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1.
PLoS One ; 15(1): e0227676, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31935257

RESUMO

Zika virus infection during pregnancy is associated with miscarriage and with a broad spectrum of fetal and neonatal developmental abnormalities collectively known as congenital Zika syndrome (CZS). Symptomology of CZS includes malformations of the brain and skull, neurodevelopmental delay, seizures, joint contractures, hearing loss and visual impairment. Previous studies of Zika virus in pregnant rhesus macaques (Macaca mulatta) have described injury to the developing fetus and pregnancy loss, but neonatal outcomes following fetal Zika virus exposure have yet to be characterized in nonhuman primates. Herein we describe the presentation of rhesus macaque neonates with a spectrum of clinical outcomes, including one infant with CZS-like symptoms including cardiomyopathy, motor delay and seizure activity following maternal infection with Zika virus during the first trimester of pregnancy. Further characterization of this neonatal nonhuman primate model of gestational Zika virus infection will provide opportunities to evaluate the efficacy of pre- and postnatal therapeutics for gestational Zika virus infection and CZS.


Assuntos
Modelos Animais de Doenças , Infecção por Zika virus/veterinária , Zika virus/patogenicidade , Animais , Cardiomiopatias/virologia , Feminino , Feto/virologia , Macaca mulatta , Microcefalia/virologia , Gravidez , Complicações Infecciosas na Gravidez/veterinária , Complicações Infecciosas na Gravidez/virologia , Primeiro Trimestre da Gravidez , Convulsões/virologia , Infecção por Zika virus/virologia
3.
Malays J Pathol ; 41(1): 75-78, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31025643

RESUMO

We report a case of congenital cytomegalovirus and Herpes simplex virus infection suspected via ultrasound indicated by the presence of fetal cerebral abnormalities. The pregnancy was electively terminated at 31 weeks of gestation. The postmortem examination of the foetus showed brain with lissencephaly. The histopathological examination revealed numerous enlarged cells containing cytomegalic inclusions and multinucleated giant cells in multiple fetal organs and placenta. Documented evidence of histopathological detection of cytomegalovirus inclusions in multiple organs are very sparse in literature. This case highlights the causal relationship of viral infections in early pregnancy and abnormalities of the central nervous system.


Assuntos
Infecções por Citomegalovirus/congênito , Infecções por Citomegalovirus/patologia , Feto/patologia , Herpes Simples/congênito , Herpes Simples/patologia , Complicações Infecciosas na Gravidez/patologia , Feminino , Feto/virologia , Humanos , Lisencefalia/patologia , Lisencefalia/virologia , Gravidez
4.
PLoS Negl Trop Dis ; 13(4): e0007343, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30995223

RESUMO

Congenital Zika virus (ZIKV) infection was first linked to birth defects during the American outbreak in 2015/2016. It has been proposed that mutations unique to the Asian/American-genotype explain, at least in part, the ability of Asian/American ZIKV to cause congenital Zika syndrome (CZS). Recent studies identified mutations in ZIKV infecting humans that arose coincident with the outbreak in French Polynesia and were stably maintained during subsequent spread to the Americas. Here we show that African ZIKV can infect and harm fetuses and that the S139N substitution that has been associated with the American outbreak is not essential for fetal harm. Our findings, in a vertical transmission mouse model, suggest that ZIKV will remain a threat to pregnant women for the foreseeable future, including in Africa, Southeast Asia, and the Americas. Additional research is needed to better understand the risks associated with ZIKV infection during pregnancy, both in areas where the virus is newly endemic and where it has been circulating for decades.


Assuntos
Feto/virologia , Transmissão Vertical de Doença Infecciosa/veterinária , Infecção por Zika virus/veterinária , Zika virus/genética , África , Animais , Ásia Sudeste , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Taxa de Sobrevida , Replicação Viral , Zika virus/isolamento & purificação , Infecção por Zika virus/virologia
5.
Vet Microbiol ; 230: 95-100, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30827412

