scholarly journals Neonatal Zika virus infection causes epileptic seizures, viral persistence and long-term behavioral impairment

2017 ◽  
Author(s):  
Isis N. O. Souza ◽  
Paula S. Frost ◽  
Julia V. França ◽  
Jéssica Nascimento-Viana ◽  
Rômulo L. S. Neris ◽  
...  
Keyword(s):  
Zika Virus ◽  
Neurological Disorders ◽  
Epileptic Seizures ◽  
Immunocompetent Mouse ◽  
Behavioral Impairment ◽  
Zikv Infection ◽  
Chemically Induced ◽  
Tnf Α ◽  
Mice Brain

AbstractA causal relationship between congenital Zika virus (ZIKV) exposure and microcephaly and other neurological disorders have been established, but long-term consequences of infection are still unknown. We evaluated acute and late neuropathological and behavioral consequences of ZIKV infection in a neonatal immunocompetent mouse model. ZIKV showed brain tropism, causing post-natal microcephaly and several behavioral dysfunctions. During the acute phase of infection, mice developed very frequent epileptic seizures, which are consistently reduced by TNF-α neutralization. Although adult animals recover from seizures, they become more susceptible to chemically-induced crises. Intriguingly, the virus remained actively replicating in adult animals, which show persistent necrosis and calcifications in the mice brain. Altogether the results reveal late consequences of neonatal ZIKV exposure and suggest the early inhibition of neuroinflammation as a potential treatment.

Acute and chronic neurological consequences of early-life Zika virus infection in mice

2018 ◽  
Vol 10 (444) ◽  
pp. eaar2749 ◽  
Author(s):  
Isis Nem de Oliveira Souza ◽  
Paula S. Frost ◽  
Julia V. França ◽  
Jéssica B. Nascimento-Viana ◽  
Rômulo L. S. Neris ◽  
...  
Keyword(s):  
Zika Virus ◽  
Zikv Infection ◽  
Behavioral Deficits ◽  
Chemically Induced ◽  
Tnf Α ◽  
Effective Therapeutic Strategy ◽  
Short And Long Term ◽  
Factor Α ◽  
Necrosis Factor

Although congenital Zika virus (ZIKV) exposure has been associated with microcephaly and other neurodevelopmental disorders, long-term consequences of perinatal infection are largely unknown. We evaluated short- and long-term neuropathological and behavioral consequences of neonatal ZIKV infection in mice. ZIKV showed brain tropism, causing postnatal-onset microcephaly and several behavioral deficits in adulthood. During the acute phase of infection, mice developed frequent seizures, which were reduced by tumor necrosis factor–α (TNF-α) inhibition. During adulthood, ZIKV replication persisted in neonatally infected mice, and the animals showed increased susceptibility to chemically induced seizures, neurodegeneration, and brain calcifications. Altogether, the results show that neonatal ZIKV infection has long-term neuropathological and behavioral complications in mice and suggest that early inhibition of TNF-α–mediated neuroinflammation might be an effective therapeutic strategy to prevent the development of chronic neurological abnormalities.

scholarly journals Zika virus: a new pandemic threat

2016 ◽  
Vol 10 (03) ◽  
pp. 201-207 ◽  
Author(s):  
Ahmed Ali Al-Qahtani ◽  
Nyla Nazir ◽  
Mashael R. Al-Anazi ◽  
Salvatore Rubino ◽  
Mohammed N. Al-Ahdal
Keyword(s):  
Zika Virus ◽  
Blood Donation ◽  
French Polynesia ◽  
Western Hemisphere ◽  
Zikv Infection ◽  
Rapid Spread ◽  
Screening And Identification ◽  
Pandemic Threat ◽  
Contaminated Blood

Zika virus (ZIKV) is an emerging arbovirus of the Flaviviridae family and is related to dengue, Chikungunya, West Nile, yellow fever, and Japanese encephalitis viruses. ZIKV was first discovered in Uganda in 1947. Different species of mosquito from the Aedes genus, mainly A. aegypti and A. albopictus are the vectors responsible for ZIKV infection in humans. It is also reported that ZIKV is transmitted congenitally, sexually, and through blood donation. Until recently, ZIKV outbreaks were sporadic and self-limiting. The first large epidemic was reported from Yap Island in 2007 followed by an outbreak of Zika fever in French Polynesia in 2013. Brazil is the epicenter of the current ZIKV epidemic which is rapidly spreading across the Americas. ZIKV infection remained relatively less studied in view of its low case numbers, and low clinical impact relative to other arboviruses. However, all this is set to change with its rapid spread in the Western hemisphere and suspected complications particularly microcephaly in newborn babies with ZIKV infected mothers. ZIKV is expected to substantially add to both short-term and long-term economic burden of the effected countries. Due to the large number of people travelling across the borders and some reported cases of transmission of ZIKV via contaminated blood, screening and identification of asymptomatic infected individuals are important.

