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1.
Dev Dyn ; 251(12): 1952-1967, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35706088

RESUMO

BACKGROUND: Cadherin-associated protein p120 catenin regulates cell adhesion and migration in cell cultures and is required for axial elongation in embryos. Its roles in adhesion and cell migration are regulated by phosphorylation. We determined the effects of phosphorylation of six serine and three threonine residues in p120 catenin during zebrafish (Danio rerio) embryogenesis. RESULTS: We knocked down endogenous p120 catenin-δ1 with an antisense RNA-splice-site morpholino (Sp-MO) causing defects in axis elongation. These defects were rescued by co-injections of mRNAs for wildtype mouse p120 catenin-δ1-3A or various mutated forms. Several mRNAs containing serine or threonine codons singly or doubly mutated to phosphomimetic glutamic acid rescued, and some nonphosphorylatable mutants did not. CONCLUSIONS: We discovered that phosphorylation of serine residue S252 or S879 is required for convergent extension of zebrafish embryos, since rescue occurred only when these residues were mutated to glutamic acid. In addition, the phosphorylation of either S268 or S269 is required, not both, consistent with the presence of only a single one of these residues in two isoforms of zebrafish and Xenopus laevis. In summary, phosphorylation of multiple serine and threonine residues of p120 catenin activates migration of presomitic mesoderm of zebrafish embryos facilitating elongation of the dorsal axis.


Assuntos
Serina , Peixe-Zebra , Camundongos , Animais , Fosforilação , Peixe-Zebra/metabolismo , Serina/metabolismo , Ácido Glutâmico/metabolismo , Cateninas/genética , Cateninas/metabolismo , Caderinas/genética , Caderinas/metabolismo , Mesoderma/metabolismo , Treonina/metabolismo
2.
PLoS Pathog ; 15(8): e1007899, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31415679

RESUMO

West Nile Virus (WNV), an emerging and re-emerging RNA virus, is the leading source of arboviral encephalitic morbidity and mortality in the United States. WNV infections are acutely controlled by innate immunity in peripheral tissues outside of the central nervous system (CNS) but WNV can evade the actions of interferon (IFN) to facilitate CNS invasion, causing encephalitis, encephalomyelitis, and death. Recent studies indicate that STimulator of INterferon Gene (STING), canonically known for initiating a type I IFN production and innate immune response to cytosolic DNA, is required for host defense against neurotropic RNA viruses. We evaluated the role of STING in host defense to control WNV infection and pathology in a murine model of infection. When challenged with WNV, STING knock out (-/-) mice displayed increased morbidity and mortality compared to wild type (WT) mice. Virologic analysis and assessment of STING activation revealed that STING signaling was not required for control of WNV in the spleen nor was WNV sufficient to mediate canonical STING activation in vitro. However, STING-/- mice exhibited a clear trend of increased viral load and virus dissemination in the CNS. We found that STING-/- mice exhibited increased and prolonged neurological signs compared to WT mice. Pathological examination revealed increased lesions, mononuclear cellular infiltration and neuronal death in the CNS of STING-/- mice, with sustained pathology after viral clearance. We found that STING was required in bone marrow derived macrophages for early control of WNV replication and innate immune activation. In vivo, STING-/- mice developed an aberrant T cell response in both the spleen and brain during WNV infection that linked with increased and sustained CNS pathology compared to WT mice. Our findings demonstrate that STING plays a critical role in immune programming for the control of neurotropic WNV infection and CNS disease.


Assuntos
Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Imunidade Inata/imunologia , Proteínas de Membrana/fisiologia , Replicação Viral , Febre do Nilo Ocidental/imunologia , Vírus do Nilo Ocidental/imunologia , Animais , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/virologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Carga Viral , Febre do Nilo Ocidental/metabolismo , Febre do Nilo Ocidental/virologia
3.
J Infect Dis ; 221(6): 882-889, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-31621854

RESUMO

BACKGROUND: Virus infections result in a range of clinical outcomes for the host, from asymptomatic to severe or even lethal disease. Despite global efforts to prevent and treat virus infections to limit morbidity and mortality, the continued emergence and re-emergence of new outbreaks as well as common infections such as influenza persist as a health threat. Challenges to the prevention of severe disease after virus infection include both a paucity of protective vaccines as well as the early identification of individuals with the highest risk that may require supportive treatment. METHODS: We completed a screen of mice from the Collaborative Cross (CC) that we infected with influenza, severe acute respiratory syndrome-coronavirus, and West Nile virus. RESULTS: The CC mice exhibited a range of disease manifestations upon infections, and we used this natural variation to identify strains with mortality after infection and strains exhibiting no mortality. We then used comprehensive preinfection immunophenotyping to identify global baseline immune correlates of protection from mortality to virus infection. CONCLUSIONS: These data suggest that immune phenotypes might be leveraged to identify humans at highest risk of adverse clinical outcomes upon infection, who may most benefit from intensive clinical interventions, in addition to providing insight for rational vaccine design.