RESUMO

Vertical transmission of bovine papillomavirus (BPV) infection was investigated on livers and kidneys of four foetuses from cows suffering from BPV-2-associated urothelial cancers of the urinary bladder. PCR analysis revealed the presence of BPV-2 E5 DNA in the livers and kidneys of two foetuses. Amplified DNA fragments, composed of 502 bp, showed a 100% homology with BPV-2 sequences (GenBank accession number: M20219.1). BPV-2 was found to be transcriptionally active. Indeed, reverse transcriptase (RT)-PCR showed BPV-2 E5 transcripts. Sequencing of amplified cDNA, composed of 154 bp, showed a 100% identity with BPV-2 E5 sequences (GenBank accession number: M20219.1). Western blot analysis revealed the presence of dimers of E5 oncoprotein. Furthermore, a statistically significant increase of the phosphorylated (activated) form of the platelet-derived growth factor ß receptor (PDGFßR) was also detected in the fetal tissues. PDGFßR is believed to form the most important interaction with the E5 oncoprotein, thus regulating biological activity of virus protein. The strong concordance between virus found in fetal organs with virus detected in infected mothers provides evidence that BPV-2 can spread through blood and vertical infection occurs via transplacental transmission. Finally, molecular findings of this study raise unsolved questions about the potential role of BPVs in reproductive disorders. The presence of E5 oncoprotein, as in adult organs, may also activate the constitutive receptor PDGFßR in foetal organs, which plays a pivotal role in angiogenesis and embryonic development. Therefore, abnormal phosphorylation of PDGFßR may be involved in vascular and organogenesis abnormalities other than cancer.


Assuntos
Doenças dos Bovinos/congênito , Doenças dos Bovinos/transmissão , Transmissão Vertical de Doença Infecciosa/veterinária , Infecções por Papillomavirus/veterinária , Placenta/virologia , Animais , Bovinos , Doenças dos Bovinos/virologia , Feminino , Feto/virologia , Rim/virologia , Fígado/virologia , Proteínas Oncogênicas Virais/genética , Papillomaviridae/genética , Infecções por Papillomavirus/congênito , Gravidez , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética
6.
PLoS One ; 14(3): e0213279, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30830946

RESUMO

BACKGROUND: Mitochondrial toxicity related to maternal combined antiretroviral treatment (cART) may have an impact on the heart of HIV-exposed uninfected (HEU) fetuses. Our objective was to evaluate fetal cardiovascular and mitochondrial biomarkers in HIV pregnancies. METHODS: Prospective cohort including 47 HIV-infected and 47 non HIV-infected pregnancies. Fetal echocardiography was performed at 26-32 weeks of pregnancy. Umbilical cord blood and placental tissue were collected to study mitochondrial DNA content (mtDNA) (ratio 12SrRNA/RNAseP) and mitochondrial function (cytochrome c oxidase, COX, enzymatic activity) normalized by mitochondrial content (citrate synthase, CS). RESULTS: HEU fetuses showed hypertrophic hearts (left myocardial wall thickness: HIV mean 3.21 mm (SD 0.81) vs. non-HIV 2.72 (0.42), p = 0.012), with signs of systolic and diastolic dysfunction (isovolumic relaxation time: HIV 52.2 ms (8.85) vs. non-HIV 42.5 ms (7.30); p<0.001). Cord blood mitochondrial content was significantly increased in HIV-exposed fetuses (CS activity: HIV 82.9 nmol/min.mg of protein (SD 40.5) vs. non-HIV 56.7 nmol/min.mg of protein (28.4); p = 0.007), with no differences in mtDNA content and COX activity. Both myocardial and mitochondrial mass parameters were significantly associated with zidovudine exposure. CONCLUSIONS: HEU fetuses showed signs of increased myocardial and mitochondrial mass associated with maternal zidovudine treatment, suggesting a fetal adaptive response to cART toxicity.


Assuntos
Terapia Antirretroviral de Alta Atividade , Feto/patologia , Infecções por HIV/complicações , HIV/efeitos dos fármacos , Coração/fisiopatologia , Mitocôndrias/patologia , Complicações Infecciosas na Gravidez/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adulto , Estudos de Casos e Controles , Ecocardiografia , Feminino , Sangue Fetal , Feto/efeitos dos fármacos , Feto/virologia , Idade Gestacional , HIV/isolamento & purificação , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Coração/efeitos dos fármacos , Coração/virologia , Humanos , Troca Materno-Fetal , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/virologia , Gravidez , Complicações Infecciosas na Gravidez/virologia , Efeitos Tardios da Exposição Pré-Natal/virologia , Estudos Prospectivos
8.
PLoS Pathog ; 15(1): e1007507, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30657788

