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1.
Viruses ; 13(3)2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33808725

RESUMEN

The rapid spread of the virus in Latin America and the association of the infection with microcephaly in newborns or Guillain-Barré Syndrome in adults prompted the WHO to declare the Zika virus (ZIKV) epidemic to be an international public health emergency in 2016. As the virus was first discovered in monkeys and is spread not only by mosquitos but also from human to human, we investigated the stability to the human complement of ZIKV derived from mosquito (ZIKVInsect), monkey (ZIKVVero), or human cells (ZIKVA549 and ZIKVFibro), respectively. At a low serum concentration (10%), which refers to complement concentrations found on mucosal surfaces, the virus was relatively stable at 37 °C. At higher complement levels (up to 50% serum concentration), ZIKV titers differed significantly depending on the cell line used for the propagation of the virus. While the viral titer of ZIKVInsect decreased about two orders in magnitude, when incubated with human serum, the virus derived from human cells was more resistant to complement-mediated lysis (CML). By virus-capture assay and Western blots, the complement regulator protein CD55 was identified to be incorporated into the viral envelope. Blocking of CD55 by neutralizing Abs significantly increased the sensitivity to human complement. Taken together, these data indicate that the incorporation of CD55 from human cells contributes to the stability of ZIKV against complement-mediated virolysis.

2.
Viruses ; 13(3)2021 03 22.
Artículo en Inglés | MEDLINE | ID: mdl-33810110

RESUMEN

Congenital Zika virus (ZIKV) infection may present with a broad spectrum of clinical manifestations. Some sequelae, particularly neurodevelopmental problems, may have a later onset. We conducted a prospective cohort study of 799 high-risk pregnant women who were followed up until delivery. Eighty-three women and/or newborns were considered ZIKV exposed and/or infected. Laboratory diagnosis was made by polymerase chain reaction in the pregnant mothers and their respective newborns, as well as Dengue virus, Chikungunya virus, and ZIKV serology. Serology for toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, and syphilis infections were also performed in microcephalic newborns. The newborns included in the study were followed up until their third birthday. Developmental delay was observed in nine patients (13.2%): mild cognitive delay in three patients, speech delay in three patients, autism spectrum disorder in two patients, and severe neurological abnormalities in one microcephalic patient; sensorineural hearing loss, three patients and dysphagia, six patients. Microcephaly due to ZIKV occurred in three patients (3.6%). Clinical manifestations can appear after the first year of life in children infected/exposed to ZIKV, emphasizing the need for long-term follow-up.

3.
Libyan J Med ; 16(1): 1909902, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33849406

RESUMEN

Zika virus (ZIKV) is a serious public health concern that may lead to neurological disorders in affected individuals. The virus can be transmitted from an infected mother to her fetus, via mosquitoes, or sexually. ZIKV infections are associated with increased risk for Guillain-Barré syndrome (GBS) and congenital microcephaly in newborns infected prenatally. Dysregulations of intracellular microRNAs (miRNAs) in infected neurons have been linked to different neurological diseases. To determine the potential role of miRNAs in ZIKV infection we developed a chronically infected neuroblastoma cell line and carried out differential expression analyses of miRNAs with reference to an uninfected neuroblastoma cell line. A total of 3192miRNAs were evaluated and 389 were found to be upregulated < 2-fold and 1291 were downregulated < 2-fold. In particular, we determined that hsa-mir-431-5p, hsa-mir-3687, hsa-mir-4655-5p, hsa-mir-6071, hsa-mir-762, hsa-mir-5787, and hsa-mir-6825-3p were significantly downregulated, ranging from -5711 to -660-fold whereas, has-mir-4315, hsa-mir-5681b, hsa-mir-6511a-3p, hsa-mir-1264, hsa-mir-4418, hsa-mir-4497, hsa-mir-4485-3p, hsa-mir-4715-3p, hsa-mir-4433-3p, hsa-mir-4708-3p, hsa-mir-1973 and hsa-mir-564 were upregulated, ranging from 20-0.8-fold. We carried out target gene alignment of these miRNAs with the ZIKV genome to predict the function of the differentially expressed miRNAs and their potential impact on ZIKV pathogenesis. These miRNAs might prove useful as novel diagnostic or therapeutic markers and targets for further research on ZIKV infection and neuronal injury resulting from ZIKV infectivity in developing fetal brain neurons.

