the SEBOV dis-ease course appears to be several daysslower than that seen following ZEBOVinfection and rates of survival appear to behigher (Ellis et al., 1978; Fisher-Hoch et al.,1992; Geisbert et al., 2008).Different species of NHP, namely Africangreen monkeys, rhesus macaques andsquirrel monkeys (Saimiri sciureus), havebeen experimentally infected with MARV(Simpson et al., 1968; Simpson, 1969; Lubet al., 1995). Wild-type MARV is uniformlylethal for all species. After an incubationperiod of 2-6 days, all NHPs develop afebrile illness that is independent of boththe inoculum dose and the route of infec-tion. The clinical presentation is more orless identical in all three species, showingfever (40-40.5°C), anorexia, weight loss andunresponsiveness. Hemorrhaging from therectum or injection site and diarrhea canbe found occasionally (Simpson et al.,1968). Rhesus macaques in particulardevelop petechial skin rashes, resemblinghuman cases where rashes have beendescribed on the arms and thighs, and to alesser extend on the thorax, face and neck.Rashes were not typically seen in Africangreen monkeys (Simpson, 1969). A rapiddeterioration in the condition of these ani-mals was followed by hypothermia, shockand finally death, which occurred at 6-13days post-infection. Marked thrombocy-topenia, lymphopenia and blood coagula-tion abnormalities can also be found ininfected animals. Both the levels of livertransaminases and the neutrophil countincrease during the course of disease(Simpson et al., 1968; Simpson, 1969; Gon-char et al., 1991; Johnson et al., 1996).Virus can be det

ected in the blood as earlyas 3 days after infection and peak viremiatiters reach 10PFU/ml. Table 1. Infection in animal models and humans Mouse (wt) Mouse (ad)* Guinea pig (wt) Guinea pig (ad) NHP (wt) Human ViremiaLowHighLowHighHighHighUnknownElevated Table 2. Ebola virus infection in mice Deciency Mouse strain ZEBOV (ad)(i.p.) ZEBOV (ad)(s.c.) ZEBOV (wt)(i.p.) ZEBOV (wt)(s.c.)NoneBALB/c, C57BL/6+………SCID++++Rag-2++++Nude++……Beige+………IFN- knockout+………Adaptive immune responseTNF- knockout+………IFN- / -receptor knockout++++Innate immune responseSTAT1 knockout++++OtherLymphotoxin- knockout++……+=lethal infection; …=no apparent disease; ad=adapted strain; i.p.=intraperitoneal; s.c.=subcutaneous; wt=wild-type strain [summarized from Bray (Bray, 2001)]. dmm.biologists.orgFilovirus disease modeling CLINICAL PUZZLEAlthough rodent models have some simi-larities to the human disease, they are oflimited value for clinical disease presenta-tion of human filovirus infection becausethe disease course in rodents differs fromthat reported in humans and NHPs (Gibbet al., 2001; Geisbert et al., 2002; Feldmannet al., 2003). In addition, important clini-cal signs such as maculopapular rash andan elevated temperature throughout thecourse of the disease are missing. Mice donot display all of the characteristics ofDIC, which is a hallmark of filovirus infec-tion in primates that includes prolongationof PT and aPTT, circulating fibrin degra-dation products, decreased plasma fib-rinogen and decreased fibrin deposition(Bray et al., 2001; Geisbert and Hensley,2004; Sanchez et al., 2007). Compared withmice, infected guinea pigs develop moresevere coagulation defects, including adrop in platelet counts and an increase incoagulation time, but the level of fibrindeposition and coagulopathy are not ashigh as the levels seen in NHPs (Connollyet al., 1999; Reed and Mohamadzadeh,2007). Further, lymphocyte bystanderapoptosis, an important feature in pri-mates and mice, is not as prominent inguinea pigs (Bray et al., 1998; Connolly etal., 1999; Bradfute et al., 2007). Mice dif-fer from guinea pigs and monkeys in thatthey display a decrease in blood urea nitro-gen (BUN), rather than an increase (Bray,2001). Additionally, the