RESUMO

Zika virus (ZIKV) infection during pregnancy in humans is associated with an increased incidence of congenital anomalies including microcephaly as well as fetal death and miscarriage and collectively has been referred to as Congenital Zika Syndrome (CZS). Animal models for ZIKV infection in pregnancy have been developed including mice and non-human primates (NHPs). In macaques, fetal CZS outcomes from maternal ZIKV infection range from none to significant. In the present study we develop the olive baboon (Papio anubis), as a model for vertical transfer of ZIKV during pregnancy. Four mid-gestation, timed-pregnant baboons were inoculated with the French Polynesian ZIKV isolate (104 ffu). This study specifically focused on the acute phase of vertical transfer. Dams were terminated at 7 days post infection (dpi; n = 1), 14 dpi (n = 2) and 21 dpi (n = 1). All dams exhibited mild to moderate rash and conjunctivitis. Viremia peaked at 5-7 dpi with only one of three dams remaining mildly viremic at 14 dpi. An anti-ZIKV IgM response was observed by 14 dpi in all three dams studied to this stage, and two dams developed a neutralizing IgG response by either 14 dpi or 21 dpi, the latter included transfer of the IgG to the fetus (cord blood). A systemic inflammatory response (increased IL2, IL6, IL7, IL15, IL16) was observed in three of four dams. Vertical transfer of ZIKV to the placenta was observed in three pregnancies (n = 2 at 14 dpi and n = 1 at 21 dpi) and ZIKV was detected in fetal tissues in two pregnancies: one associated with fetal death at ~14 dpi, and the other in a viable fetus at 21 dpi. ZIKV RNA was detected in the fetal cerebral cortex and other tissues of both of these fetuses. In the fetus studied at 21 dpi with vertical transfer of virus to the CNS, the frontal cerebral cortex exhibited notable defects in radial glia, radial glial fibers, disorganized migration of immature neurons to the cortical layers, and signs of pathology in immature oligodendrocytes. In addition, indices of pronounced neuroinflammation were observed including astrogliosis, increased microglia and IL6 expression. Of interest, in one fetus examined at 14 dpi without detection of ZIKV RNA in brain and other fetal tissues, increased neuroinflammation (IL6 and microglia) was observed in the cortex. Although the placenta of the 14 dpi dam with fetal death showed considerable pathology, only minor pathology was noted in the other three placentas. ZIKV was detected immunohistochemically in two placentas (14 dpi) and one placenta at 21 dpi but not at 7 dpi. This is the first study to examine the early events of vertical transfer of ZIKV in a NHP infected at mid-gestation. The baboon thus represents an additional NHP as a model for ZIKV induced brain pathologies to contrast and compare to humans as well as other NHPs.


Assuntos
Córtex Cerebral/patologia , Infecção por Zika virus/patologia , Zika virus/patogenicidade , Animais , Encéfalo/patologia , Córtex Cerebral/lesões , Córtex Cerebral/virologia , Modelos Animais de Doenças , Feminino , Morte Fetal , Doenças Fetais/patologia , Feto/virologia , Transmissão Vertical de Doença Infecciosa , Microcefalia , Papio anubis/microbiologia , Papio anubis/virologia , Placenta/virologia , Gravidez , Complicações Infecciosas na Gravidez/virologia , Viremia , Zika virus/genética , Infecção por Zika virus/virologia
9.
Vet Pathol ; 56(2): 277-281, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30244663

RESUMO

Bovine parainfluenza virus-3 (BPIV-3) is a recognized respiratory pathogen of cattle, and it has also been identified in aborted fetuses. However, little is known of this agent as a reproductive pathogen and detailed descriptions of fetal pathology on natural cases are lacking in the scientific literature. This article describes and illustrates lesions in a fetus spontaneously aborted by a first-calving Holstein heifer, naturally infected with BPIV-3 genotype A, broadening the current knowledge on fetal pathology by this virus. Fetal autopsy revealed diffusely reddened, rubbery and unexpanded lungs. Histologically, there was necrotizing bronchiolitis/alveolitis with intraluminal fibrin exudate and syncytial cells in the bronchiolar/alveolar spaces, and non-suppurative peribronchiolitis and perivascular interstitial pneumonia. In the small intestine there was multifocal necrotizing cryptitis and occasional necrotic syncytial enterocytes. Intralesional and extralesional BPIV-3 antigen was detected by immunohistochemistry in the lung and small intestine, and BPIV-3a was identified in fetal tissues by RT-PCR and sequencing.