4.
Anat Rec (Hoboken) ; 2021 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-33834635

RESUMEN

Zika virus (ZIKV) is an emerging pathogen of public health concern, associated with a dramatic burden in places where the virus caused outbreaks between 2015 and 2017. In the Americas, the ZIKV was first reported in Brazil and rapidly spread through the Americas. Since its first report, a number of studies have been published as we continue to learn, not only about modes of transmission, but also clinical manifestations, risk of congenital anomalies, including microcephaly and neurological malformations in fetuses born from mothers infected during pregnancy. Interventions to reduce the burden of ZIKV infection are restricted to mosquito control, and for Aedes spp mosquitoes the strategies implemented to that end proved to be unsuccessful so far. Hence the lessons we can learn following the ZIKV epidemics become of paramount importance in the development of drug treatments and in search for a vaccine.

5.
Front Cell Infect Microbiol ; 11: 637710, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33796483

RESUMEN

Apoptosis, pyroptosis and necroptosis are regulated processes of cell death which can be crucial for viral disease outcomes in hosts because of their effects on viral pathogenicity and host resistance. Zika virus (ZIKV) is a mosquito-borne flavivirus, which infects humans and can cause neurological disorders. Neural developmental disorders and microcephaly could occur in infected fetuses. Several types of nervous cells have been reported to be susceptible to ZIKV infection. Human astrocytes play important roles in the nutritional support and defense of neurons. In this study, we show that human astrocytes are susceptible to ZIKV infection and undergo progressive cell death after infection. In infected astrocytes we detected no cleavage or activation of pro-caspase-3 and pro-caspase-1. Apoptotic substrates and increased secretion of interleukin (IL)-1ß or IL-18 were not detected, either. These ruled out the occurrence of apoptosis or pyroptosis in ZIKV-infected astrocytes. We detected, however, an increase of phosphorylated receptor-interacting serine/threonine-protein kinase (RIPK)1, RIPK3, and mixed lineage kinase domain-like (MLKL) protein, indicating that programmed necrosis, or necroptosis, was induced in infected astrocytes. The phosphorylation and cell death were inhibited in cells pre-treated with GSK'872, an inhibitor of RIPK3, while inhibition of RIPK1 with an inhibitor, Necrostatin-1, had no effect, suggesting that ZIKV-induced necroptosis was RIPK1-independent in astrocytes. Consistent with this finding, the inhibition of RIPK1 had no effect on the phosphorylation of MLKL. We showed evidence that MLKL phosphorylation was RIPK3-dependent and ZBP-1, which could stimulate RIPK3, was upregulated in ZIKV-infected astrocytes. Finally, we demonstrated that in GSK'872-pre-treated astrocytes, viral replication increased significantly, which indicates that necroptosis may be protective against viral replication in astrocytes. Our finding that astrocytes uniquely underwent necroptosis in response to ZIKV infection provides insight and helps us better understand the viral pathogenesis in the ZIKV-infected central nervous system.

6.
Artículo en Inglés | MEDLINE | ID: mdl-33836919

RESUMEN

INTRODUCTION: The objectives of this study were to determine the prevalence of malocclusion among children with Zika virus-associated microcephaly (MZV) and to describe the most common malocclusion in this population. METHODS: This was a cross-sectional study including patients aged between 30 and 36 months diagnosed with MZV. Healthy children were randomly selected with the same sociodemographic characteristics as the control group. Information about arch-type, primate spaces, arch form, overbite, overjet, midline deviation, anterior crossbite, anterior open bite, and the posterior crossbite was recorded. The statistical analysis used descriptive analysis, Pearson chi-square test, and multivariate logistic regression. RESULTS: Forty children comprised the MZV group, and 40 comprised the control group. Our results demonstrated a significantly higher prevalence of malocclusions in children who had MZV than the control group (P <0.001). Patients with MZV were more likely to have late eruption (P <0.001), hypoplastic maxillary arch (P <0.001), hypoplastic mandibular arch (P <0.001), excessive overjet (P <0.001), and posterior crossbite (P = 0.004). CONCLUSIONS: The prevalence of malocclusion was higher among children with MZV. Late eruption, hypoplastic maxillary arch, hypoplastic mandibular arch, excessive overjet, and posterior crossbite were the most common characteristics for this population.