histopathologicfeatures of filovirus disease in humans aremore closely mirrored by NHPs thanrodent models (Zaki and Goldsmith, 1999).NHPs are excellent models with which tostudy filovirus pathogenesis because theyclosely resemble the clinical disease andpathology described in humans. Whenselecting a suitable NHP model, the species,sex and age of the NHPs, together with theroute of infection and the administrationdose, must all be taken into considerationbecause all of these factors will have aninfluence on the study(Geisbert et al.,2004). Cynomolgus and rhesus macaquesare considered the ‘gold standard’ modelsfor filovirus infections, and studies usingrhesus macaques have additional advan-tages in that this species is widely used inthe pharmaceutical industry and its genomesequence has been published (Geisbert etal., 2004; Rhesus Macaque GenomeSequencing and Analysis Consortium,2007). Nevertheless, the increase demandfor NHPs for biodefense and infectious dis-ease research has contributed to a currentshortage of macaques (Cohen, 2000; Pat-terson and Carrion, 2005; Satkoski et al.,2008). In the future, the development of amodel that uses a smaller species of NHP,such as certain species of new world mon-keys, might help to ease the burden.Despite the differences in clinical pre-sentation and pathogenesis, rodents canserve an important role for the initial in vivoevaluation of filovirus vaccines and treat-ment schemes (Huggins et al., 1995; Wilsonet al., 2000). In particular, mice offer cer-tain advantages including the ease withwhich large numbers of animals can beobtained and the availability of numerousstrains, including genetically engineeredstrains, as well as a wide range of well-char-acterized reagents. However, one must usecaution when interpreting data fromrodents, because a number of antiviral ther-apies and vaccines have been shown to beeffective in rodents but then failed in NHPmodels (Bray and Paragas, 2002; Geisbertet al., 2002; Feldmann et al., 2005b; Reed andMohamadzadeh, 2007). This might be theresult of considerable differences betweenrodent and primate immunology (Mestasand Hughes, 2004), particularly the stronginnate immune response in rodents (Bray,COMPETING INTERESTSThe authors declare no competing financial interest.AUTHOR CONTRIBUTIONAll authors were responsible for the literature reviewand the preparation of the manuscript. All authorshave approved the manuscript prior to submission.Aleksandrowicz, P., Wolf, K., Falzarano, D., Feldmann,H., Seebach, J. and Schnittler, H.(2008). Viralhaemorrhagic fever and vascular alterations.Borisevich, I. V., Mikhailov, V. V., Krasnianskii, V. P.,Gradoboev, V. N., Lebedinskaia, E. V., Potryvaeva,N. V. and Timan’kova, G. D.(1995). Developmentand study of the properties of immunoglobulinagainst Ebola fever. Vopr. Virusol. Bowen, E. T., Platt, G. S., Simpson, D. I., McArdell, L. B.and Raymond, R. T.(1978). Ebola haemorrhagicfever: experimental infection of monkeys. Trans. R. Soc.Trop. Med. Hyg. Bowen, E. T., Platt, G. S., Lloyd, G., Raymond, R. T. andSimpson, D. I.(1980). A comparative study of strainsof Ebola virus isolated from southern Sudan andnorthern Zai

re in 1976. J. Med. Virol. Bradfute, S. B., Braun, D. R., Shamblin, J. D., Geisbert,J. B., Paragas, J., Garrison, A., Hensley, L. E. andGeisbert, T. W.(2007). Lymphocyte death in a mousemodel of Ebola virus infection. J. Infect. Dis. Suppl. 2Bray, M.(2001). The role of the Type I interferonresponse in the resistance of mice to filovirusinfection. J. Gen. Virol. Bray, M. and Paragas, J.(2002). Experimental therapyof filovirus infections. Antiviral Res. Bray, M., Davis, K., Geisbert, T., Schmaljohn, C. andHuggins, J.(1998). A mouse model for evaluation ofprophylaxis and therapy of Ebola hemorrhagic fever. Infect. Dis. Bray, M., Hatfill, S., Hensley, L. and Huggins, J. W.