Assuntos
Aborto Animal/patologia , Doenças dos Bovinos/patologia , Doenças Fetais/veterinária , Vírus da Parainfluenza 3 Bovina , Infecções por Respirovirus/veterinária , Aborto Animal/etiologia , Aborto Animal/virologia , Animais , Bovinos , Doenças dos Bovinos/virologia , Feminino , Doenças Fetais/patologia , Doenças Fetais/virologia , Feto/patologia , Feto/virologia , Vírus da Parainfluenza 3 Bovina/genética , Filogenia , Gravidez , Infecções por Respirovirus/complicações , Infecções por Respirovirus/patologia , Infecções por Respirovirus/virologia
10.
Transbound Emerg Dis ; 66(1): 454-462, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30354028

RESUMO

Since its first appearance in 2011, Schmallenberg virus (SBV) has been repeatedly detected in aborted ruminant foetuses or severely malformed newborns whose mothers were naturally infected during pregnancy. However, especially the knowledge about dynamics of foetal infection in cattle is still scarce. Therefore, a total of 36 pregnant heifers were experimentally infected during two animal trials with SBV between days 60 and 150 of gestation. The foetuses were collected between 10 and 35 days after infection and virologically and pathologically investigated. Overall, 33 heifers yielded normally developed, macroscopically inconspicuous foetuses, but abundant virus replication was evident at the maternal/foetal interface and viral genome was detectable in at least one organ system of 18 out of 35 foetuses. One heifer was found to be not pregnant at autopsy. One of the animals aborted at day 4 after infection, viral RNA was detectable in the lymphatic tissue of the dam, in the maternal and foetal placenta, and in organs and lymphatic tissue of the foetus. In another foetus, SBV typical malformations like torticollis and arthrogryposis were observed. The corresponding dam was infected at day 90 of pregnancy and viral genome was detectable in the cerebellum of the unborn. Interestingly, no common patterns of infected foetal organs or maternal/foetal placentas could be identified, and both, sites of virus replication and genome loads, varied to a high degree in the individual foetuses. It is therefore concluded, that SBV infects in many cases also the bovine foetus of naïve pregnant cattle, however, the experimentally observed low abortion/malformation rate is in concordance to the reported low rates in the field during the first outbreak wave following the introduction of SBV. This observation speaks for a natural resistance of most bovine foetuses even during the vulnerable phase of early pregnancy, which has to be further studied in the future.


Assuntos
Infecções por Bunyaviridae/veterinária , Doenças dos Bovinos/transmissão , Transmissão Vertical de Doença Infecciosa/veterinária , Orthobunyavirus/patogenicidade , Complicações Infecciosas na Gravidez/veterinária , Feto Abortado/virologia , Aborto Animal/virologia , Animais , Infecções por Bunyaviridae/transmissão , Infecções por Bunyaviridae/virologia , Bovinos , Doenças dos Bovinos/virologia , Surtos de Doenças , Feminino , Feto/virologia , Gravidez , Complicações Infecciosas na Gravidez/virologia , Prenhez , Ruminantes
11.
Virus Res ; 260: 151-162, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30529234

RESUMO

Although porcine reproductive and respiratory syndrome virus (PRRSV) readily crosses the maternal fetal interface (MFI) in third trimester, fetal resilience varies within litters. The aim of this study was to characterize PRRSV-2 concentration in MFI and fetuses at five time points after experimental inoculation of late gestation gilts and use this information to classify potentially resistant, resilient and susceptible fetuses. The secondary objective was to verify the relationship between PRRS viral load and intrauterine growth retardation (IUGR). Three PRRSV-inoculated pregnant gilts and 1 sham-inoculated control were euthanized at five time points in days post infection (DPI; 2, 5, 8, 12, 14). The preservation status of each fetus was determined and MFI samples adjacent to the umbilical stump of each fetus, as well as serum, thymus, umbilical cord and amniotic fluid were collected. Viral load was quantified using probe-based reverse-transcriptase quantitative PCR (RT-qPCR) targeting PRRSV NVSL 97-7895 ORF7. Our result show the MFI was largely PRRSV infected by 2 DPI and virus was first detected in fetal sera and umbilical cord by 5 DPI, and in fetal thymus and amniotic fluid by 8 DPI. This indicates that PRRSV-2 quickly crossed the placenta and traveled toward the fetus via umbilical circulation within one week of the dam's inoculation. Fetal compromise was first observed on 8 DPI and increased progressively through to 14 DPI. However, several factors were associated with fetal resilience. The random forest model identified that 'viral load in fetal thymus' and duration of infection ('DPI') as the most important factors predicting fetal resilience and resistance. Moreover, IUGR fetuses had lower viral load and were less frequently compromised or dead compared to non-IUGR and average cohorts. Understanding the mechanisms of fetal resilience to PRRSV will improve selection strategies for replacement gilts.