scholarly journals Late Neurological Consequences of Zika Virus Infection: Risk Factors and Pharmaceutical Approaches

2019 ◽  
Vol 12 (2) ◽  
pp. 60 ◽  
Author(s):  
Isis N. O. Souza ◽  
Fernanda G. Q. Barros-Aragão ◽  
Paula S. Frost ◽  
Claudia P. Figueiredo ◽  
Julia R. Clarke
Keyword(s):  
Zika Virus ◽  
Late Onset ◽  
Neurological Complications ◽  
Therapeutic Approaches ◽  
Zikv Infection ◽  
Clinical Surveillance ◽  
Infection Risk Factors

Zika virus (ZIKV) infection was historically considered a disease with mild symptoms and no major consequences to human health. However, several long-term, late onset, and chronic neurological complications, both in congenitally-exposed babies and in adult patients, have been reported after ZIKV infection, especially after the 2015 epidemics in the American continent. The development or severity of these conditions cannot be fully predicted, but it is possible that genetic, epigenetic, and environmental factors may contribute to determine ZIKV infection outcomes. This reinforces the importance that individuals exposed to ZIKV are submitted to long-term clinical surveillance and highlights the urgent need for the development of therapeutic approaches to reduce or eliminate the neurological burden of infection. Here, we review the epidemiology of ZIKV-associated neurological complications and the role of factors that may influence disease outcome. Moreover, we discuss experimental and clinical evidence of drugs that have shown promising results in vitro or in vitro against viral replication and and/or ZIKV-induced neurotoxicity.

scholarly journals Sofosbuvir protects Zika virus-infected mice from mortality, preventing short- and long-term sequela

2017 ◽  
Author(s):  
André C. Ferreira ◽  
Camila Z. Valle ◽  
Patricia A. Reis ◽  
Giselle Barbosa-Lima ◽  
Yasmine Rangel Vieira ◽  
...  
Keyword(s):  
Zika Virus ◽  
Neurological Disorders ◽  
Health Concern ◽  
Virus Challenge ◽  
Significant Public Health Concern ◽  
Significant Public Health ◽  
Short And Long Term ◽  
Long Term Behavior

ABSTRACTZika virus (ZIKV) caused significant public health concern, because of its association with congenital malformations, neurological disorders in adults and, more recently, with deaths. Considering the necessity to mitigate the cases ZIKV-associated diseases, antiviral interventions against this virus are an urgent necessity. Sofosbuvir, a drug in clinical use against Hepatitis C Virus (HCV), is among the FDA-approved substances endowed with anti-ZIKV activity. In this work, we further investigated the in vivo activity of sofosbuvir against ZIKV. Neonatal Swiss mice were infected with ZIKV (2 x 107 PFU) and treated with sofosbuvir at 20 mg/kg/day, a concentration compatible with pre-clinical development of this drug. We found that sofosbuvir reduced acute levels of ZIKV from 60 to 90 % in different anatomical compartments, such as in blood plasma, spleen, kidney and brain. Early treatment with sofosbuvir doubled the percentage and time of survival of ZIKV-infected animals, despite the aggressive virus challenge assayed and also prevented the acute neuromotor impairment triggered by the virus. On the long-term behavior analysis of ZIKV-associated sequelae, sofosbuvir prevented loss of hippocampal- and amygdala-dependent memory. Our results point out that sofosbuvir inhibits ZIKV replication in vivo, which is consistent with the prospective necessity of antiviral drugs to treat ZIKV-infected individuals.

scholarly journals Evidence of Zika virus circulation in asymptomatic pregnant women in Northeast, Brazil

2021 ◽  
Vol 15 (6) ◽  
pp. e0009412
Author(s):  
Rebeca Costa Castelo Branco ◽  
Patrícia Brasil ◽  
Josélio Maria Galvão Araújo ◽  
Flávia Oliveira Cardoso ◽  
Zulmira Silva Batista ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Umbilical Cord ◽  
Zika Virus ◽  
Venous Blood ◽  
Rapid Test ◽  
Northeast Brazil ◽  
Zikv Infection ◽  
Long Term Impact ◽  
Maternity Clinics

