Rift Valley fever virus 78kDa envelope protein attenuates virus replication in macrophage-derived cell lines and viral virulence in mice.

Terry Juelich,Kendra N Johnson,Kaori Terasaki,Lihong Zhang,Birte Kalveram,Shinji Makino,Alexander N Freiberg,Jonas Klingström,Jennifer K Smith

doi:10.1371/journal.pntd.0009785

Terry Juelich, Kendra N Johnson + Show 7 more

Open Access

https://doi.org/10.1371/journal.pntd.0009785

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Abstract

Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus with a wide host range including ruminants and humans. RVFV outbreaks have had devastating effects on public health and the livestock industry in African countries. However, there is no approved RVFV vaccine for human use in non-endemic countries and no FDA-approved antiviral drug for RVFV treatment. The RVFV 78kDa protein (P78), which is a membrane glycoprotein, plays a role in virus dissemination in the mosquito host, but its biological role in mammalian hosts remains unknown. We generated an attenuated RVFV MP-12 strain-derived P78-High virus and a virulent ZH501 strain-derived ZH501-P78-High virus, both of which expressed a higher level of P78 and carried higher levels of P78 in the virion compared to their parental viruses. We also generated another MP-12-derived mutant virus (P78-KO virus) that does not express P78. MP-12 and P78-KO virus replicated to similar levels in fibroblast cell lines and Huh7 cells, while P78-High virus replicated better than MP-12 in Vero E6 cells, fibroblast cell lines, and Huh7 cells. Notably, P78-High virus and P78-KO virus replicated less efficiently and more efficiently, respectively, than MP-12 in macrophage cell lines. ZH501-P78-High virus also replicated poorly in macrophage cell lines. Our data further suggest that inefficient binding of P78-High virus to the cells led to inefficient virus internalization, low virus infectivity and reduced virus replication in a macrophage cell line. P78-High virus and P78-KO virus showed lower and higher virulence than MP-12, respectively, in young mice. ZH501-P78-High virus also exhibited lower virulence than ZH501 in mice. These data suggest that high levels of P78 expression attenuate RVFV virulence by preventing efficient virus replication in macrophages. Genetic alteration leading to increased P78 expression may serve as a novel strategy for the attenuation of RVFV virulence and generation of safe RVFV vaccines.

Highlights

Rift Valley fever virus (RVFV) is the causative agent for Rift Valley fever, a major public health concern in African countries
Rift Valley fever virus (RVFV) is the causative agent of Rift Valley fever, which is primarily endemic in African countries
Because RVFV is transmitted by several mosquito species that are ubiquitous in non-endemic areas, there is a potential risk that the virus will spread outside of the current endemic areas

Summary

Introduction

Rift Valley fever virus (RVFV) is the causative agent for Rift Valley fever, a major public health concern in African countries. RVFV has a significant impact on the livestock industry because of its high mortality rate in young ruminants and high abortion rate in pregnant animals. Ocular diseases, which can result in permanent vision loss, are reported in up to 10% of infected humans [3], and association of the virus infection with miscarriage in pregnant women has been recently reported [4,5]. RVFV is a Category A pathogen, which is the highest risk group to national security and public health according to the CDC/NIAID categorization of biodefense priority pathogens, and it is included in the WHO R&D blueprint list [8]. There is no approved RVFV vaccine for human use in non-endemic countries and no FDA-approved antiviral drug for RVFV treatment

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