Assuntos
Estruturas Animais/virologia , Resistência à Doença , Feto/virologia , Síndrome Respiratória e Reprodutiva Suína/imunologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/isolamento & purificação , Complicações Infecciosas na Gravidez/veterinária , Carga Viral , Animais , Feminino , Síndrome Respiratória e Reprodutiva Suína/patologia , Síndrome Respiratória e Reprodutiva Suína/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/genética , Gravidez , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/patologia , Complicações Infecciosas na Gravidez/virologia , Reação em Cadeia da Polimerase em Tempo Real , Suínos
12.
J Virol ; 93(3)2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30429352

RESUMO

Since the discovery of enterovirus A71 (EV-A71) half a century ago, it has been recognized as the cause of large-scale outbreaks of hand-foot-and-mouth disease worldwide, particularly in the Asia-Pacific region, causing great concern for public health and economic burdens. Detailed mechanisms on the modulation of immune responses after EV-A71 infection have not been fully known, and the lack of appropriate models hinders the development of promising vaccines and drugs. In the present study, NOD-scid IL2Rγ-/- (NSG) mice with a human immune system (humanized mice) at the age of 4 weeks were found to be susceptible to a human isolate of EV-A71 infection. After infection, humanized mice displayed limb weakness, which is similar to the clinical features found in some of the EV-A71-infected patients. Histopathological examination indicated the presence of vacuolation, gliosis, or meningomyelitis in brain stem and spinal cord, which were accompanied by high viral loads detected in these organs. The numbers of activated human CD4+ and CD8+ T cells were upregulated after EV-A71 infection, and EV-A71-specific human T cell responses were found. Furthermore, the secretion of several proinflammatory cytokines, such as human gamma interferon (IFN-γ), interleukin-8 (IL-8), and IL-17A, was elevated in the EV-A71-infected humanized mice. Taken together, our results suggested that the humanized mouse model permits insights into the human immune responses and the pathogenesis of EV-A71 infection, which may provide a platform for the evaluation of anti-EV-A71 drug candidates in the future.IMPORTANCE Despite causing self-limited hand-food-and-mouth disease in younger children, EV-A71 is consistently associated with severe forms of neurological complications and pulmonary edema. Nevertheless, only limited vaccines and drugs have been developed over the years, which is possibly due to a lack of models that can more accurately recapitulate human specificity, since human is the only natural host for wild-type EV-A71 infection. Our humanized mouse model not only mimics histological symptoms in patients but also allows us to investigate the function of the human immune system during infection. It was found that human T cell responses were activated, accompanied by an increase in the production of proinflammatory cytokines in EV-A71-infected humanized mice, which might contribute to the exacerbation of disease pathogenesis. Collectively, this model allows us to delineate the modulation of human immune responses during EV-A71 infection and may provide a platform to evaluate anti-EV-A71 drug candidates in the future.


Assuntos
Linfócitos T CD8-Positivos/patologia , Enterovirus Humano A/patogenicidade , Infecções por Enterovirus/patologia , Feto/patologia , Carga Viral/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Células Cultivadas , Enterovirus Humano A/isolamento & purificação , Infecções por Enterovirus/imunologia , Infecções por Enterovirus/virologia , Feto/imunologia , Feto/virologia , Humanos , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID
13.
JCI Insight ; 3(21)2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30385728

