scholarly journals A Haploid Genetic Screen Identifies Heparan Sulfate Proteoglycans Supporting Rift Valley Fever Virus Infection

2015 ◽  
Vol 90 (3) ◽  
pp. 1414-1423 ◽  
Author(s):  
Amber M. Riblett ◽  
Vincent A. Blomen ◽  
Lucas T. Jae ◽  
Louis A. Altamura ◽  
Robert W. Doms ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Golgi Complex ◽  
Rift Valley ◽  
Rift Valley Fever ◽  
Rift Valley Fever Virus ◽  
Hemorrhagic Fever ◽  
Cell Types ◽  
Fever Virus ◽  
Host Cells ◽  
Valley Fever

ABSTRACTRift Valley fever virus (RVFV) causes recurrent insect-borne epizootics throughout the African continent, and infection of humans can lead to a lethal hemorrhagic fever syndrome. Deep mutagenesis of haploid human cells was used to identify host factors required for RVFV infection. This screen identified a suite of enzymes involved in glycosaminoglycan (GAG) biogenesis and transport, including several components of thecis-oligomeric Golgi (COG) complex, one of the central components of Golgi complex trafficking. In addition, disruption ofPTAR1led to RVFV resistance as well as reduced heparan sulfate surface levels, consistent with recent observations that PTAR1-deficient cells exhibit altered Golgi complex morphology and glycosylation defects. A variety of biochemical and genetic approaches were utilized to show that both pathogenic and attenuated RVFV strains require GAGs for efficient infection on some, but not all, cell types, with the block to infection being at the level of virion attachment. Examination of other members of theBunyaviridaefamily for GAG-dependent infection suggested that the interaction with GAGs is not universal among bunyaviruses, indicating that these viruses, as well as RVFV on certain cell types, employ additional unidentified virion attachment factors and/or receptors.IMPORTANCERift Valley fever virus (RVFV) is an emerging pathogen that can cause severe disease in humans and animals. Epizootics among livestock populations lead to high mortality rates and can be economically devastating. Human epidemics of Rift Valley fever, often initiated by contact with infected animals, are characterized by a febrile disease that sometimes leads to encephalitis or hemorrhagic fever. The global burden of the pathogen is increasing because it has recently disseminated beyond Africa, which is of particular concern because the virus can be transmitted by widely distributed mosquito species. There are no FDA-licensed vaccines or antiviral agents with activity against RVFV, and details of its life cycle and interaction with host cells are not well characterized. We used the power of genetic screening in human cells and found that RVFV utilizes glycosaminoglycans to attach to host cells. This furthers our understanding of the virus and informs the development of antiviral therapeutics.

scholarly journals A ΩXaV motif in the Rift Valley fever virus NSs protein is essential for degrading p62, forming nuclear filaments and virulence

2015 ◽  
Vol 112 (19) ◽  
pp. 6021-6026 ◽  
Author(s):  
Normand Cyr ◽  
Cynthia de la Fuente ◽  
Lauriane Lecoq ◽  
Irene Guendel ◽  
Philippe R. Chabot ◽  
...  
Keyword(s):  
Rift Valley ◽  
Rift Valley Fever ◽  
Excision Repair ◽  
Rna Virus ◽  
Nonstructural Protein ◽  
Rift Valley Fever Virus ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Valley Fever ◽  
Infected Cells

Rift Valley fever virus (RVFV) is a single-stranded RNA virus capable of inducing fatal hemorrhagic fever in humans. A key component of RVFV virulence is its ability to form nuclear filaments through interactions between the viral nonstructural protein NSs and the host general transcription factor TFIIH. Here, we identify an interaction between a ΩXaV motif in NSs and the p62 subunit of TFIIH. This motif in NSs is similar to ΩXaV motifs found in nucleotide excision repair (NER) factors and transcription factors known to interact with p62. Structural and biophysical studies demonstrate that NSs binds to p62 in a similar manner as these other factors. Functional studies in RVFV-infected cells show that the ΩXaV motif is required for both nuclear filament formation and degradation of p62. Consistent with the fact that the RVFV can be distinguished from otherBunyaviridae-family viruses due to its ability to form nuclear filaments in infected cells, the motif is absent in the NSs proteins of otherBunyaviridae-family viruses. Taken together, our studies demonstrate that p62 binding to NSs through the ΩXaV motif is essential for degrading p62, forming nuclear filaments and enhancing RVFV virulence. In addition, these results show how the RVFV incorporates a simple motif into the NSs protein that enables it to functionally mimic host cell proteins that bind the p62 subunit of TFIIH.

scholarly journals Sorafenib Impedes Rift Valley Fever Virus Egress by Inhibiting Valosin-Containing Protein Function in the Cellular Secretory Pathway

