Spectrum of disease outcomes in mice infected with YFV-17D

Erickson, Andrea K.; Pfeiffer, Julie K.

doi:10.1099/vir.0.000075

Cited by 23 publications

(32 citation statements)

References 60 publications

(63 reference statements)

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“…In contrast, αβR −/− and αβR −/− λR −/− mice were highly viremic during the first 5 days postinfection ( Fig. 2A ), demonstrating the critical role of type I IFN in controlling early viral replication and consistent with previous findings ( 7 , 12 , 13 ). IFN-λ did not appear to have any impact on peripheral viral replication even when type I IFN signaling was abrogated.…”

Section: Resultssupporting

confidence: 91%

“…A major limitation in understanding this lies in the restricted human and nonhuman primate tropism of YFV and the lack of proper animal models. Mice are poorly susceptible to YFV infection ( 7 , 8 ) and hence are not appropriate for fully characterizing the mechanisms that regulate YFV pathogenesis or attenuation.…”

Section: Introductionmentioning

confidence: 99%

“…The type I IFN family, which consists of 17 members, induces signaling through the IFN-α/β receptor (IFN-α/βR). Type I IFN is responsible for the immune response to many viruses, such as lymphocytic choriomeningitis virus (LCMV), Semliki Forest virus, and vesicular stomatitis virus ( 11 ), and can inhibit YFV-Asibi and YFV-17D infection in mice ( 7 , 12 , 13 ). The effect of type I IFNs is apparently species specific, as both YFV-17D and virulent YFV can escape the human type I IFN-induced antiviral state ( 14 , 15 ).…”

Section: Introductionmentioning

confidence: 99%

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Type III Interferon-Mediated Signaling Is Critical for Controlling Live Attenuated Yellow Fever Virus Infection In Vivo

Douam

Albrecht

Hrebikova

et al. 2017

mBio

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Yellow fever virus (YFV) is an arthropod-borne flavivirus, infecting ~200,000 people worldwide annually and causing about 30,000 deaths. The live attenuated vaccine strain, YFV-17D, has significantly contributed in controlling the global burden of yellow fever worldwide. However, the viral and host contributions to YFV-17D attenuation remain elusive. Type I interferon (IFN-α/β) signaling and type II interferon (IFN-γ) signaling have been shown to be mutually supportive in controlling YFV-17D infection despite distinct mechanisms of action in viral infection. However, it remains unclear how type III IFN (IFN-λ) integrates into this antiviral system. Here, we report that while wild-type (WT) and IFN-λ receptor knockout (λR−/−) mice were largely resistant to YFV-17D, deficiency in type I IFN signaling resulted in robust infection. Although IFN-α/β receptor knockout (α/βR−/−) mice survived the infection, mice with combined deficiencies in both type I signaling and type III IFN signaling were hypersusceptible to YFV-17D and succumbed to the infection. Mortality was associated with viral neuroinvasion and increased permeability of the blood-brain barrier (BBB). α/βR−/− λR−/− mice also exhibited distinct changes in the frequencies of multiple immune cell lineages, impaired T-cell activation, and severe perturbation of the proinflammatory cytokine balance. Taken together, our data highlight that type III IFN has critical immunomodulatory and neuroprotective functions that prevent viral neuroinvasion during active YFV-17D replication. Type III IFN thus likely represents a safeguard mechanism crucial for controlling YFV-17D infection and contributing to shaping vaccine immunogenicity.

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Section: Resultssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Type III Interferon-Mediated Signaling Is Critical for Controlling Live Attenuated Yellow Fever Virus Infection In Vivo

Douam

Albrecht

Hrebikova

et al. 2017

mBio

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“…Host IFN signalling is the major barrier to the viscerotropism and for pathogenicity of neurotropic flaviviruses (58). In line, wild-type mice are poorly susceptible to infection with flaviviruses (28, 59–61) including YFV-17D infection/vaccination (34, 35, 62). Likewise, type I (IFN-α/β) and type II (IFN-γ) interferon signalling mutually controls YFV-17D infection.…”

Section: Methodsmentioning

confidence: 99%

“…Likewise, type I (IFN-α/β) and type II (IFN-γ) interferon signalling mutually controls YFV-17D infection. Unlike humans (63, 64), type I IFN (IFN-α/β) can restrict YFV-Asibi as well as YFV-17D infection in mice (34, 35, 62, 65). Similarly, IFN-γ exerts restriction on YFV-17D replication, dissemination and clearance in mice (35, 66).…”