RESUMO

BACKGROUND: An intricate fetal-maternal immune crosstalk during pregnancy is essential for a healthy birth. Hence, the infection-induced alterations of maternal immunity often lead to adverse outcomes for mother and/or child. The emergence of Zika virus (ZIKV) infection in pregnant women has been associated with more than 3,000 cases of microcephaly and nervous system malformations. METHODS: To explore the potential correlation of ZIKV-induced alteration of maternal immunity with fetal abnormalities, we performed extensive sera immunoprofiling of 74 pregnant women: 30 symptomatic ZIKV+ pregnant patients and 30 healthy pregnant controls in ZIKV-endemic Rio de Janeiro, along with 14 healthy pregnant controls in non-endemic Los Angeles. RESULTS: Extensive multiplexing analysis of 69 cytokines revealed that CXCL10, CCL2, and CCL8 chemokines were specifically associated with symptomatic ZIKV+ infection during pregnancy, and distinct immunoprofiles were detected at different trimesters in ZIKV-infected pregnant women. Intriguingly, the high CCL2 level and its inverse correlation with CD163, TNFRSF1A, and CCL22 levels was apparently associated with ZIKV-induced abnormal birth. CONCLUSION: Our findings provide insights into the alteration of ZIKV-elicited maternal immunity, serving as a potential clinical biomarker platform. FUNDING: NIH (CA200422, CA180779, DE023926, AI073099, AI116585, AI129496, AI140705, AI069120, AI056154, AI078389, AI28697, AI40718 and AI129534-01), Hastings Foundation, Fletcher Jones Foundation, Departamento de Ciência e Tecnologia (DECIT/25000.072811/2016-17) do Ministério da Saúde do Brasil, and Coordenação de Aperfeiçoamento de Pessoal de Nivel Superior CAPES/88887.116627/2016-01.


Assuntos
Biomarcadores/metabolismo , Feto/anormalidades , Microcefalia/etiologia , Infecção por Zika virus/metabolismo , Zika virus/imunologia , Adolescente , Adulto , Biomarcadores/sangue , Brasil/epidemiologia , Citocinas/sangue , Citocinas/metabolismo , Feminino , Feto/metabolismo , Feto/virologia , Voluntários Saudáveis , Humanos , Imunidade Materno-Adquirida/fisiologia , Microcefalia/epidemiologia , Gravidez , Resultado da Gravidez/epidemiologia , Trimestres da Gravidez , Estados Unidos/epidemiologia , Adulto Jovem , Infecção por Zika virus/complicações , Infecção por Zika virus/epidemiologia
14.
PLoS One ; 13(10): e0206093, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30359409

RESUMO

Zika virus (ZIKV) is an emerging arbovirus of the Flaviviridae family. Although infection with ZIKV generally leads to mild disease, its recent emergence in the Americas has been associated with an increase in the development of the Guillain-Barré syndrome in adults, as well as with neurological complications, in particular congenital microcephaly, in new-borns. To date, little information is available on neuroinflammation induced by ZIKV, notably in microglial cells in the context of their metabolic activity, a series of chemical transformations that are essential for their growth, reproduction, structural maintenance and environmental responses. Therefore, in the present study we investigated the metabolomic profile of ZIKV-infected microglia. Microglial cells were exposed to ZIKV at different time points and were analyzed by a Liquid Chromatography-High Resolution mass spectrometry-based metabolomic approach. The results show that ZIKV infection in microglia leads to modulation of the expression of numerous metabolites, including lysophospholipids, particulary Lysophosphatidylcholine, and phospholipids such as Phosphatidylcholine, Phosphatidylserine, Ceramide and Sphingomyelin, and carboxylicic acids as Undecanedioic and Dodecanedioic acid. Some of these metabolites are involved in neuronal differentiation, regulation of apoptosis, virion architecture and viral replication. ZIKV infection was associated with concomitant secretion of inflammatory mediators linked with central nervous system inflammation such as IL-6, TNF-α, IL-1ß, iNOS and NO. It also resulted in the upregulation of the expression of the gene encoding CX3CR1, a chemokine receptor known to regulate functional synapse plasticity and signaling between microglial cells. These findings highlight an important role for microglia and their metabolites in the process of neuroinflammation that occurs during ZIKV pathogenesis.


Assuntos
Metaboloma/fisiologia , Microglia/metabolismo , Infecção por Zika virus/metabolismo , Animais , Células Cultivadas , Culicidae , Feto/citologia , Feto/virologia , Humanos , Metabolômica , Microcefalia/metabolismo , Microcefalia/patologia , Microglia/patologia , Células Vero , Replicação Viral/fisiologia , Zika virus/fisiologia , Infecção por Zika virus/patologia
15.
Viruses ; 10(10)2018 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-30282919