Assuntos
Mortalidade , Infecções por Vírus de RNA/imunologia , Infecções por Vírus de RNA/mortalidade , Animais , Camundongos de Cruzamento Colaborativo , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Vírus da Influenza A/imunologia , Influenza Humana , Masculino , Camundongos , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/mortalidade , RNA , Infecções por Vírus de RNA/virologia , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/mortalidade , Linfócitos T/imunologia , Linfócitos T/metabolismo , Vacinas Virais/imunologia , Febre do Nilo Ocidental/imunologia , Febre do Nilo Ocidental/mortalidade , Vírus do Nilo Ocidental/imunologia
4.
J Infect Dis ; 219(7): 1162-1171, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30371803

RESUMO

BACKGROUND: A challenge to the design of improved therapeutic agents and prevention strategies for neuroinvasive infection and associated disease is the lack of known natural immune correlates of protection. A relevant model to study such correlates is offered by the Collaborative Cross (CC), a panel of recombinant inbred mouse strains that exhibit a range of disease manifestations upon infection. METHODS: We performed an extensive screen of CC-F1 lines infected with West Nile virus (WNV), including comprehensive immunophenotyping, to identify groups of lines that exhibited viral neuroinvasion or neuroinvasion with disease and lines that remained free of WNV neuroinvasion and disease. RESULTS: Our data reveal that protection from neuroinvasion and disease is multifactorial and that several immune outcomes can contribute. Immune correlates identified include decreased suppressive activity of regulatory T cells at steady state, which correlates with peripheral restriction of the virus. Further, a rapid contraction of WNV-specific CD8+ T cells in the brain correlated with protection from disease. CONCLUSIONS: These immune correlates of protection illustrate additional networks and pathways of the WNV immune response that cannot be observed in the C57BL/6 mouse model. Additionally, correlates of protection exhibited before infection, at baseline, provide insight into phenotypic differences in the human population that may predict clinical outcomes upon infection.


Assuntos
Camundongos de Cruzamento Colaborativo/imunologia , Doenças do Sistema Nervoso/imunologia , Febre do Nilo Ocidental/imunologia , Vírus do Nilo Ocidental/imunologia , 2',5'-Oligoadenilato Sintetase/genética , Imunidade Adaptativa , Animais , Encéfalo/imunologia , Encéfalo/patologia , Relação CD4-CD8 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Camundongos de Cruzamento Colaborativo/genética , Modelos Animais de Doenças , Heterozigoto , Imunidade Inata , Imunofenotipagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doenças do Sistema Nervoso/microbiologia , Polimorfismo Genético , Baço/imunologia , Baço/patologia , Linfócitos T Reguladores/imunologia , Febre do Nilo Ocidental/complicações , Febre do Nilo Ocidental/genética
5.
PLoS Pathog ; 12(11): e1005996, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27806117

RESUMO

Infection with West Nile virus (WNV) leads to a range of disease outcomes, including chronic infection, though lack of a robust mouse model of chronic WNV infection has precluded identification of the immune events contributing to persistent infection. Using the Collaborative Cross, a population of recombinant inbred mouse strains with high levels of standing genetic variation, we have identified a mouse model of persistent WNV disease, with persistence of viral loads within the brain. Compared to lines exhibiting no disease or marked disease, the F1 cross CC(032x013)F1 displays a strong immunoregulatory signature upon infection that correlates with restraint of the WNV-directed cytolytic response. We hypothesize that this regulatory T cell response sufficiently restrains the immune response such that a chronic infection can be maintained in the CNS. Use of this new mouse model of chronic neuroinvasive virus will be critical in developing improved strategies to prevent prolonged disease in humans.


Assuntos
Linfócitos T Reguladores/imunologia , Febre do Nilo Ocidental/imunologia , Animais , Doença Crônica , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , Vírus do Nilo Ocidental/imunologia
6.
Front Virol ; 32023.
Artigo em Inglês | MEDLINE | ID: mdl-37383986

