scholarly journals Rift Valley Fever Virus Propagates in Human Villous Trophoblast Cell Lines and Induces Cytokine mRNA Responses Known to Provoke Miscarriage

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2265
Author(s):  
Yong-Dae Gwon ◽  
Seyed Alireza Nematollahi Mahani ◽  
Ivan Nagaev ◽  
Lucia Mincheva-Nilsson ◽  
Magnus Evander
Keyword(s):  
Inflammatory Response ◽  
Mrna Expression ◽  
Cell Lines ◽  
Rift Valley ◽  
Rift Valley Fever ◽  
Rift Valley Fever Virus ◽  
Trophoblast Cell ◽  
Wild Type ◽  
Valley Fever ◽  
Protective Environment

The mosquito-borne Rift Valley fever (RVF) is a prioritised disease that has been listed by the World Health Organization for urgent research and development of counteraction. Rift Valley fever virus (RVFV) can cause a cytopathogenic effect in the infected cell and induce hyperimmune responses that contribute to pathogenesis. In livestock, the consequences of RVFV infection vary from mild symptoms to abortion. In humans, 1–3% of patients with RVFV infection develop severe disease, manifested as, for example, haemorrhagic fever, encephalitis or blindness. RVFV infection has also been associated with miscarriage in humans. During pregnancy, there should be a balance between pro-inflammatory and anti-inflammatory mediators to create a protective environment for the placenta and foetus. Many viruses are capable of penetrating that protective environment and infecting the foetal–maternal unit, possibly via the trophoblasts in the placenta, with potentially severe consequences. Whether it is the viral infection per se, the immune response, or both that contribute to the pathogenesis of miscarriage remains unknown. To investigate how RVFV could contribute to pathogenesis during pregnancy, we infected two human trophoblast cell lines, A3 and Jar, representing normal and transformed human villous trophoblasts, respectively. They were infected with two RVFV variants (wild-type RVFV and RVFV with a deleted NSs protein), and the infection kinetics and 15 different cytokines were analysed. The trophoblast cell lines were infected by both RVFV variants and infection caused upregulation of messenger RNA (mRNA) expression for interferon (IFN) types I–III and inflammatory cytokines, combined with cell line-specific mRNA expression of transforming growth factor (TGF)-β1 and interleukin (IL)-10. When comparing the two RVFV variants, we found that infection with RVFV lacking NSs function caused a hyper-IFN response and inflammatory response, while the wild-type RVFV suppressed the IFN I and inflammatory response. The induction of certain cytokines by RVFV infection could potentially lead to teratogenic effects that disrupt foetal and placental developmental pathways, leading to birth defects and other pregnancy complications, such as miscarriage.

scholarly journals Comparison of Rift Valley fever virus replication in North American livestock and wildlife cell lines

2015 ◽  
Vol 6 ◽  
Author(s):  
Natasha N. Gaudreault ◽  
Sabarish V. Indran ◽  
P. K. Bryant ◽  
Juergen A. Richt ◽  
William C. Wilson
Keyword(s):  
Cell Lines ◽  
Virus Replication ◽  
North American ◽  
Rift Valley ◽  
Rift Valley Fever ◽  
Rift Valley Fever Virus ◽  
Fever Virus ◽  
Valley Fever

scholarly journals T7 RNA polymerase-dependent and -independent systems for cDNA-based rescue of Rift Valley fever virus

2008 ◽  
Vol 89 (9) ◽  
pp. 2157-2166 ◽  
Author(s):  
Matthias Habjan ◽  
Nicola Penski ◽  
Martin Spiegel ◽  
Friedemann Weber
Keyword(s):  
Rna Polymerase ◽  
Rift Valley ◽  
Rift Valley Fever ◽  
Cell Clone ◽  
Rift Valley Fever Virus ◽  
Fever Virus ◽  
T7 Rna Polymerase ◽  
Wild Type ◽  
Valley Fever ◽  
Pol I