RESUMO

The recent emergence of Zika virus (ZIKV) in Brazil was associated with an increased number of fetal brain infections that resulted in a spectrum of congenital neurological complications known as congenital Zika syndrome (CZS). Herein, we generated de novo from sequence data an early Asian lineage ZIKV isolate (ZIKV-MY; Malaysia, 1966) not associated with microcephaly and compared the in vitro replication kinetics and fetal brain infection in interferon α/ß receptor 1 knockout (IFNAR1-/-) dams of this isolate and of a Brazilian isolate (ZIKV-Natal; Natal, 2015) unequivocally associated with microcephaly. The replication efficiencies of ZIKV-MY and ZIKV-Natal in A549 and Vero cells were similar, while ZIKV-MY replicated more efficiently in wild-type (WT) and IFNAR-/- mouse embryonic fibroblasts. Viremias in IFNAR1-/- dams were similar after infection with ZIKV-MY or ZIKV-Natal, and importantly, infection of fetal brains was also not significantly different. Thus, fetal brain infection does not appear to be a unique feature of Brazilian ZIKV isolates.


Assuntos
Encéfalo/virologia , Feto/virologia , Complicações Infecciosas na Gravidez/virologia , Infecção por Zika virus/patologia , Infecção por Zika virus/virologia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placenta/virologia , Gravidez , Receptor de Interferon alfa e beta/deficiência , Receptor de Interferon alfa e beta/genética , Células Vero , Viremia , Replicação Viral , Zika virus/fisiologia
16.
Cytokine ; 111: 255-264, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30199767

RESUMO

Zika virus (ZIKV) has caused substantial concern worldwide owing to its association with severe birth defects, such as microcephaly and other congenital malformations. Inflammasomes, i.e., multi-protein complexes that induce inflammation and pyroptosis, are predicted to contribute to the immune response to this flavivirus. Accordingly, in this study, the in situ inflammasome response was evaluated in fatal cases of ZIKV-linked microcephaly. Brain tissue samples were collected from eight babies, including four ZIKV-positive microcephalic neonates who died after birth and four flavivirus-negative neonatal controls who died of other causes and whose central nervous system (CNS) architecture was preserved. In the ZIKV-positive newborn/stillbirth babies, the major histopathological alterations included atrophy of the cortical layer, a predominance of mononuclear cell infiltration in the Virchow-Robin space, neuronal necrosis, vacuolization and neuronal degeneration, neuronophagy, and gliosis. An immunohistochemical analysis of tissues in the neural parenchyma showed significantly higher expression of the receptors NLRP1, NLRP3, and AIM2, cytokines IL-1ß, IL-18, and IL-33, and enzymes caspase 1, iNOS, and arginase 1 in ZIKV-positive microcephaly cases than in flavivirus-negative controls. These results suggest that inflammasome activation can aggravate the neuroinflammatory response and consequently increase CNS damage in neonates with fetal neural ZIKV infection and microcephaly.


Assuntos
Sistema Nervoso Central/patologia , Sistema Nervoso Central/virologia , Inflamassomos/fisiologia , Microcefalia/patologia , Microcefalia/virologia , Infecção por Zika virus/patologia , Zika virus/patogenicidade , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/virologia , Sistema Nervoso Central/metabolismo , Citocinas/metabolismo , Feminino , Feto/metabolismo , Feto/virologia , Humanos , Recém-Nascido , Inflamassomos/metabolismo , Masculino , Microcefalia/metabolismo , Gravidez , Complicações Infecciosas na Gravidez/metabolismo , Complicações Infecciosas na Gravidez/patologia , Complicações Infecciosas na Gravidez/virologia , Infecção por Zika virus/metabolismo , Infecção por Zika virus/virologia
17.
Vet Microbiol ; 223: 119-125, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30173737

RESUMO

We have evaluated the cross-protection of a modified-live virus (MLV) vaccine based on porcine reproductive and respiratory syndrome virus (PRRSV)-2, against a heterologous PRRSV-1 challenge in late term pregnancy gilts. Gilts were vaccinated 42 days prior to breeding and then challenged intranasally with PRRSV-1 at 93 days of gestation. No local or systemic adverse effects related to vaccination were observed in the vaccinated gilts throughout the study. Vaccination resulted in a longer gestation period, a higher number of live-born and weaned piglets, and a significant decrease in the number of stillborn piglets compared to the unvaccinated group. The PRRSV-2 MLV vaccine was also able to significantly reduce PRRSV-1 viremia. At the time of PRRSV-1 challenge, vaccinated gilts had significantly higher PRRSV-1 specific interferon-γ secreting cells but low neutralizing antibody titers against PRRSV-1 compared to unvaccinated gilts. This correlated with a reduction of PRRSV-1 viremia, indicating that cell-mediated rather than humoral immunity played a role in PRRSV-1 clearance from the blood. Fetal thymic tissues from vaccinated pregnant gilts had fewer PRRSV-1 positive cells compared to unvaccinated gilts. Taken together these results indicate that vaccination of gilts with PRRSV-2 MLV vaccine can provide cross-protection against PRRSV-1 challenge and improve reproductive performance.


