Animal Models of Lassa Fever

Sattler, Rachel A.; Paessler, Slobodan; Ly, Hinh; Huang, Cheng

doi:10.3390/pathogens9030197

Cited by 30 publications

(41 citation statements)

References 63 publications

(316 reference statements)

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“…Indeed, several laboratories have used LCMV to develop surrogate animal models for LF (reviewed in [19]). For example, the LCMV (WE strain) can cause a disease in rhesus macaques [20] and HHD mice [21] that reproduces certain aspects of LASV pathogenesis such as vascular leakage.…”

Section: Introductionmentioning

confidence: 99%

Virulent infection of outbred Hartley guinea pigs with recombinant Pichinde virus as a surrogate small animal model for human Lassa fever

et al. 2020

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Arenaviruses, such as Lassa virus (LASV), can cause severe and fatal hemorrhagic fevers (e.g., Lassa fever, LF) in humans with no vaccines or therapeutics. Research on arenavirus-induced hemorrhagic fevers (AHFs) has been hampered by the highly virulent nature of these viral pathogens, which require high biocontainment laboratory, and the lack of an immune-competent small animal model that can recapitulate AHF disease and pathological features. Guinea pig infected with Pichinde virus (PICV), an arenavirus that does not cause disease in humans, has been established as a convenient surrogate animal model for AHFs as it can be handled in a conventional laboratory. The PICV strain P18, derived from sequential passaging of the virus 18 times in strain 13 inbred guinea pigs, causes severe febrile illness in guinea pigs that is reminiscent of lethal LF in humans. As inbred guinea pigs are not readily available and are difficult to maintain, outbred Hartley guinea pigs have been used but they show a high degree of disease heterogeneity upon virulent P18 PICV infection. Here, we describe an improved outbred guineapig infection model using recombinant rP18 PICV generated by reverse genetics technique followed by plaque purification, which consistently shows >90% mortality and virulent infection. Comprehensive virological, histopathological, and immunohistochemical analyses of the rP18virus infected animals show similar features of human LASV infection. Our data demonstrate that this improved animal model can serve as a safe, affordable, and convenient surrogate small animal model for studying human LF pathogenesis and for evaluating efficacy of preventative or therapeutic approaches.

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Section: Introductionmentioning

confidence: 99%

Virulent infection of outbred Hartley guinea pigs with recombinant Pichinde virus as a surrogate small animal model for human Lassa fever

et al. 2020

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“…Furthermore, little has been known about the mechanisms of innate immunity in Mastomys and other natural rodent reservoirs of LASV, and an experimental system is lacking to directly address these important questions. Laboratory mice are of different rodent species and do not persistently shed virus upon LASV infection ( [58], reviewed in [19]). As such, we are unable to determine whether LASV Z inhibits innate immunity of their natural rodent hosts in a similar manner or mechanism as seen in humans and whether and how strain variations of the Z protein or other viral proteins may affect LASV interactions within the natural rodent hosts.…”

Section: Discussionmentioning

confidence: 99%

“…Various animal models have been developed to characterize the degrees of viral virulence and disease pathology mediated by LASV infection (reviewed in [19]). Accumulating evidence has suggested that different LASV isolates can mediate differential degrees of virulence and disease pathogenesis in animal models.…”

Section: Introductionmentioning

confidence: 99%

Effect of Strain Variations on Lassa Virus Z Protein-Mediated Human RIG-I Inhibition

Huang

Brisse

et al. 2020

Viruses

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Mammarenaviruses include several known human pathogens, such as the prototypic lymphocytic choriomeningitis virus (LCMV) that can cause neurological diseases and Lassa virus (LASV) that causes endemic hemorrhagic fever infection. LASV-infected patients show diverse clinical manifestations ranging from asymptomatic infection to hemorrhage, multi-organ failures and death, the mechanisms of which have not been well characterized. We have previously shown that the matrix protein Z of pathogenic arenaviruses, including LASV and LCMV, can strongly inhibit the ability of the innate immune protein RIG-I to suppress type I interferon (IFN-I) expression, which serves as a mechanism of viral immune evasion and virulence. Here, we show that Z proteins of diverse LASV isolates derived from rodents and humans have a high degree of sequence variations at their N- and C-terminal regions and produce variable degrees of inhibition of human RIG-I (hRIG-I) function in an established IFN-β promoter-driven luciferase (LUC) reporter assay. Additionally, we show that Z proteins of four known LCMV strains can also inhibit hRIG-I at variable degrees of efficiency. Collectively, our results confirm that Z proteins of pathogenic LASV and LCMV can inhibit hRIG-I and suggest that strain variations of the Z proteins can influence their efficiency to suppress host innate immunity that might contribute to viral virulence and disease heterogeneity.

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“…While different animal species have been developed as animal models of LF [4], they all have certain constraints. For example, the use of NHPs, such as marmosets or rhesus macaques, can incur exorbitant expenses of high containment BSL4 facilities and experienced lab personnel (veterinarians) needed to conduct LASV studies.…”

Section: Discussionmentioning

confidence: 99%

“…The description of different animal models of LF has recently been reviewed elsewhere [4]. Each of the known LF animal models has its advantages and disadvantages.…”

Section: Introductionmentioning

confidence: 99%

Pichinde Virus Infection of Outbred Hartley Guinea Pigs as a Surrogate Animal Model for Human Lassa Fever: Histopathological and Immunohistochemical Analyses

et al. 2020

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Lassa virus (LASV) is a mammarenavirus (arenavirus) that causes zoonotic infection in humans that can lead to fatal hemorrhagic Lassa fever (LF) disease. Currently, there are no FDA-approved vaccines or therapeutics against LASV. Development of treatments against LF and other related arenavirus-induced hemorrhagic fevers (AHFs) requires relevant animal models that can recapitulate clinical and pathological features of AHF diseases in humans. Laboratory mice are generally resistant to LASV infection, and non-human primates, while being a good animal model for LF, are limited by their high cost. Here, we describe a small, affordable, and convenient animal model that is based on outbred Hartley guinea pigs infected with Pichinde virus (PICV), a mammarenavirus that is non-pathogenic in humans, for use as a surrogate model of human LF. We conducted a detailed analysis of tissue histopathology and immunohistochemical analysis of different organs of outbred Hartley guinea pigs infected with different PICV strains that show differential disease phenotypes and pathologies. Comparing to infection with the avirulent PICV strain (P2 or rP2), animals infected with the virulent strain (P18 or rP18) show extensive pathological changes in different organs that sustain high levels of virus replication. The similarity of tissue pathology and viral antigen distribution between the virulent PICV–guinea pig model and lethal human LASV infection supports a role of this small animal model as a surrogate model of studying human LF in order to understand its pathogenesis and for evaluating potential preventative and therapeutic options against AHFs.

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Animal Models of Lassa Fever

Cited by 30 publications

References 63 publications

Virulent infection of outbred Hartley guinea pigs with recombinant Pichinde virus as a surrogate small animal model for human Lassa fever

Virulent infection of outbred Hartley guinea pigs with recombinant Pichinde virus as a surrogate small animal model for human Lassa fever

Effect of Strain Variations on Lassa Virus Z Protein-Mediated Human RIG-I Inhibition

Pichinde Virus Infection of Outbred Hartley Guinea Pigs as a Surrogate Animal Model for Human Lassa Fever: Histopathological and Immunohistochemical Analyses

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