Rift Valley fever virus (RVFV) is responsible for large and recurrent outbreaks of acute febrile illness among humans and domesticated animals in Africa. It belongs to the family Bunyaviridae, genus Phlebovirus, and its negative-stranded RNA genome consists of three segments. Here, we report the establishment and characterization of two different systems to rescue the RVFV wild-type strain ZH548. The first system is based on the BHK-21 cell clone BSR-T7/5, which stably expresses T7 RNA polymerase (T7 pol). Rescue of wild-type RVFV was achieved with three T7 pol-driven cDNA plasmids representing the viral RNA segments in the antigenomic sense. The second system involves 293T cells transfected with three RNA pol I-driven plasmids for the viral segments and two RNA pol II-driven support plasmids to express the viral polymerase components L and N. It is known that the 5′ triphosphate group of T7 pol transcripts strongly activates the antiviral interferon system via the intracellular RNA receptor RIG-I. Nonetheless, both the T7 pol and the pol I/II system were of similar efficiency. This was even true for the rescue of a RVFV mutant lacking the interferon antagonist nonstructural proteins. Further experiments demonstrated that the unresponsiveness of BHK-21 and BSR-T7/5 cells to T7 pol transcripts is most probably due to a deficiency in the RIG-I pathway. Our reverse genetics systems now enable us to manipulate the genome of RVFV and study its virulence mechanisms. Moreover, the finding that BHK-derived cell lines have a compromised RIG-I pathway may explain their suitability for propagating and rescuing a wide variety of viruses.

Vaccination with Rift Valley fever virus live attenuated vaccine strain Smithburn caused meningoencephalitis in alpacas

2021 ◽  
pp. 104063872110152
Author(s):  
Tasneem Anthony ◽  
Antoinette van Schalkwyk ◽  
Marco Romito ◽  
Lieza Odendaal ◽  
Sarah J. Clift ◽  
...  
Keyword(s):  
Vaccine Strain ◽  
Rift Valley ◽  
Rift Valley Fever ◽  
Rift Valley Fever Virus ◽  
Close Association ◽  
Wild Type Virus ◽  
Post Inoculation ◽  
Wild Type ◽  
Valley Fever ◽  
Neuronal Necrosis

Rift Valley fever (RVF) is a zoonotic, viral, mosquito-borne disease that causes considerable morbidity and mortality in humans and livestock in Africa and the Arabian Peninsula. In June 2018, 4 alpaca inoculated subcutaneously with live attenuated RVF virus (RVFV) Smithburn strain exhibited pyrexia, aberrant vocalization, anorexia, neurologic signs, and respiratory distress. One animal died the evening of inoculation, and 2 at ~20 d post-inoculation. Concern regarding potential vaccine strain reversion to wild-type RVFV or vaccine-induced disease prompted autopsy of the latter two. Macroscopically, both alpacas had severe pulmonary edema and congestion, myocardial hemorrhages, and cyanotic mucous membranes. Histologically, they had cerebral nonsuppurative encephalomyelitis with perivascular cuffing, multifocal neuronal necrosis, gliosis, and meningitis. Lesions were more severe in the 4-mo-old cria. RVFV antigen and RNA were present in neuronal cytoplasm, by immunohistochemistry and in situ hybridization (ISH) respectively, and cerebrum was also RVFV positive by RT-rtPCR. The virus clustered in lineage K (100% sequence identity), with close association to Smithburn sequences published previously (identity: 99.1–100%). There was neither evidence of an aberrant immune-mediated reaction nor reassortment with wild-type virus. The evidence points to a pure infection with Smithburn vaccine strain as the cause of the animals’ disease.

scholarly journals Genetic Evidence for an Interferon-Antagonistic Function of Rift Valley Fever Virus Nonstructural Protein NSs

2001 ◽  
Vol 75 (3) ◽  
pp. 1371-1377 ◽  
Author(s):  
Michèle Bouloy ◽  
Christian Janzen ◽  
Pierre Vialat ◽  
Huot Khun ◽  
Jovan Pavlovic ◽  
...  
Keyword(s):  
Rift Valley ◽  
Rift Valley Fever ◽  
Nonstructural Protein ◽  
Rift Valley Fever Virus ◽  
Fever Virus ◽  
Sub Saharan Africa ◽  
Wild Type ◽  
Valley Fever ◽  
Viral Virulence ◽  
Deficient Mice

