How do you study the pathogenesis of Lassa fever virus? (hint – very, very carefully)

Arenavirus How do you study a virus which is so pathogenic, you are (rightly) not allowed to work with it under normal laboratory conditions? Ideally, you need to see how the whole virus works during infection, but in some cases, and Lasse fever is a good example, that’s not such a good idea…

Lassa virus (LASV), the agent of a severe and often fatal hemorrhagic illness known as Lassa fever (LF), is endemic in West Africa and estimated to infect more than 300,000 individuals yearly, hospitalizing 100,000 and causing 20,000 or more deaths. LASV has entered Europe and America via travelers incubating the virus. As a Category A Select Agent, LASV is also a potential bioterrorism threat. We know that early host immune response to LASV is crucial for survival – infected individuals with high virus titres fail to mount an effective innate/adaptive immune response and invariably die, whereas those with less virus in their blood respond immunologically with a T cell response and survive.

By making recombinants between the highly pathogenic Lassa fever virus and the non-pathogenic (for humans, although mice or not so fortunate) closely related Arenavirus lymphocytic choriomeningitis virus (LCMV), Michael Oldstone and colleagues show how potentially life-saving immune responses to the LASV glycoprotein are generated. In addition, the vigorous antiviral immune response to LASV Gp in the recombinant LCMV/LASV hybrid suggests that this construct might be evaluated as a potential vaccine candidate against LASV infection. Even without that, this recombinant virus will serve as a useful tool for uncovering mechanisms of cell binding, entry, infection and immune subversion initiated by the glycoprotein of LASV in a BSL-2 environment rather than the highly restrictive BSL-4 environment required by work with the wild-type LASV.

 

Pathogenesis of Lassa fever virus infection: I. Susceptibility of mice to recombinant Lassa Gp/LCMV chimeric virus. Virology. 2013 May 15. pii: S0042-6822(13)00219-5. doi: 10.1016/j.virol.2013.04.010
Lassa virus (LASV) is a BSL-4 restricted agent. To allow study of infection by LASV under BSL-2 conditions, we generated a recombinant virus in which the LASV glycoprotein (Gp) was placed on the backbone of lymphocytic choriomeningitis virus (LCMV) Cl13 nucleoprotein, Z and polymerase genes (rLCMV Cl13/LASV Gp). The recombinant virus displayed high tropism for dendritic cells following in vitro or in vivo infection. Inoculation of immunocompetent adults resulted in an acute infection, generation of virus-specific CD8+ T cells and clearance of the infection. Inoculation of newborn mice with rLCMV Cl13/LASV Gp resulted in a life-long persistent infection. Interestingly, adoptive transfer of rLCMV Cl13/LASV Gp immune memory cells into such persistently infected mice failed to purge virus but, in contrast, cleared virus from mice persistently infected with wt LCMV Cl13.

See also: The Pathogenesis of Lassa Fever

 

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