7.
J Trop Pediatr ; 67(1)2021 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-33822234

RESUMEN

BACKGROUND: Zika virus (ZIKV)-associated congenital microcephaly is an important contributor to pediatric death, and more robust pediatric mortality risk metrics are needed to help guide life plans and clinical decision making for these patients. Although common etiologies of pediatric and adult mortality differ, early life health can impact adult outcomes-potentially through DNA methylation. Hence, in this pilot study, we take an early step in identifying pediatric mortality risk metrics by examining associations of ZIKV infection and associated congenital microcephaly with existing adult DNA methylation-based mortality biomarkers: GrimAge and Zhang's mortality score (ZMS). METHODS: Mortality measures were calculated from previously published HumanMethylationEPIC BeadChip data from 44 Brazilian children aged 5-40 months (18 with ZIKV-associated microcephaly; 7 normocephalic, exposed to ZIKV in utero; and 19 unexposed controls). We used linear models adjusted for chronological age, sex, methylation batch and white blood cell proportions to evaluate ZIKV and mortality marker relationships. RESULTS: We observed significant decreases in GrimAge-component plasminogen activator inhibitor-1 [PAI-1; ß = -2453.06 pg/ml, 95% confidence interval (CI) -3652.96, -1253.16, p = 0.0002], and ZMS-site cg14975410 methylation (ß = -0.06, 95% CI -0.09, -0.03, p = 0.0003) among children with microcephaly compared to controls. PAI-1 (ß = -2448.70 pg/ml, 95% CI -4384.45, -512.95, p = 0.01) and cg14975410 (ß = 0.01, 95% CI -0.04, 0.06, p = 0.64) results in comparisons of normocephalic, ZIKV-exposed children to controls were not statistically significant. CONCLUSION: Our results suggest that elements of previously-identified adult epigenetic markers of mortality risk are associated with ZIKV-associated microcephaly, a known contributor to pediatric mortality risk. These findings may provide insights for efforts aimed at developing pediatric mortality markers.

8.
Cell Stem Cell ; 2021 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-33838105

RESUMEN

Viral infection in early pregnancy is a major cause of microcephaly. However, how distinct viruses impair human brain development remains poorly understood. Here we use human brain organoids to study the mechanisms underlying microcephaly caused by Zika virus (ZIKV) and herpes simplex virus (HSV-1). We find that both viruses efficiently replicate in brain organoids and attenuate their growth by causing cell death. However, transcriptional profiling reveals that ZIKV and HSV-1 elicit distinct cellular responses and that HSV-1 uniquely impairs neuroepithelial identity. Furthermore, we demonstrate that, although both viruses fail to potently induce the type I interferon system, the organoid defects caused by their infection can be rescued by distinct type I interferons. These phenotypes are not seen in 2D cultures, highlighting the superiority of brain organoids in modeling viral infections. These results uncover virus-specific mechanisms and complex cellular immune defenses associated with virus-induced microcephaly.

9.
Vaccines (Basel) ; 9(3)2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33810028

RESUMEN

Zika virus (ZIKV) infection and its associated congenital and other neurological disorders, particularly microcephaly and other fetal developmental abnormalities, constitute a World Health Organization (WHO) Zika Virus Research Agenda within the WHO's R&D Blueprint for Action to Prevent Epidemics, and continue to be a Public Health Emergency of International Concern (PHEIC) today. ZIKV pathogenicity is initiated by viral infection and propagation across multiple placental and fetal tissue barriers, and is critically strengthened by subverting host immunity. ZIKV immune evasion involves viral non-structural proteins, genomic and non-coding RNA and microRNA (miRNA) to modulate interferon (IFN) signaling and production, interfering with intracellular signal pathways and autophagy, and promoting cellular environment changes together with secretion of cellular components to escape innate and adaptive immunity and further infect privileged immune organs/tissues such as the placenta and eyes. This review includes a description of recent advances in the understanding of the mechanisms underlying ZIKV immune modulation and evasion that strongly condition viral pathogenesis, which would certainly contribute to the development of anti-ZIKV strategies, drugs, and vaccines.

10.
PLoS Negl Trop Dis ; 15(3): e0009183, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33657175

RESUMEN

Global Zika virus (ZIKV) outbreaks and their strong link to microcephaly have raised major public health concerns. ZIKV has been reported to affect the innate immune responses in neural stem/progenitor cells (NS/PCs). However, it is unclear how these immune factors affect neurogenesis. In this study, we used Asian-American lineage ZIKV strain PRVABC59 to infect primary human NS/PCs originally derived from fetal brains. We found that ZIKV overactivated key molecules in the innate immune pathways to impair neurogenesis in a cell stage-dependent manner. Inhibiting the overactivated innate immune responses ameliorated ZIKV-induced neurogenesis reduction. This study thus suggests that orchestrating the host innate immune responses in NS/PCs after ZIKV infection could be promising therapeutic approach to attenuate ZIKV-associated neuropathology.