(2001). Haematological, biochemical and coagulationchanges in mice, guinea-pigs and monkeys infectedwith a mouse-adapted variant of Ebola Zaire virus. Comp. Pathol. Cohen, J.(2000). AIDS research: vaccine studies stymiedby shortage of animals. Science Clinical termsEcchymoses– bruise-like black-and-blue orpurple skin lesions caused by ruptured bloodvesselsViral hemorrhagic fevers (VHFs)– a diversegroup of animal and human illnesses that arecaused by RNA viruses, characterized by feverand bleeding disorders and can progress tohigh fever, shock and death in extreme casesHypovolemic shock– decreased blood volumecausing insufficient blood circulation, alsoknown as hypovolemiaLymphadenopathy– abnormal swelling andenlargement of the lymph nodes, indicative ofMaculopapular rash– a flat, red skin rashcovered with bumps, thus containingcharacteristics of both macules (flat, discoloredregions) and papules (raised bumps)– black, tar-like stools associated withgastrointestinal bleedingMyalgiaPetechiae– small reddish or purplish spotsresulting from a localized hemorrhage in skin ormucous membraneThrombocytopenia– a persistent low bloodplatelet countViremia– presence of viruses in the blood Clinical and basic researchopportunitiesCreating small animal models of (SEBOV), Cote d’Ivoire ebolavirus(CIEBOV) and (REBOV)Development of an immunocompetentmouse model for MARVDevelopment of EBOV and MARV models insmaller non-human primate speciesIn vivo screening studies for new EBOV andMARV therapeutics and vaccinesUsing animal models for clinical effectivenessstudies in accordance with new guidelinesset by the Food & Drug Administration (FDA)and Center for Biologics Evaluation andResearch (CBER) Filovirus disease modeling CLINICAL PUZZLEConnolly, B. 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Pathogenic potential offiloviruses: role of geographic origin of primate hostand virus strain. J. Infect. Dis. Geisbert, T. W. and Hensley, L. E.new insights into disease aetiopathology and possibletherapeutic interventions. Expert Rev. Mol. Med. Geisbert, T. W. and Jahrling, P. B.(2004). Exoticemerging viral diseases: progress and challenges. Med. Geisbert, T. W., Pushko, P., Anderson, K., Smith, J.,Davis, K. J. and Jahrling, P. B.(2002). Evaluation innonhuman primates of vaccines against Ebola virus.Emerg. Infect. Dis. Geisbert, T. W., Hensley, L. E., Larsen, T., Young, H. A.,Reed, D. S., Geisbert, J. B., Scott, D. P., Kagan, E.,Jahrling, P. B. and Davis, K. J.(2003). Pathogenesis ofEbola hemorrhagic fever in cynomolgus macaques:evidence that dendritic cells are early and sustainedtargets of infection. Am. J. Pathol. Geisbert, T. W., Jahrling, P. B., Larsen, T., Davis, K. andy, L.(2004). Filovirus pathogenesis innonhuman primates. In Ebola and Marburg Viruses(ed.H. D. Klenk and H. 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, K.J., Geisbert, J. B., Leung, A., Feldmann, F., Hensley,L. E., Feldmann, H. and Jones, S. M.Recombinant vesicular stomatitis virus vectormediates postexposure protection against SudanEbola hemorrhagic fever in nonhuman primates. Virol. Gibb, T. R., Bray, M., Geisbert, T. W., Steele, K. E., Kell,W. M., Davis, K. J. and Jaax, N. K.Pathogenesis of experimental Ebola Zaire virusinfection in BALB/c mice. J. Comp. Pathol. Gonchar, N. I., Pshenichnov, V. A., Pokhodiaev, V. A.,Lopatov, K. L. and Firsova, I. V.(1991). The sensitivityof different experimental animals to the Marburgvirus. Vopr. Virusol. Huggins, J., Zhang, Z. and Monath, T. I.Inhibition of Ebola virus replication in vitroSCID mouse model by S-adenosylhomocysteinehydrolase inhibitors. Antiviral Res. Suppl.Jaax, N. K., Davis, K. J., Geisbert, T. J., Vogel, P., Jaax, G.P., Topper, M. and Jahrling, P. B.(1996). 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