ABSTRACT Rift Valley fever virus (RVFV), a phlebovirus of the family Bunyaviridae, is a major public health threat in Egypt and sub-Saharan Africa. The viral and host cellular factors that contribute to RVFV virulence and pathogenicity are still poorly understood. All pathogenic RVFV strains direct the synthesis of a nonstructural phosphoprotein (NSs) that is encoded by the smallest (S) segment of the tripartite genome and has an undefined accessory function. In this report, we show that MP12 and clone 13, two attenuated RVFV strains with mutations in the NSs gene, were highly virulent in IFNAR−/− mice lacking the alpha/beta interferon (IFN-α/β) receptor but remained attenuated in IFN-γ receptor-deficient mice. Both attenuated strains proved to be excellent inducers of early IFN-α/β production. In contrast, the virulent strain ZH548 failed to induce detectable amounts of IFN-α/β and replicated extensively in both IFN-competent and IFN-deficient mice. Clone 13 has a defective NSs gene with a large in-frame deletion. This defect in the NSs gene results in expression of a truncated protein which is rapidly degraded. To investigate whether the presence of the wild-type NSs gene correlated with inhibition of IFN-α/β production, we infected susceptible IFNAR−/− mice with S gene reassortant viruses. When the S segment of ZH548 was replaced by that of clone 13, the resulting reassortants became strong IFN inducers. When the defective S segment of clone 13 was exchanged with the wild-type S segment of ZH548, the reassortant virus lost the capacity to stimulate IFN-α/β production. These results demonstrate that the ability of RVFV to inhibit IFN-α/β production correlates with viral virulence and suggest that the accessory protein NSs is an IFN antagonist.

Exploration of (hetero)aryl Derived Thienylchalcones for Antiviral and Anticancer Activities

2019 ◽  
Vol 15 (2) ◽  
pp. 150-161 ◽  
Author(s):  
Vikrant Patil ◽  
Siddappa A. Patil ◽  
Renukadevi Patil ◽  
Alejandro Bugarin ◽  
Kenneth Beaman ◽  
...  
Keyword(s):  
Cell Lines ◽  
Anticancer Agents ◽  
Rift Valley ◽  
Rift Valley Fever ◽  
Rift Valley Fever Virus ◽  
Neutral Red ◽  
Valley Fever ◽  
Neutral Red Assay ◽  
Tacaribe Virus ◽  
Visual Assay

Background: Search for new antiviral and anticancer agents are essential because of the emergence of drug resistance in recent years. In continuation of our efforts in identifying the new small molecule antiviral and anticancer agents, we identified chalcones as potent antiviral and anticancer agents. Objective: With the aim of identifying the broad acting antiviral and anticancer agents, we discovered substituted aryl/heteroaryl derived thienyl chalcones as antiviral and anticancer agents. Method: A focused set of thienyl chalcone derivaties II-VI was screened for selected viruses Hepatitis B virus (HBV), Herpes simplex virus 1 (HSV-1), Human cytomegalovirus (HCMV), Dengue virus 2 (DENV2), Influenza A (H1N1) virus, MERS coronavirus, Poliovirus 1 (PV 1), Rift Valley fever (RVF), Tacaribe virus (TCRV), Venezuelan equine encephalitis virus (VEE) and Zika virus (ZIKV) using the National Institute of Allergy and Infectious Diseases (NIAID)’s Division of Microbiology and Infectious Diseases (DMID) antiviral screening program. Additionally, a cyclopropylquinoline derivative IV has been screened for 60 human cancer cell lines using the Development Therapeutics Program (DTP) of NCI. Results: All thienyl chalcone derivatives II-VI displayed moderate to excellent antiviral activity towards several viruses tested. Compounds V and VI were turned out be active compounds towards human cytomegalovirus for both normal strain (AD169) as well as resistant isolate (GDGr K17). Particularly, cyano derivative V showed very high potency (EC50: <0.05 µM) towards AD169 strain of HCMV compared to standard drug Ganciclovir (EC50: 0.12 µM). Additionally, it showed moderate activity in the secondary assay (AD169; EC50: 2.30 µM). The cyclopropylquinoline derivative IV displayed high potency towards Rift Valley fever virus (RVFV) and Tacaribe virus (TCRV) towards Rift Valley fever virus (RVFV). The cyclopropylquinoline derivative IV is nearly 28 times more potent in our initial in vitro visual assay (EC50: 0.39 µg/ml) and nearly 17 times more potent in neutral red assay (EC50: 0.71 μg/ml) compared to the standard drug Ribavirin (EC50: 11 µg/ml; visual assay and EC50: 12 µg/ml; neutral red assay). It is nearly 12 times more potent in our initial in vitro visual assay (EC50: >1 µg/ml) and nearly 8 times more potent in neutral red assay (EC50: >1.3 µg/ml) compared to the standard drug Ribavirin (EC50: 12 µg/ml; visual assay and EC50: 9.9 µg/ml; neutral red assay) towards Tacaribe virus (TCRV). Additionally, cyclopropylquinoline derivative IV has shown strong growth inhibitory activity towards three major cancers (colon, breast, and leukemia) cell lines and moderate growth inhibition shown towards other cancer cell lines screened. Conclusion: Compounds V and VI were demonstrated viral inhibition towards Human cytomegalovirus, whereas cyclopropylquinoline derivative IV towards Rift Valley fever virus and Tacaribe virus. Additionally, cyclopropylquinoline derivative IV has displayed very good cytotoxicity against colon, breast and leukemia cell lines in vitro.