11.
Sci Rep ; 11(1): 6492, 2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33753816

RESUMEN

Zika virus (ZIKV), a flavivirus transmitted primarily by infected mosquitos, can cause neurological symptoms such as Guillian-Barré syndrome and microcephaly. We developed several vaccinia virus (VACV) vaccine candidates for ZIKV based on replication-inducible VACVs (vINDs) expressing ZIKV pre-membrane (prM) and envelope (E) proteins (vIND-ZIKVs). These vIND-ZIKVs contain elements of the tetracycline operon and replicate only in the presence of tetracyclines. The pool of vaccine candidates was narrowed to one vIND-ZIKV containing a novel mutation in the signal peptide of prM that led to higher expression and secretion of E and production of virus-like particles, which was then tested for safety, immunogenicity, and efficacy in mice. vIND-ZIKV grows to high titers in vitro in the presence of doxycycline (DOX) but is replication-defective in vivo in the absence of DOX, causing no weight loss in mice. C57BL/6 mice vaccinated once with vIND-ZIKV in the absence of DOX (as a replication-defective virus) developed robust levels of E-peptide-specific IFN-γ-secreting splenocytes and anti-E IgG titers, with modest levels of serum-neutralizing antibodies. Vaccinated mice treated with anti-IFNAR1 antibody were completely protected from ZIKV viremia post-challenge after a single dose of vIND-ZIKV. Furthermore, mice with prior immunity to VACV developed moderate anti-E IgG titers that increased after booster vaccination, and were protected from viremia only after two vaccinations with vIND-ZIKV.

12.
Sci Rep ; 11(1): 6770, 2021 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-33762667

RESUMEN

Zika virus was responsible for the microcephaly epidemic in Brazil which began in October 2015 and brought great challenges to the scientific community and health professionals in terms of diagnosis and classification. Due to the difficulties in correctly identifying Zika cases, it is necessary to develop an automatic procedure to classify the probability of a CZS case from the clinical data. This work presents a machine learning algorithm capable of achieving this from structured and unstructured available data. The proposed algorithm reached 83% accuracy with textual information in medical records and image reports and 76% accuracy in classifying data without textual information. Therefore, the proposed algorithm has the potential to classify CZS cases in order to clarify the real effects of this epidemic, as well as to contribute to health surveillance in monitoring possible future epidemics.

13.
J Matern Fetal Neonatal Med ; : 1-7, 2021 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-33781162

RESUMEN

Zika virus (ZIKV) is a widespread flavivirus transmitted to humans through the bite of Aedes mosquitoes. The number of ZIKV cases increased significantly between 2015 and 2016, and Brazil was the first to report autochthonous transmission of infection. The main neurological disorder related to ZIKV infection is microcephaly. Fetal magnetic resonance imaging (MRI) is the gold standard examination for the analysis of fetal brain infection, followed by obstetric ultrasonography. Cerebral atrophy, intracranial calcifications, ventriculomegaly, cerebellar, and brain gyrus abnormalities are some of the most common findings. Postnatal MRI shows high sensitivity and specificity. Corpus callosum abnormalities, cerebellar hypoplasia, and choroid plexus dilation can be also observed. We present a review of congenital ZIKV infection with emphasis on pre and postnatal brain findings using ultrasonography, MRI, computed tomography, and three-dimensional reconstruction models.