RESUMO

Zika virus (ZIKV) is a mosquito-borne flavivirus that causes an acute febrile illness. ZIKV can be transmitted between sexual partners and from mother to fetus. Infection is strongly associated with neurologic complications in adults, including Guillain-Barré syndrome and myelitis, and congenital ZIKV infection can result in fetal injury and congenital Zika syndrome (CZS). Development of an effective vaccine is imperative to protect against ZIKV vertical transmission and CZS. Recombinant Vesicular Stomatitis virus (rVSV) is a highly effective and safe vector for the delivery of foreign immunogens for vaccine purposes. Here, we evaluate an rVSV vaccine expressing the full length pre-membrane (prM) and ZIKV envelope (E) proteins (VSV-ZprME), shown to be immunogenic in murine models of ZIKV infection, for its capacity to induce immune responses in nonhuman primates. Moreover, we assess the efficacy of the rVSVΔM-ZprME vaccine in the protection of pigtail macaques against ZIKV infection. Administration of the rVSVΔM-ZprME vaccine was safe, but it did not induce robust anti-ZIKV T-cell responses, IgM or IgG antibodies, or neutralizing antibodies in most animals. Post ZIKV challenge, animals that received the rVSVΔM control vaccine lacking ZIKV antigen had higher levels of plasma viremia compared to animals that received the rVSVΔM-ZprME vaccine. Anti-ZIKV neutralizing Ab titers were detected in a single animal that received the rVSVΔM-ZprME vaccine that was associated with reduced plasma viremia. The overall suboptimal ZIKV-specific cellular and humoral responses post-immunization indicates the rVSVΔM-ZprME vaccine did not elicit an immune response in this pilot study. However, recall antibody response to the rVSVΔM-ZprME vaccine indicates it may be immunogenic and further developments to the vaccine construct could enhance its potential as a vaccine candidate in a nonhuman primate pre-clinical model.

7.
Commun Biol ; 5(1): 243, 2022 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-35304593

RESUMO

Zika virus infection can result in devastating pregnancy outcomes when it crosses the placental barrier. For human pregnancies, the mechanisms of vertical transmission remain enigmatic. Utilizing a human placenta-cotyledon perfusion model, we examined Zika virus exposure in the absence of maternal factors. To distinguish responses related to viral infection vs. recognition, we evaluated cotyledons perfused with either active or inactivated Zika virus. Active Zika virus exposure resulted in infection, cell death and syncytium injury. Pathology corresponded with transcriptional changes related to inflammation and innate immunity. Inactive Zika virus exposure also led to syncytium injury and related changes in gene expression but not cell death. Our observations reveal pathologies and innate immune responses that are dependent on infection or virus placenta interactions independent of productive infection. Importantly, our findings indicate that Zika virus can infect and compromise placentas in the absence of maternal humoral factors that may be protective.


Assuntos
Complicações Infecciosas na Gravidez , Infecção por Zika virus , Zika virus , Feminino , Humanos , Transmissão Vertical de Doenças Infecciosas , Placenta , Gravidez , Complicações Infecciosas na Gravidez/patologia , Zika virus/fisiologia
8.
Immunohorizons ; 5(4): 157-169, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33893179

RESUMO

The goal of a successful immune response is to clear the pathogen while sparing host tissues from damage associated with pathogen replication and active immunity. Regulatory T cells (Treg) have been implicated in maintaining this balance as they contribute both to the organization of immune responses as well as restriction of inflammation and immune activation to limit immunopathology. To determine if Treg abundance prior to pathogen encounter can be used to predict the success of an antiviral immune response, we used genetically diverse mice from the collaborative cross infected with West Nile virus (WNV). We identified collaborative cross lines with extreme Treg abundance at steady state, either high or low, and used mice with these extreme phenotypes to demonstrate that baseline Treg quantity predicted the magnitude of the CD8 T cell response to WNV infection, although higher numbers of baseline Tregs were associated with reduced CD8 T cell functionality in terms of TNF and granzyme B expression. Finally, we found that abundance of CD44+ Tregs in the spleen at steady state was correlated with an increased early viral load within the spleen without an association with clinical disease. Thus, we propose that Tregs participate in disease tolerance in the context of WNV infection by tuning an appropriately focused and balanced immune response to control the virus while at the same time minimizing immunopathology and clinical disease. We hypothesize that Tregs limit the antiviral CD8 T cell function to curb immunopathology at the expense of early viral control as an overall host survival strategy.


Assuntos
Encéfalo/imunologia , Linfócitos T CD8-Positivos/imunologia , Baço/imunologia , Linfócitos T Reguladores/imunologia , Febre do Nilo Ocidental/imunologia , Animais , Encéfalo/patologia , Encéfalo/virologia , Linfócitos T CD8-Positivos/metabolismo , Granzimas/imunologia , Granzimas/metabolismo , Tolerância Imunológica , Masculino , Camundongos , Baço/patologia , Baço/virologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Carga Viral , Febre do Nilo Ocidental/patologia , Febre do Nilo Ocidental/virologia , Vírus do Nilo Ocidental/imunologia , Vírus do Nilo Ocidental/fisiologia
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