scholarly journals Replication of Rift Valley Fever Virus in Amphibian and Reptile-Derived Cell Lines

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 681
Author(s):  
Melanie Rissmann ◽  
Matthias Lenk ◽  
Franziska Stoek ◽  
Claudia A. Szentiks ◽  
Martin Eiden ◽  
...  
Keyword(s):  
Cell Lines ◽  
Rift Valley ◽  
Rift Valley Fever ◽  
Rift Valley Fever Virus ◽  
Field Studies ◽  
African Countries ◽  
Valley Fever ◽  
Pond Turtle

Rift Valley fever phlebovirus (RVFV) is a zoonotic arthropod-borne virus, which has led to devastating epidemics in African countries and on the Arabian Peninsula. Results of in-vivo, in-vitro and field studies suggested that amphibians and reptiles may play a role as reservoir hosts of RVFV, promoting its maintenance during inter-epidemic periods. To elucidate this hypothesis, we examined two newly established reptile-derived cell lines (Egyptian cobra and Chinese pond turtle) and five previously generated reptile- and amphibian-derived cell lines for their replicative capacity for three low- and high-pathogenic RVFV strains. At different time points after infection, viral loads (TCID50), genome loads and the presence of intracellular viral antigen (immunofluorescence) were assessed. Additionally, the influence of temperatures on the replication was examined. Except for one cell line (read-eared slider), all seven cell lines were infected by all three RVFV strains. Two different terrapin-derived cell lines (Common box turtle, Chinese pond turtle) were highly susceptible. A temperature-dependent replication of RVFV was detected for both amphibian and reptile cells. In conclusion, the results of this study indicate the general permissiveness of amphibian and reptile cell lines to RVFV and propose a potential involvement of terrapins in the virus ecology.

scholarly journals Rift Valley Fever Virus MP-12 Vaccine Is Fully Attenuated by a Combination of Partial Attenuations in the S, M, and L Segments

2015 ◽  
Vol 89 (14) ◽  
pp. 7262-7276 ◽  
Author(s):  
Tetsuro Ikegami ◽  
Terence E. Hill ◽  
Jennifer K. Smith ◽  
Lihong Zhang ◽  
Terry L. Juelich ◽  
...  
Keyword(s):  
United States ◽  
Rift Valley ◽  
Rift Valley Fever ◽  
Rift Valley Fever Virus ◽  
The United States ◽  
Fever Virus ◽  
Pathogenic Strain ◽  
Wild Type ◽  
Valley Fever ◽  
Content Type