14.
Infect Genet Evol ; 91: 104785, 2021 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-33652117

RESUMEN

Autochthonous Zika virus (ZIKV) transmission in Brazil was first identified in April 2015 in Brazil, with the first ZIKV-associated microcephaly cases detected in October 2015. Despite efforts on understanding ZIKV transmission in Brazil, little is known about the virus epidemiology and genetic diversity in Minas Gerais (MG), the second most populous state in the country. We report molecular and genomic findings from the main public health laboratory in MG. Until January 2020, 26,817 ZIKV suspected infections and 86 congenital syndrome cases were reported in MG state. We tested 8552 ZIKV and microcephaly suspected cases. Ten genomes were generated on-site directly from clinical samples. A total of 1723 confirmed cases were detected in Minas Gerais, with two main epidemic waves; the first and larger epidemic wave peaked in March 2016, with the second smaller wave that peaked in March 2017. Dated molecular clock analysis revealed that multiple introductions occurred in Minas Gerais between 2014 and 2015, suggesting that the virus was circulating unnoticed for at least 16 months before the first confirmed laboratory case that we retrospectively identified in December 2015. Our findings highlight the importance of continued genomic surveillance strategies combined with traditional epidemiology to assist public health laboratories in monitoring and understanding the diversity of circulating arboviruses, which might help attenuate the public health impact of infectious diseases.

15.
PLoS Negl Trop Dis ; 15(3): e0009216, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33684110

RESUMEN

BACKGROUND: While Zika virus (ZIKV) is now widely recognized as a teratogen, the frequency and full spectrum of adverse outcomes of congenital ZIKV infection remains incompletely understood. METHODS: Participants in the MERG cohort of pregnant women with rash, recruited from the surveillance system from December/2015-June/2017. Exposure definition was based on a combination of longitudinal data from molecular, serologic (IgM and IgG3) and plaque reduction neutralization tests for ZIKV. Children were evaluated by a team of clinical specialists and by transfontanelle ultrasound and were classified as having microcephaly and/or other signs/symptoms consistent with congenital Zika syndrome (CZS). Risks of adverse outcomes were quantified according to the relative evidence of a ZIKV infection in pregnancy. FINDINGS: 376 women had confirmed and suspected exposure to ZIKV. Among evaluable children born to these mothers, 20% presented with an adverse outcome compatible with exposure to ZIKV during pregnancy. The absolute risk of microcephaly was 2.9% (11/376), of calcifications and/or ventriculomegaly was 7.2% (13/180), of additional neurologic alterations was 5.3% (13/245), of ophthalmologic abnormalities was 7% (15/214), and of dysphagia was 1.8% (4/226). Less than 1% of the children experienced abnormalities across all of the domains simultaneously. Interpretation: Although approximately one-fifth of children with confirmed and suspected exposure to ZIKV in pregnancy presented with at least one abnormality compatible with CZS, the manifestations presented more frequently in isolation than in combination. Due to the rare nature of some outcomes and the possibility of later manifestations, large scale individual participant data meta-analysis and the long-term evaluation of children are imperative to identify the full spectrum of this syndrome and to plan actions to reduce damages.

16.
BMC Pregnancy Childbirth ; 21(1): 214, 2021 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-33731027

RESUMEN

BACKGROUND: Prevalence of neonatal microcephaly in populations without Zika-epidemics is sparse. The study aimed to report baseline prevalence of congenital microcephaly and its relationship with prenatal factors in an area at risk of Zika outbreak. METHODS: This study included singletons born after 24 gestational weeks in 2017-2018 at four hospitals in Guangzhou, China. Microcephaly was defined as a head circumference at birth >3SD below the mean for sex and gestational age. Prevalence of microcephaly was estimated by binomial exact method. Multivariable logistic regression was used to examine the associations of microcephaly with prenatal factors. The population attributable fraction (PAF) for associated risk factors was calculated. RESULTS: Of 46,610 live births included, 154 (3.3, 95% CI 2.8-3.9 per 1000 live births) microcephalies were identified. Maternal hepatitis B virus carriers (HBV, OR 1.80, 95% CI 1.05-3.10) and primipara (OR 2.68, 95% CI 1.89-3.81) had higher risk of having a microcephalic baby. Higher prevalence of microcephaly was observed in women who had premature labor (OR 1.98, 95% CI 1.17-3.34) and had a baby with fetal growth restriction (OR 16.38, 95% CI 11.81-22.71). Four identified factors (HBV, primiparity, preterm labor, and fetal growth restriction) contributed to 66.4% of the risk of microcephaly. CONCLUSIONS: The prevalence of microcephaly in Guangzhou was higher than expected. This study identified four prenatal risk factors that, together, contributed to two-thirds of the increased risk of microcephaly. This is the first reported association between maternal HBV carrier status and microcephaly.