Section: Methodsmentioning

confidence: 99%

A chimeric Japanese encephalitis vaccine protects against lethal yellow fever virus infection without inducing neutralizing antibodies

Mishra

Boudewijns

Schmid

et al. 2019

Preprint

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ABSTRACTRecent massive outbreaks of yellow fever virus (YFV) in West Africa and Brazil resulted in rapid depletion of global vaccine emergency stockpiles and raised concerns about being not prepared against future YFV epidemics. Here we report that a live-attenuated virus similar to the Japanese encephalitis virus (JEV) vaccine JE-CVax/Imojev® that consists of YFV-17D vaccine from which the structural (prM/E) genes have been replaced with those of the JEV SA14-14-2 vaccine strain confers full protection in mice against lethal YFV challenge. In contrast to the YFV-17D mediated protection against YFV, this protection is not mediated by neutralizing antibodies but correlates with YFV-specific non-neutralizing antibodies and T cell responses against cell-associated YFV NS1 and other YFV non-structural (NS) proteins. Our findings reveal the importance of YFV NS proteins to mediate protection and demonstrate that chimeric flavivirus vaccines, such as Imojev® can confer protection against two flaviviruses. This dual protection has implications for the possible off-label use of JE-CVax in case of emergency and vaccine shortage during YFV outbreaks. In addition, populations in Asia that have been vaccinated with Imojev® may already be protected against YFV should outbreaks ever occur on that continent as feared by WHO.IMPORTANCEEfficient and safe vaccines exist against yellow fever (e.g. YFV-17D) that provide long-lasting protection by rapidly inducing neutralizing antibody responses. However, vaccine supply cannot cope with an increasing demand posed by massive urban outbreaks in recent years. Here we report that JE-CVax/Imojev®, a YFV-17D-based chimeric Japanese encephalitis vaccine also efficiently protects against YFV infection in mice. In case of shortage of the YFV vaccine during yellow fever outbreaks, (off-label) use of JE-CVax/Imojev® may be considered. Moreover, wider use of JE-CVax/Imojev® in Asia may lower the risk of the much-feared YFV spill over to the continent. More in general chimeric vaccines that combine surface antigens and replication machineries of two distinct flaviviruses can be considered dual vaccines, for the latter pathogen without induction of surface-specific antibodies. Following this rationale, novel flavivirus vaccines that do not hold a risk for antibody-dependent enhancement (ADE) of infection [inherent to current dengue vaccines and dengue vaccine candidates] could be designed.

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Viral infections in humans and mice with genetic deficiencies of the type I IFN response pathway

Meyts

Casanova

2021

Eur J Immunol

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Type I IFNs are so‐named because they interfere with viral infection in vertebrate cells. The study of cellular responses to type I IFNs led to the discovery of the JAK‐STAT signaling pathway, which also governs the response to other cytokine families. We review here the outcome of viral infections in mice and humans with engineered and inborn deficiencies, respectively, of (i) IFNAR1 or IFNAR2, selectively disrupting responses to type I IFNs, (ii) STAT1, STAT2, and IRF9, also impairing cellular responses to type II (for STAT1) and/or III (for STAT1, STAT2, IRF9) IFNs, and (iii) JAK1 and TYK2, also impairing cellular responses to cytokines other than IFNs. A picture is emerging of greater redundancy of human type I IFNs for protective immunity to viruses in natural conditions than was initially anticipated. Mouse type I IFNs are essential for protection against a broad range of viruses in experimental conditions. These findings suggest that various type I IFN‐independent mechanisms of human cell‐intrinsic immunity to viruses have yet to be discovered.

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Spectrum of disease outcomes in mice infected with YFV-17D

Cited by 23 publications

References 60 publications

Type III Interferon-Mediated Signaling Is Critical for Controlling Live Attenuated Yellow Fever Virus Infection In Vivo

Type III Interferon-Mediated Signaling Is Critical for Controlling Live Attenuated Yellow Fever Virus Infection In Vivo

A chimeric Japanese encephalitis vaccine protects against lethal yellow fever virus infection without inducing neutralizing antibodies

Viral infections in humans and mice with genetic deficiencies of the type I IFN response pathway

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