Animal Models for Dengue and Zika Vaccine Development

Santos, Eduardo Alves dos; Fink, Katja

doi:10.1007/978-981-10-8727-1_16

Cited by 22 publications

(24 citation statements)

References 145 publications

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Section: T Cell Responses In Mice and Non-human Primates (Nhp)mentioning

confidence: 99%

“…Mice are not natural hosts for flaviviruses as the murine type I IFN system provides a very effective defense, which thwarts viral dissemination and thus prevents them being useful models of severe disease phenotypes (74). As such, to establish a model of productive viral infection, which can be used to examine T cell function and test potential vaccine candidates, multiple strains of immunocompromised mice have been generated (74). These strains include mice deficient in either type I or type II or both IFN receptors, mice with STAT2 knocked-out, mice with mouse STAT2 replaced by human STAT2, and more nuanced models where type I IFN receptors are absent in specific cells or tissues (74).…”

Section: T Cell Responses In Mice and Non-human Primates (Nhp)mentioning

confidence: 99%

“…As such, to establish a model of productive viral infection, which can be used to examine T cell function and test potential vaccine candidates, multiple strains of immunocompromised mice have been generated (74). These strains include mice deficient in either type I or type II or both IFN receptors, mice with STAT2 knocked-out, mice with mouse STAT2 replaced by human STAT2, and more nuanced models where type I IFN receptors are absent in specific cells or tissues (74). In combination with either mouse-adapted or human viral strains, this has established an infection model that closely, but not perfectly, mimics human disease.…”

Section: T Cell Responses In Mice and Non-human Primates (Nhp)mentioning

confidence: 99%

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Two Is Better Than One: Evidence for T-Cell Cross-Protection Between Dengue and Zika and Implications on Vaccine Design

et al. 2020

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Dengue virus (DENV, family Flaviviridae, genus Flavivirus) exists as four distinct serotypes. Generally, immunity after infection with one serotype is protective and lifelong, though exceptions have been described. However, secondary infection with a different serotype can result in more severe disease for a minority of patients. Host responses to the first DENV infection involve the development of both cross-reactive antibody and T cell responses, which, depending upon their precise balance, may mediate protection or enhance disease upon secondary infection with a different serotype. Abundant evidence now exists that responses elicited by DENV infection can cross-react with other members of the genus Flavivirus, particularly Zika virus (ZIKV). Cohort studies have shown that prior DENV immunity is associated with protection against Zika. Cross-reactive antibody responses may enhance infection with flaviviruses, which likely accounts for the cases of severe disease seen during secondary DENV infections. Data for T cell responses are contradictory, and even though cross-reactive T cell responses exist, their clinical significance is uncertain. Recent mouse experiments, however, show that cross-reactive T cells are capable of mediating protection against ZIKV. In this review, we summarize and discuss the evidence that T cell responses may, at least in part, explain the cross-protection seen against ZIKV from DENV infection, and that T cell antigens should therefore be included in putative Zika vaccines.

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Section: T Cell Responses In Mice and Non-human Primates (Nhp)mentioning

confidence: 99%

Section: T Cell Responses In Mice and Non-human Primates (Nhp)mentioning

confidence: 99%

Section: T Cell Responses In Mice and Non-human Primates (Nhp)mentioning

confidence: 99%

See 1 more Smart Citation

Two Is Better Than One: Evidence for T-Cell Cross-Protection Between Dengue and Zika and Implications on Vaccine Design

et al. 2020

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“…Non-human primate models have had limited utility because of the absence of clinical signs of DENV disease with the exception of a study in rhesus macaques using unusually high titers of inoculum (10 7 infectious particles/macaque) [66]. Unlike humans, wild-type mice are naturally resistant against DENV, as the virus does not inhibit murine interferon (IFN) signaling [67]. Additionally, some wild type (WT) murine models show signs not seen in the human disease [68,69].…”

Section: Mouse Models For Dengue Researchmentioning

confidence: 99%

“…Modification of certain genetic characteristics of mice allows improvements in the efficiency of viral replication of different strains of DENV. The host activation of the IFN signaling pathway is necessary for both inflammatory and antiviral responses to curtail DENV [67]. Therefore, development of IFN-deficient mouse models appears to be the next logical step to overcome this hurdle.…”

Section: Knockout Mouse Models For the Study Of Denvmentioning

confidence: 99%

Humanized Mice in Dengue Research: A Comparison with Other Mouse Models

et al. 2020

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Dengue virus (DENV) is an arbovirus of the Flaviviridae family and is an enveloped virion containing a positive sense single-stranded RNA genome. DENV causes dengue fever (DF) which is characterized by an undifferentiated syndrome accompanied by fever, fatigue, dizziness, muscle aches, and in severe cases, patients can deteriorate and develop life-threatening vascular leakage, bleeding, and multi-organ failure. DF is the most prevalent mosquito-borne disease affecting more than 390 million people per year with a mortality rate close to 1% in the general population but especially high among children. There is no specific treatment and there is only one licensed vaccine with restricted application. Clinical and experimental evidence advocate the role of the humoral and T-cell responses in protection against DF, as well as a role in the disease pathogenesis. A lot of pro-inflammatory factors induced during the infectious process are involved in increased severity in dengue disease. The advances in DF research have been hampered by the lack of an animal model that recreates all the characteristics of this disease. Experiments in nonhuman primates (NHP) had failed to reproduce all clinical signs of DF disease and during the past decade, humanized mouse models have demonstrated several benefits in the study of viral diseases affecting humans. In DENV studies, some of these models recapitulate specific signs of disease that are useful to test drugs or vaccine candidates. However, there is still a need for a more complete model mimicking the full spectrum of DENV. This review focuses on describing the advances in this area of research.

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MEK/ERK MAP kinase limits poly I:C‐induced antiviral gene expression in RAW264.7 macrophages by reducing interferon‐beta expression

et al. 2021

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Toll-like receptor 3 (TLR3) recognizes viral double-stranded RNA (or the synthetic dsRNA analog poly I:C) and induces a signal transduction pathway that results in activation of transcription factors that induce expression of antiviral genes including type I interferon (IFN-I). Secreted IFN-I positively feeds back to amplify antiviral gene expression. In this report, we study the role of MEK/ERK MAP kinase in modulating antiviral gene expression downstream of TLR3. We find MEK/ERK is a negative regulator of antiviral gene expression by limiting expression of IFN-b. However, MEK/ERK does not limit antiviral responses downstream of the type I interferon receptor. These findings provide insights into regulatory mechanisms of antiviral gene expression and reveal potential targets for modulating antiviral immunity.

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Animal Models for Dengue and Zika Vaccine Development

Cited by 22 publications

References 145 publications

Two Is Better Than One: Evidence for T-Cell Cross-Protection Between Dengue and Zika and Implications on Vaccine Design

Two Is Better Than One: Evidence for T-Cell Cross-Protection Between Dengue and Zika and Implications on Vaccine Design

Humanized Mice in Dengue Research: A Comparison with Other Mouse Models

MEK/ERK MAP kinase limits poly I:C‐induced antiviral gene expression in RAW264.7 macrophages by reducing interferon‐beta expression

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