Assuntos
Administração Intranasal/veterinária , Síndrome Respiratória e Reprodutiva Suína/prevenção & controle , Vírus da Síndrome Respiratória e Reprodutiva Suína/imunologia , Reprodução , Vacinas Virais/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Proteção Cruzada , Feminino , Feto/virologia , Interferon gama/metabolismo , Síndrome Respiratória e Reprodutiva Suína/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/genética , Gravidez , Natimorto/veterinária , Suínos , Vacinação/veterinária , Vacinas Atenuadas/imunologia , Viremia/veterinária , Desmame
18.
Viruses ; 10(8)2018 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-30081449

RESUMO

Congenital human cytomegalovirus (HCMV) is the most common viral infection of the developing fetus, and a significant cause of neurodevelopmental abnormalities in infants and children. Congenital HCMV infections account for an estimated 25% of all cases of hearing loss in the US. It has long been argued that maternal adaptive immune responses to HCMV can modify both the likelihood of intrauterine transmission of HCMV, and the severity of fetal infection and risk of long term sequelae in infected infants. Over the last two decades, multiple studies have challenged this paradigm, including findings that have demonstrated that the vast majority of infants with congenital HCMV infections in most populations are born to women with established immunity prior to conception. Furthermore, the incidence of clinically apparent congenital HCMV infection in infants born to immune and non-immune pregnant women appears to be similar. These findings from natural history studies have important implications for the design, development, and testing of prophylactic vaccines and biologics for this perinatal infection. This brief overview will provide a discussion of existing data from human natural history studies and animal models of congenital HCMV infections that have described the role of maternal immunity in the natural history of this perinatal infection.


Assuntos
Infecções por Citomegalovirus/congênito , Infecções por Citomegalovirus/imunologia , Citomegalovirus/fisiologia , Imunidade Materno-Adquirida , Transmissão Vertical de Doença Infecciosa , Imunidade Adaptativa , Animais , Ensaios Clínicos como Assunto , Feminino , Feto/imunologia , Feto/virologia , Humanos , Lactente , Recém-Nascido , Gravidez , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/virologia , Útero/virologia
20.
Ann Biomed Eng ; 46(12): 1963-1974, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30003503

RESUMO

Recent global epidemics of viral infection such as Zika virus (ZIKV) and associated birth defects from maternal-fetal viral transmission highlights the critical unmet need for experimental models that adequately recapitulates the biology of the human maternal-fetal interface and downstream fetal development. Herein, we report an in vitro biomimetic placenta-fetus model of the maternal-fetal interface and downstream fetal cells. Using a tissue engineering approach, we built a 3D model incorporating placental trophoblast and endothelial cells into an extracellular matrix environment and validated formation of the maternal-fetal interface. We utilized this model to study ZIKV exposure to the placenta and neural progenitor cells. Our results indicated ZIKV infects both trophoblast and endothelial cells, leading to a higher viral load exposed to fetal cells downstream of the barrier. Viral inhibition by chloroquine reduced the amount of virus both in the placenta and transmitted to fetal cells. A sustained downstream neural cell viability in contrast to significantly reduced viability in an acellular model indicates that the placenta sequesters ZIKV consistent with clinical observations. These findings suggest that the placenta can modulate ZIKV exposure-induced fetal damage. Moreover, such tissue models can enable rigorous assessment of potential therapeutics for maternal-fetal medicine.


Assuntos
Feto , Transmissão Vertical de Doença Infecciosa , Modelos Biológicos , Placenta , Complicações Infecciosas na Gravidez , Infecção por Zika virus , Zika virus/metabolismo , Feminino , Feto/embriologia , Feto/patologia , Feto/virologia , Humanos , Placenta/metabolismo , Placenta/patologia , Placenta/virologia , Gravidez , Complicações Infecciosas na Gravidez/metabolismo , Complicações Infecciosas na Gravidez/patologia , Infecção por Zika virus/embriologia , Infecção por Zika virus/patologia , Infecção por Zika virus/transmissão
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