Type I interferons are essential while type II interferon is dispensable for protection against St. Louis encephalitis virus infection in the mouse brain
Abstract:St. Louis encephalitis virus (SLEV) is a neglected mosquito-borne flavivirus that causes severe neurological disease in humans. SLEV replication in the central nervous system (CNS) induces the local production of interferons (IFNs), which are attributed to host protection. The antiviral response to SLEV infection in the CNS is not completely understood, which led us to characterize the roles of IFNs using mouse models of St. Louis encephalitis. We infected mice deficient in type I IFN receptor (ABR −/-) or def… Show more
“…By contrast, no bioluminescent signal was detected in the control 129 mouse group, which remained healthy throughout the experiment ( Figure 4(B,C) ). These results are consistent with previous findings that type I IFN signaling control of flavivirus infection [ 32 ]. Figure 4.…”
Section: Resultssupporting
confidence: 94%
“…4B and 4C). These results are consistent with previous findings that type I IFN signaling control of flavivirus infection (32).…”
Section: Establishment Of a Bli-based Animal Model Of Yel-avd And Yel-andsupporting
Yellow fever virus (YFV) is a re-emerging flavivirus, which can lead to severe clinical manifestations and high mortality, with no specific antiviral therapies available. The live-attenuated yellow fever vaccine 17D (YF17D) has been widely used for over eighty years. However, the emergence of yellow fever vaccine-associated viscerotropic disease (YFL-AVD) and yellow fever vaccine-associated neurotropic disease (YFL-AND) raised non-negligible concerns. Additionally, the attenuation mechanism of YF17D is still unclear. Thus, the development of convenient models is crucial to understand the mechanisms behind YF17D attenuation and its adverse effects. In this work, we generated a reporter YF17D expressing nano-luciferase (NLuc).
In vitro
and
in vivo
characterization demonstrated that the NLuc-YF17D shared similar biological properties with its parental strain and the NLuc activity can reflect viral infectivity reliably. Combined with
in vivo
bioluminescence imaging, a series of mice models of YF17D infection was established, which will be useful for the evaluation of antiviral medicines and novel vaccine candidates. Especially, we demonstrated that intraperitoneally (i.p.) infection of NLuc-YF17D in type I interferon receptor-deficient mice A129 resulted in outcomes resembling YEL-AVD and YEL-AND, evidenced by viral replication in multiple organs and invasion of the central neuronal system. Finally,
in vitro
and
in vivo
assays based on this reporter virus were established to evaluate the antiviral activities of validated antiviral agents. In conclusion, the bioluminescent reporter virus described herein provides a powerful platform to study YF17D attenuation and vaccine-associated diseases as well as to develop novel countermeasures against YFV.
“…By contrast, no bioluminescent signal was detected in the control 129 mouse group, which remained healthy throughout the experiment ( Figure 4(B,C) ). These results are consistent with previous findings that type I IFN signaling control of flavivirus infection [ 32 ]. Figure 4.…”
Section: Resultssupporting
confidence: 94%
“…4B and 4C). These results are consistent with previous findings that type I IFN signaling control of flavivirus infection (32).…”
Section: Establishment Of a Bli-based Animal Model Of Yel-avd And Yel-andsupporting
Yellow fever virus (YFV) is a re-emerging flavivirus, which can lead to severe clinical manifestations and high mortality, with no specific antiviral therapies available. The live-attenuated yellow fever vaccine 17D (YF17D) has been widely used for over eighty years. However, the emergence of yellow fever vaccine-associated viscerotropic disease (YFL-AVD) and yellow fever vaccine-associated neurotropic disease (YFL-AND) raised non-negligible concerns. Additionally, the attenuation mechanism of YF17D is still unclear. Thus, the development of convenient models is crucial to understand the mechanisms behind YF17D attenuation and its adverse effects. In this work, we generated a reporter YF17D expressing nano-luciferase (NLuc).