17.
Int J Infect Dis ; 105: 595-597, 2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33713818

RESUMEN

Zika virus (ZIKV) is a Flavivirus transmitted by Aedes mosquitoes, and was responsible for a worldwide outbreak between 2013 and 2016. However, no ZIKV outbreak has been described in Southeast Asia since 2017. In this study, we report the first microcephaly case with probable ZIKV infection during pregnancy in Lao People's Democratic Republic.

18.
PLoS Negl Trop Dis ; 15(3): e0009048, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33657112

RESUMEN

BACKGROUND: In the French Territories in the Americas (FTA), the risk of birth defects possibly associated with Zika virus (ZIKV) infection was 7.0% (95%CI: 5.0 to 9.5) among foetuses/infants of 546 women with symptomatic RT-PCR confirmed ZIKV infection during pregnancy. Many of these defects were isolated measurement-based microcephaly (i.e. without any detected brain or clinical abnormalities) or mild neurological conditions. We wanted to estimate the proportion of such minor findings among live births of women who were pregnant in the same region during the outbreak period but who were not infected with ZIKV. METHODS: In Guadeloupe, pregnant women were recruited at the time of delivery and tested for ZIKV infection. The outcomes of live born infants of ZIKV non-infected women were compared to those of ZIKV-exposed live born infants in Guadeloupe, extracted from the FTA prospective cohort. RESULTS: Of 490 live born infants without exposure to ZIKV, 42 infants (8.6%, 95%CI: 6.2-11.4) had mild abnormalities that have been described as 'potentially linked to ZIKV infection'; all but one of these was isolated measurement-based microcephaly. Among the 241 live born infants with ZIKV exposure, the proportion of such abnormalities, using the same definition, was similar (6.6%, 95%CI: 3.8-10.6). CONCLUSIONS: Isolated anthropometric abnormalities and mild neurological conditions were as prevalent among infants with and without in-utero ZIKV exposure. If such abnormalities had not been considered as 'potentially linked to ZIKV' in the original prospective cohort in Guadeloupe, the overall estimate of the risk of birth defects considered due to the virus would have been significantly lower, at approximately 1.6% (95% CI: 0.4-4.1). TRIAL REGISTRATION: ClinicalTrials.gov (NCT02916732).

19.
J Virol ; 2021 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-33658344

RESUMEN

Infection with the Zika virus (ZIKV), a member of the Flaviviridae family, can cause serious neurological disorders, most notably microcephaly in newborns. Here we investigated the innate immune response to ZIKV infection in cells of the nervous system. In human neural progenitor cells (hNPCs), a target for ZIKV infection and likely involved in ZIKV-associated neuropathology, viral infection failed to elicit an antiviral interferon (IFN) response. However, pharmacological inhibition of TLR3 partially restored this deficit. Analogous results were obtained in human iPSC-derived astrocytes, which are capable of mounting a strong antiviral cytokine response. There, ZIKV is sensed by both RIG-I and MDA5 and induces an IFN response as well as expression of pro-inflammatory cytokines such as interleukin-6 (IL-6). Upon inhibition of TLR3, also in astrocytes the antiviral cytokine response was enhanced, whereas amounts of pro-inflammatory cytokines were reduced. To study the underlying mechanism, we used human epithelial cells as an easy to manipulate model system. We found that ZIKV is sensed in these cells by RIG-I to induce a robust IFN response and by TLR3 to trigger the expression of pro-inflammatory cytokines, including IL-6. ZIKV induced upregulation of IL-6 activated the STAT3 pathway, which decreased STAT1 phosphorylation in a SOCS-3 dependent manner, thus reducing the IFN response. In conclusion, we show that TLR3 activation by ZIKV suppresses IFN responses triggered by RIG-I-like receptors.ImportanceZika virus (ZIKV) has a pronounced neurotropism and infections with this virus can cause serious neurological disorders, most notably microcephaly and the Guillain-Barré syndrome. Our studies reveal that during ZIKV infection, recognition of viral RNA by TLR3 enhances the production of inflammatory cytokines and suppresses the interferon response triggered by RIG-I-like receptors (RLR) in a SOCS3-dependent manner, thus facilitating virus replication. The discovery of this crosstalk between antiviral (RLR) and inflammatory (TLR) responses may have important implications for our understanding of ZIKV-induced pathogenesis.