2017 ◽  
Vol 91 (21) ◽  
Author(s):  
Ashwini Brahms ◽  
Rajini Mudhasani ◽  
Chelsea Pinkham ◽  
Krishna Kota ◽  
Farooq Nasar ◽  
...  
Keyword(s):  
Host Cell ◽  
Golgi Complex ◽  
Rift Valley ◽  
Rift Valley Fever ◽  
Secretory Pathway ◽  
Rift Valley Fever Virus ◽  
Fever Virus ◽  
Sub Saharan Africa ◽  
Microscopy Imaging ◽  
Valley Fever

ABSTRACT There is an urgent need for therapeutic development to combat infections caused by Rift Valley fever virus (RVFV), which causes devastating disease in both humans and animals. In an effort to repurpose drugs for RVFV treatment, our previous studies screened a library of FDA-approved drugs. The most promising candidate identified was the hepatocellular and renal cell carcinoma drug sorafenib. Mechanism-of-action studies indicated that sorafenib targeted a late stage in virus infection and caused a buildup of virions within cells. In addition, small interfering RNA (siRNA) knockdown studies suggested that nonclassical targets of sorafenib are important for the propagation of RVFV. Here we extend our previous findings to identify the mechanism by which sorafenib inhibits the release of RVFV virions from the cell. Confocal microscopy imaging revealed that glycoprotein Gn colocalizes and accumulates within the endoplasmic reticulum (ER) and the transport of Gn from the Golgi complex to the host cell membrane is reduced. Transmission electron microscopy demonstrated that sorafenib caused virions to be present inside large vacuoles inside the cells. p97/valosin-containing protein (VCP), which is involved in membrane remodeling in the secretory pathway and a known target of sorafenib, was found to be important for RVFV egress. Knockdown of VCP resulted in decreased RVFV replication, reduced Gn Golgi complex localization, and increased Gn ER accumulation. The intracellular accumulation of RVFV virions was also observed in cells transfected with siRNA targeting VCP. Collectively, these data indicate that sorafenib causes a disruption in viral egress by targeting VCP and the secretory pathway, resulting in a buildup of virions within dilated ER vesicles. IMPORTANCE In humans, symptoms of RVFV infection mainly include a self-limiting febrile illness. However, in some cases, infected individuals can also experience hemorrhagic fever, neurological disorders, liver failure, and blindness, which could collectively be lethal. The ability of RVFV to expand geographically outside sub-Saharan Africa is of concern, particularly to the Americas, where native mosquito species are capable of virus transmission. Currently, there are no FDA-approved therapeutics to treat RVFV infection, and thus, there is an urgent need to understand the mechanisms by which the virus hijacks the host cell machinery to replicate. The significance of our research is in identifying the cellular target of sorafenib that inhibits RVFV propagation, so that this information can be used as a tool for the further development of therapeutics used to treat RVFV infection.

scholarly journals Rift Valley Fever Virus Strain MP-12 Enters Mammalian Host Cells via Caveola-Mediated Endocytosis

2012 ◽  
Vol 86 (23) ◽  
pp. 12954-12970 ◽  
Author(s):  
B. Harmon ◽  
B. R. Schudel ◽  
D. Maar ◽  
C. Kozina ◽  
T. Ikegami ◽  
...  
Keyword(s):  
Virus Strain ◽  
Rift Valley ◽  
Rift Valley Fever ◽  
Rift Valley Fever Virus ◽  
Fever Virus ◽  
Host Cells ◽  
Mammalian Host ◽  
Valley Fever

scholarly journals First Serological Evidence of Crimean-Congo Hemorrhagic Fever Virus and Rift Valley Fever Virus in Ruminants in Tunisia

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 769
Author(s):  
Khaoula Zouaghi ◽  
Ali Bouattour ◽  
Hajer Aounallah ◽  
Rebecca Surtees ◽  
Eva Krause ◽  
...  
Keyword(s):  
Risk Factors ◽  
Potential Risk ◽  
Rift Valley ◽  
Rift Valley Fever ◽  
Rift Valley Fever Virus ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Valley Fever ◽  
Hemorrhagic Fever Virus ◽  
Potential Risk Factors

Crimean-Congo hemorrhagic fever virus (CCHFV, Nairoviridae family) and Rift Valley fever virus (RVFV, Phenuiviridae family) are zoonotic vector-borne pathogens with clinical relevance worldwide. Our study aimed to determine seroprevalences of these viruses and potential risk factors among livestock (cattle, sheep, and goats) in Tunisia. Sera were tested for antibodies against CCHFV (n = 879) and RVFV (n = 699) using various enzyme-linked immunosorbent assays (ELISAs) and indirect immunofluorescence assays (IIFA). The overall seroprevalence of IgG antibodies was 8.6% (76/879) and 2.3% (16/699) against CCHFV and RVFV, respectively. For CCHF seropositivity bioclimatic zones and breed were potential risk factors for the three tested animal species; while the season was associated with cattle and sheep seropositivity, tick infestation was associated with cattle and goats seropositivity and age as a risk factor was only associated with cattle seropositivity. Age and season were significantly associated with RVFV seropositivity in sheep. Our results confirm the circulation of CCHFV and RVFV in Tunisia and identified the principal risk factors in ruminants. This knowledge could help to mitigate the risk of ruminant infections and subsequently also human infections.