In vitro
and
in vivo
characterization demonstrated that the NLuc-YF17D shared similar biological properties with its parental strain and the NLuc activity can reflect viral infectivity reliably. Combined with
in vivo
bioluminescence imaging, a series of mice models of YF17D infection was established, which will be useful for the evaluation of antiviral medicines and novel vaccine candidates. Especially, we demonstrated that intraperitoneally (i.p.) infection of NLuc-YF17D in type I interferon receptor-deficient mice A129 resulted in outcomes resembling YEL-AVD and YEL-AND, evidenced by viral replication in multiple organs and invasion of the central neuronal system. Finally,
in vitro
and
in vivo
assays based on this reporter virus were established to evaluate the antiviral activities of validated antiviral agents. In conclusion, the bioluminescent reporter virus described herein provides a powerful platform to study YF17D attenuation and vaccine-associated diseases as well as to develop novel countermeasures against YFV.
“…Thus, neutrophils are known to participate in severe neurological disease caused by SLEV, but it is unknown whether neutrophils contribute to protection or disease development. In accordance with in-vivo studies with other flaviviruses, mouse models of SLEV infection have shown that viral replication and access to the central nervous system are major factors in disease development, as absence of a functional type-I IFN response renders mice completely susceptible to SLEV infection, disease and death [ 98 ]. Excessive SLEV replication in the tissues of IFNAR −/− mice result in early and aggravated onset of neurological disease, including the production of the neutrophil-chemoattractant CXCL1 and increases in MPO levels in infected brains [ 95 , 98 ].…”
Section: Participation Of Neutrophils and Neutrophil-associated Molecules In Flaviviral Diseasesmentioning
Neutrophils are first-line responders to infections and are recruited to target tissues through the action of chemoattractant molecules, such as chemokines. Neutrophils are crucial for the control of bacterial and fungal infections, but their role in the context of viral infections has been understudied. Flaviviruses are important human viral pathogens transmitted by arthropods. Infection with a flavivirus may result in a variety of complex disease manifestations, including hemorrhagic fever, encephalitis or congenital malformations. Our understanding of flaviviral diseases is incomplete, and so is the role of neutrophils in such diseases. Here we present a comprehensive overview on the participation of neutrophils in severe disease forms evolving from flavivirus infection, focusing on the role of chemokines and their receptors as main drivers of neutrophil function. Neutrophil activation during viral infection was shown to interfere in viral replication through effector functions, but the resulting inflammation is significant and may be detrimental to the host. For congenital infections in humans, neutrophil recruitment mediated by CXCL8 would be catastrophic. Evidence suggests that control of neutrophil recruitment to flavivirus-infected tissues may reduce immunopathology in experimental models and patients, with minimal loss to viral clearance. Further investigation on the roles of neutrophils in flaviviral infections may reveal unappreciated functions of this leukocyte population while increasing our understanding of flaviviral disease pathogenesis in its multiple forms.
“…Cell culture supernatant was collected at 48 h post-infection in dose-dependent assays of 7DMA, and 24 h post-infection in antiviral effect and cell viability assay for i7DMA. Viral loads were assessed using plaque-forming assays ( Rocha et al, 2021 ). Cell culture viability was assessed using MTT assays [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] according to recommendations from the manufacturer (Merck).…”
A short 3-step synthesis of the antiviral agent 7DMA is described herein. The nature of a major by-product formed during the key N-glycosylation of 6-chloro-7-deaza-7-iodopurine with perbenzoylated 2-methyl-ribose under Vorbrüggen conditions was also investigated. Spectroscopic analyses support that the solvent itself is converted into a nucleophilic species competing with the nucleobase and further reacting with the activated riboside in an unanticipated fashion. These findings call for a revision of reaction conditions when working with weakly reactive nucleobases in the presence of Lewis acids. 7DMA thus obtained was evaluated for its efficacy against an emerging flavivirus in vitro.
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