Development of Rift valley fever encephalitis in rats is mediated by early infection of olfactory epithelium and neuroinvasion across the cribriform plate

Boyles, Devin A.; Schwarz, Madeline M.; Albe, Joseph R.; McMillen, Cynthia M.; O’Malley, Katherine J.; Reed, Douglas S.; Hartman, Amy L.

doi:10.1099/jgv.0.001522

Cited by 13 publications

(21 citation statements)

References 43 publications

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“…High viral RNA loads in the brain at 7 dpi and onward were accompanied by cortical lesions and patchy antigen staining throughout the brain parenchyma. In animals challenged by intranasal or aerosol RVFV inoculation, RVFV has been shown to first infect the olfactory bulb then spread caudally into the cerebrum and cerebellum [ 12 , 13 , 39 ]. However, the method of entry into the CNS is unknown for challenge that begins at the periphery such as infection by mosquito bite or FP injection.…”

Section: Discussionmentioning

confidence: 99%

Genetic diversity of collaborative cross mice enables identification of novel rift valley fever virus encephalitis model

et al. 2022

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Rift Valley fever (RVF) is an arboviral disease of humans and livestock responsible for severe economic and human health impacts. In humans, RVF spans a variety of clinical manifestations, ranging from an acute flu-like illness to severe forms of disease, including late-onset encephalitis. The large variations in human RVF disease are inadequately represented by current murine models, which overwhelmingly die of early-onset hepatitis. Existing mouse models of RVF encephalitis are either immunosuppressed, display an inconsistent phenotype, or develop encephalitis only when challenged via intranasal or aerosol exposure. In this study, the genetically defined recombinant inbred mouse resource known as the Collaborative Cross (CC) was used to identify mice with additional RVF disease phenotypes when challenged via a peripheral foot-pad route to mimic mosquito-bite exposure. Wild-type Rift Valley fever virus (RVFV) challenge of 20 CC strains revealed three distinct disease phenotypes: early-onset hepatitis, mixed phenotype, and late-onset encephalitis. Strain CC057/Unc, with the most divergent phenotype, which died of late-onset encephalitis at a median of 11 days post-infection, is the first mouse strain to develop consistent encephalitis following peripheral challenge. CC057/Unc mice were directly compared to C57BL/6 mice, which uniformly succumb to hepatitis within 2–4 days of infection. Encephalitic disease in CC057/Unc mice was characterized by high viral RNA loads in brain tissue, accompanied by clearance of viral RNA from the periphery, low ALT levels, lymphopenia, and neutrophilia. In contrast, C57BL/6 mice succumbed from hepatitis at 3 days post-infection with high viral RNA loads in the liver, viremia, high ALT levels, lymphopenia, and thrombocytopenia. The identification of a strain of CC mice as an RVFV encephalitis model will allow for future investigation into the pathogenesis and treatment of RVF encephalitic disease and indicates that genetic background makes a major contribution to RVF disease variation.

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Section: Discussionmentioning

confidence: 99%

Genetic diversity of collaborative cross mice enables identification of novel rift valley fever virus encephalitis model

et al. 2022

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“…Previous studies showed that aerosol infection leads to more severe and earlier development of RVFE in mice than infection via intraperitoneal or subcutaneous injection [ 19 ]. Similarly, increased severity of RVF-associated disease after aerosol exposure has been reported in humans [ 19 , 20 , 21 , 22 , 23 ]. Large amounts of virus have been detected along the olfactory epithelium and the olfactory bulb in rats and mice that were intranasally infected [ 20 , 24 ].…”

Section: Introductionmentioning

confidence: 61%

“…Similarly, increased severity of RVF-associated disease after aerosol exposure has been reported in humans [ 19 , 20 , 21 , 22 , 23 ]. Large amounts of virus have been detected along the olfactory epithelium and the olfactory bulb in rats and mice that were intranasally infected [ 20 , 24 ]. Other mechanisms of neuroinvasion, including penetration of the blood–brain barrier (BBB) or travel via neuromuscular junctions, seem to be less likely [ 20 ].…”