scholarly journals Co-circulation of Orthobunyaviruses and Rift Valley Fever Virus in Mauritania, 2015

2021 ◽  
Vol 12 ◽  
Author(s):  
Nicole Cichon ◽  
Yahya Barry ◽  
Franziska Stoek ◽  
Abdellah Diambar ◽  
Aliou Ba ◽  
...  
Keyword(s):  
Rift Valley ◽  
High Performance ◽  
Rift Valley Fever ◽  
Rift Valley Fever Virus ◽  
Small Ruminants ◽  
Hemorrhagic Fever ◽  
Cross Reactivity ◽  
Fever Virus ◽  
Serum Samples ◽  
Valley Fever

Ngari virus (NRIV) has been mostly detected during concurrent outbreaks of Rift Valley fever virus (RVFV). NRIV is grouped in the genus Orthobunyavirus within the Bunyaviridae family and RVFV in the genus Phlebovirus in the family Phenuiviridae. Both are zoonotic arboviruses and can induce hemorrhagic fever displaying the same clinical picture in humans and small ruminants. To investigate if NRIV and its parental viruses, Bunyamwera virus (BUNV) and Batai virus (BATV), played a role during the Mauritanian RVF outbreak in 2015/16, we analyzed serum samples of sheep and goats from central and southern regions in Mauritania by quantitative real-time RT-PCR, serum neutralization test (SNT) and ELISA. 41 of 458 samples exhibited neutralizing reactivity against NRIV, nine against BATV and three against BUNV. Moreover, complete virus genomes from BUNV could be recovered from two sheep as well as two NRIV isolates from a goat and a sheep. No RVFV-derived viral RNA was detected, but 81 seropositive animals including 22 IgM-positive individuals were found. Of these specimens, 61 samples revealed antibodies against RVFV and at least against one of the three orthobunyaviruses. An indirect ELISA based on NRIV/BATV and BUNV derived Gc protein was established as complement to SNT, which showed high performance regarding NRIV, but decreased sensitivity and specificity regarding BATV and BUNV. Moreover, we observed high cross-reactivity among NRIV and BATV serological assays. Taken together, the data indicate the co-circulation of at least BUNV and NRIV in the Mauritanian sheep and goat populations.

scholarly journals Heparan Sulfate Facilitates Rift Valley Fever Virus Entry into the Cell

2012 ◽  
Vol 86 (24) ◽  
pp. 13767-13771 ◽  
Author(s):  
S. M. de Boer ◽  
J. Kortekaas ◽  
C. A. M. de Haan ◽  
P. J. M. Rottier ◽  
R. J. M. Moormann ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Rift Valley ◽  
Rift Valley Fever ◽  
Virus Entry ◽  
Rift Valley Fever Virus ◽  
Fever Virus ◽  
Valley Fever

scholarly journals Characterization of Two Neutralizing Antibodies against Rift Valley Fever Virus Gn Protein

Viruses ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 259
Author(s):  
Meng Hao ◽  
Guanying Zhang ◽  
Shengnan Zhang ◽  
Zhengshan Chen ◽  
Xiangyang Chi ◽  
...  
Keyword(s):  
Rift Valley ◽  
Neutralizing Antibodies ◽  
Rift Valley Fever ◽  
Rift Valley Fever Virus ◽  
Severe Disease ◽  
Fever Virus ◽  
Host Cells ◽  
Valley Fever ◽  
Endosomal Membranes ◽  
Domain Iii

The Rift Valley fever virus (RVFV) is an arthropod-borne virus that can not only cause severe disease in domestic animals but also in humans. However, the licensed vaccines or available therapeutics for humans do not exist. Here, we report two Gn-specific neutralizing antibodies (NAbs), isolated from a rhesus monkey immunized with recombinant human adenoviruses type 4 expressing Rift Valley fever virus Gn and Gc protein (rHAdV4-GnGcopt). The two NAbs were both able to protect host cells from RVFV infection. The interactions between NAbs and Gn were then characterized to demonstrate that these two NAbs might preclude RVFV glycoprotein rearrangement, hindering the exposure of fusion loops in Gc to endosomal membranes after the virus invades the host cell. The target region for the two NAbs is located in the Gn domain III, implying that Gn is a desired target for developing vaccines and neutralizing antibodies against RVFV.

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