ABSTRACTRift Valley fever (RVF) is a mosquito-borne zoonotic disease endemic to Africa and characterized by a high rate of abortion in ruminants and hemorrhagic fever, encephalitis, or blindness in humans. RVF is caused by Rift Valley fever virus (RVFV; familyBunyaviridae, genusPhlebovirus), which has a tripartite negative-stranded RNA genome (consisting of the S, M, and L segments). Further spread of RVF into countries where the disease is not endemic may affect the economy and public health, and vaccination is an effective approach to prevent the spread of RVFV. A live-attenuated MP-12 vaccine is one of the best-characterized RVF vaccines for safety and efficacy and is currently conditionally licensed for use for veterinary purposes in the United States. Meanwhile, as of 2015, no other RVF vaccine has been conditionally or fully licensed for use in the United States. The MP-12 strain is derived from wild-type pathogenic strain ZH548, and its genome encodes 23 mutations in the three genome segments. However, the mechanism of MP-12 attenuation remains unknown. We characterized the attenuation of wild-type pathogenic strain ZH501 carrying a mutation(s) of the MP-12 S, M, or L segment in a mouse model. Our results indicated that MP-12 is attenuated by the mutations in the S, M, and L segments, while the mutations in the M and L segments confer stronger attenuation than those in the S segment. We identified a combination of 3 amino acid changes, Y259H (Gn), R1182G (Gc), and R1029K (L), that was sufficient to attenuate ZH501. However, strain MP-12 with reversion mutations at those 3 sites was still highly attenuated. Our results indicate that MP-12 attenuation is supported by a combination of multiple partial attenuation mutations and a single reversion mutation is less likely to cause a reversion to virulence of the MP-12 vaccine.IMPORTANCERift Valley fever (RVF) is a mosquito-transmitted viral disease that is endemic to Africa and that has the potential to spread into other countries. Vaccination is considered an effective way to prevent the disease, and the only available veterinary RVF vaccine in the United States is a live-attenuated MP-12 vaccine, which is conditionally licensed. Strain MP-12 is different from its parental pathogenic RVFV strain, strain ZH548, because of the presence of 23 mutations. This study determined the role of individual mutations in the attenuation of the MP-12 strain. We found that full attenuation of MP-12 occurs by a combination of multiple mutations. Our findings indicate that a single reversion mutation will less likely cause a major reversion to virulence of the MP-12 vaccine.

scholarly journals Safety and Immunogenicity of Four-Segmented Rift Valley Fever Virus in the Common Marmoset

2021 ◽  
Author(s):  
Paul Wichgers Schreur ◽  
Petra Mooij ◽  
Gerrit Koopman ◽  
Babs Verstrepen ◽  
Zahra Fagrouch ◽  
...  
Keyword(s):  
Rift Valley ◽  
Rift Valley Fever ◽  
Rift Valley Fever Virus ◽  
Common Marmoset ◽  
Fever Virus ◽  
Wild Type ◽  
Valley Fever ◽  
Veterinary Vaccine ◽  
The Common ◽  
Human Vaccine

Abstract Rift Valley fever virus (RVFV) is an emerging mosquito-borne bunyavirus that is highly pathogenic to wild- and domesticated ruminants, camelids and humans. While animals are exclusively infected via mosquito bites, humans can also be infected via contact with tissues or blood released during the slaughtering of RVFV-infected animals. No human vaccine is available and currently commercialized veterinary vaccines do not optimally combine efficacy with safety. We previously reported the development of two novel live-attenuated RVF vaccines, created by splitting the M genome segment and deleting the major virulence determinant NSs. The vaccine candidates, referred to as the veterinary vaccine vRVFV-4s and the human vaccine hRVFV-4s, were shown to induce protective immunity in multiple species after a single vaccination. Anticipating on accidental exposure of humans to the veterinary vaccine, and to evaluate the safety of the hRVFV-4s candidate vaccine for humans, the safety of each vaccine was evaluated in the most susceptible nonhuman primate model, the common marmoset (Callithrix jacchus). Marmosets were inoculated with high doses of each vaccine and were monitored for clinical signs as well as for vaccine virus dissemination, shedding and spreading to the environment. To accurately assess the attenuation of both vaccine viruses, separate groups of marmosets were inoculated with the parent wild-type RVFV strains. Both wild-type strains induced high viremia and disseminated to primary target organs, associated with mild- to severe morbidity, while both vaccines were well tolerated with absence of dissemination and shedding, while inducing potent neutralizing antibody responses. The results of the studies support the unprecedented safety profile of both vaccines for animals and humans.

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