Section: Introductionmentioning

confidence: 61%

Intact Type I Interferon Receptor Signaling Prevents Hepatocellular Necrosis but Not Encephalitis in a Dose-Dependent Manner in Rift Valley Fever Virus Infected Mice

Michaely

Schuwerk

Allnoch

et al. 2022

IJMS

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Rift Valley fever (RVF) is a zoonotic and emerging disease, caused by the RVF virus (RVFV). In ruminants, it leads to “abortion storms” and enhanced mortality rates in young animals, whereas in humans it can cause symptoms like severe hemorrhagic fever or encephalitis. The role of the innate and adaptive immune response in disease initiation and progression is still poorly defined. The present study used the attenuated RVFV strain clone 13 to investigate viral spread, tissue tropism, and histopathological lesions after intranasal infection in C57BL/6 wild type (WT) and type I interferon (IFN-I) receptor I knockout (IFNAR−/−) mice. In WT mice, 104 PFU RVFV (high dose) resulted in a fatal encephalitis, but no hepatitis 7–11 days post infection (dpi), whereas 103 PFU RVFV (low dose) did not cause clinical disease or significant histopathological lesions in liver and the central nervous system (CNS). In contrast, IFNAR−/− mice infected with 103 PFU RVFV developed hepatocellular necrosis resulting in death at 2–5 dpi and lacked encephalitis. These results show that IFNAR signaling prevents systemic spread of the attenuated RVFV strain clone 13, but not the dissemination to the CNS and subsequent fatal disease. Consequently, neurotropic viruses may be able to evade antiviral IFN-I signaling pathways by using the transneuronal instead of the hematogenous route.

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“…(52) Our finding is contradictory to earlier studies in RVFV-infected rats and ferrets, where acute encephalitis and infection of the brain was observed. (53, 54) However, it should be noted that in those studies the animals were infected through aerosol exposure, rather than via intravenous or subcutaneous administration, which alters the pathogenesis of RVFV. (55) A similar approach, i.e., RVFV inoculation through the olfactory system, could be used in zebrafish adults and eventually, in larvae.…”

Section: Discussionmentioning

confidence: 99%

The dissemination of Rift Valley fever virus to the eye and sensory neurons of zebrafish larvae is stat1 dependent

Horst¹,

Siekierska²,

Meulemeester³

et al. 2022

Preprint

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The Rift Valley fever virus (RVFV) is listed by the WHO as priority disease and causes haemorrhagic fever, encephalitis, and permanent blindness. To study RVFV pathogenesis and identify small-molecule antivirals, we established a novel in vivo model using zebrafish larvae. Pericardial injection of RVFV resulted in ~4 log10 viral RNA copies/larva, which was inhibited by antiviral 2'-fluoro-2'-deoxycytidine. The optical transparency of the larvae allowed detection of RVFVeGFP in the liver and sensory nervous system, including the optic tectum and retina, but not the brain or spinal cord. Thus, RVFV-induced blindness likely occurs due to direct damage to the eye and peripheral neurons, rather than the brain. Treatment with JAK-inhibitor ruxolitinib, as well as knockout of stat1a but not stat1b, enhanced RVFV replication to ~6 log10 viral RNA copies/larva and ultra-bright livers, although without dissemination to sensory neurons or the eye, hereby confirming the critical role of stat1 in RVFV pathogenesis.

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Development of Rift valley fever encephalitis in rats is mediated by early infection of olfactory epithelium and neuroinvasion across the cribriform plate

Cited by 13 publications

References 43 publications

Genetic diversity of collaborative cross mice enables identification of novel rift valley fever virus encephalitis model

Genetic diversity of collaborative cross mice enables identification of novel rift valley fever virus encephalitis model

Intact Type I Interferon Receptor Signaling Prevents Hepatocellular Necrosis but Not Encephalitis in a Dose-Dependent Manner in Rift Valley Fever Virus Infected Mice

The dissemination of Rift Valley fever virus to the eye and sensory neurons of zebrafish larvae is stat1 dependent

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