20.
Arq. ciências saúde UNIPAR ; 25(1): 37-42, jan-abr. 2021.
Artículo en Portugués | LILACS-Express | LILACS | ID: biblio-1151406

RESUMEN

As infecções ocasionadas pelos vírus da Dengue (DENV), Zika (ZIKV) e Chikungunya (CHIKV) em gestantes são de grande preocupação pelos possíveis danos causados pelos mesmos às mães e fetos. O ZIKV está relacionado à microcefalia e outras anomalias cerebrais graves em neonatos e a infecção por CHIKV em gestantes no período intraparto pode levar à transmissão vertical, com possibilidade de agravamento no quadro do neonato. E, apesar de ainda não haver relatos de ocorrência de malformações congênitas associadas à infecção por DENV em gestantes, as mesmas são consideradas um grupo de risco, pois apresentam maiores chances de evolução para formas graves ou óbito e aumento no risco de partos prematuros decorrente da infecção materna perinatal. Neste estudo, foi realizada uma análise retrospectiva dos resultados envolvendo os vírus DENV, ZIKV e CHIKV para determinar a taxa de positividade destas arboviroses em gestantes no município de São José do Rio Preto-SP, nos anos de 2018 e 2019. Para isso, foram coletados resultados de PCR em tempo real (RT-PCR) para DENV, ZIKV e CHIKV de amostras de soro e urina obtidas de 557 gestantes com histórico de febre, bem como 93 amostras de recém-nascidos (RN). Na análise dos resultados foi verificado que o sorotipo-2 de Dengue (DENV-2) foi detectado em 106/557 correspondendo a 19% das amostras, o sorotipo-1 (DENV-1) foi detectado em apenas uma amostra e o ZIKV foi detectado em duas amostras. CHIKV não foi detectado. Não foi detectado arbovírus nas amostras de RN testadas pela técnica de RT-PCR. Quanto à idade, 40% das gestantes pertenciam à faixa etária de 25 a 32 anos, seguidas pelas faixas de 33 a 40 anos e 17 a 24 anos com percentuais de 31 e 29%, respectivamente. No período, uma gestante que estava na 13ª semana de gestação foi a óbito por DENV-2. Os resultados obtidos evidenciam a importância do diagnóstico precoce das arboviroses neste grupo, viabilizando a assistência adequada às gestantes. Nesse sentido, o monitoramento da circulação simultânea de arboviroses responsáveis por causarem complicações em gestantes e infecções congênitas deve continuar em áreas endêmicas como a de São José do Rio Preto, visando um diagnóstico materno precoce e manejo adequado de gestantes testadas positivas verificando a presença de sinais de alerta e de dengue grave.


Infections caused by Dengue (DENV), Zika (ZIKV) and Chikungunya (CHIKV) viruses in pregnant women represent great concern because of the possible damage that can be caused by these viruses to both mothers and fetuses. ZIKV is related to microcephaly and other severe brain abnormalities in neonates, while CHIKV infection in pregnant women in the intrapartum period can lead to vertical transmission, with the possibility of worsening in the neonate. And although there are no reports of congenital malformations associated with DENV infection in pregnant women, they are also considered of risk group, since they have greater probability to progress to severe forms or even death. In addition, there is an increased risk of premature childbirth. In this study, a retrospective result analysis involving DENV, ZIKV and CHIKV viruses was carried out to determine the positivity rate of those arboviruses in pregnant women in the city of São José do Rio Preto-SP, in the years 2018 and 2019. For this purpose, real-time PCR results (RT-PCR) were collected for DENV, ZIKV and CHIKV from serum and urine samples obtained from 557 pregnant women with a history of fever, as well as samples from 93 newborns (NB). Dengue serotype-2 (DENV-2) was detected in 106/557, which corresponds to 19% of the samples; dengue serotype-1 (DENV-1) was detected in only one sample, and the ZIKV was detected in two samples. CHIKV was not detected. Arboviruses were not detected in the NB samples tested by the RT-PCR technique. In relation to age groups, 40% of pregnant women were between 25 to 32 years old, followed by the groups of 33 to 40 years old, and 17 to 24 years old, with 31% and 29%, respectively. In the period, a pregnant woman who was in the 13th week of pregnancy died due to DENV-2. The results obtained emphasize the importance of the early diagnosis of arboviruses in this group, thus enabling adequate assistance to pregnant women. In this sense, the monitoring of arboviruses circulation responsible for causing complications and congenital infections in pregnant women should continue in endemic areas such as São José do Rio Preto, aiming at an early maternal diagnosis and adequate management of the patients who tested positive, checking for the presence of any alert signs and severe dengue.

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