Background Zika virus (ZIKV) is a flavivirus associated with microcephaly and other fetal anormalities. However, evidence of asymptomatic ZIKV infection in pregnant women is still scarce. This study investigated the prevalence of Zika infection in asymptomatic pregnant women attending two public maternities in Maranhão state, Northeast Brazil. Methods A total of 196 women were recruited at the time of delivery by convenience sampling from two maternity clinics in São Luís, Maranhão, Brazil, between April 2017 and June 2018. Venous blood, umbilical cord blood and placental fragments from maternal and fetal sides were collected from each subject. ZIKV infection was determined by reverse transcription polymerase chain reaction (RT-qPCR) for ZIKV and by serology (IgM and IgG). Nonspecific laboratory profiles (TORCH screen) were obtained from medical records. Results The participants were mostly from São Luís and were of 19–35 years of age. They had 10–15 years of schooling and they were of mixed race, married, and Catholic. ZIKV was identified in three umbilical cord samples and in nine placental fragments. Mothers with positive ZIKV RT-qPCR were in the age group older than 19 years. Of the 196 women tested by ZIKV rapid test, 6 and 117 women were positive for anti-ZIKV IgM and anti-ZIKV IgG antibodies, respectively. Placental Immunohistochemistry study detected ZIKV in all samples positive by RT-PCR. The newborns did not show any morphological and/or psychomotor abnormalities at birth. Conclusions Asymptomatic ZIKV infection is frequent, but it was not associated to morphological and/or psychomotor abnormalities in the newborns up to 6 months post-birth. Although pathological abnormalities were not observed at birth, we cannot rule out the long term impact of apparent asymptomatic congenital ZIKV infection.

scholarly journals Persistence of Anti-Zika Virus Immunoglobulin M Antibodies in Children with Microcephaly up to Four Years after Primary Infection

2019 ◽  
Author(s):  
Gubio S. Campos ◽  
Rejane H. Carvalho ◽  
Maria da Glória Teixeira ◽  
Giovanna F. Britto e Silva ◽  
Carolina A. Rolo ◽  
...  
Keyword(s):  
Zika Virus ◽  
Primary Infection ◽  
Immune Reaction ◽  
Acute Infection ◽  
Immunoglobulin M ◽  
Zikv Infection ◽  
Igm Antibodies ◽  
Igm Antibody ◽  
Antibody Persistence

AbstractZika virus (ZIKV) is a member of the flaviviridae family of virus, considered to cause acute self-limited infection in adults, though it may lead to severe complications. It is believed that ZIKV infection elicit a classical viral immune reaction, with primary IgM antibody response and secondary IgG immunity. Persistence of IgM antibodies has been identified for other viruses belonging to the same family as ZIKV. We investigated, therefore, the presence of anti-ZIKV IgM antibodies in children with microcephaly born between January 2015 and November 2018, and their parents. We have detected persistence of IgM in 22% of children with microcephaly up to four years after primary infection. Long term IgM persistence have implications for the diagnosis of acute infection. More investigation is needed in order to correctly construe the significance of anti-ZIKV IgM persistence in the population in general, and in children with microcephaly in particular. The dynamics of IgM antibody responses against ZIKV must be known and understood to avoid misinterpretation of diagnosis for acute infection, re-infection and antibody persistence.

scholarly journals Zika Virus Causes Acute Infection and Inflammation in the Ovary of Mice Without Apparent Defects in Fertility

2019 ◽  
Vol 220 (12) ◽  
pp. 1904-1914 ◽  
Author(s):  
Elizabeth A Caine ◽  
Suzanne M Scheaffer ◽  
Darcy E Broughton ◽  
Vanessa Salazar ◽  
Jennifer Govero ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Phase ◽  
Zika Virus ◽  
Acute Infection ◽  
Long Term Effects ◽  
Zikv Infection ◽  
Infection And Inflammation ◽  
Global Concern ◽  
Follicular Reserve

Abstract Background Zika virus (ZIKV) has become a global concern because infection of pregnant mothers was linked to congenital birth defects. Zika virus is unique from other flaviviruses, because it is transmitted vertically and sexually in addition to by mosquito vectors. Prior studies in mice, nonhuman primates, and humans have shown that ZIKV targets the testis in males, resulting in persistent infection and oligospermia. However, its effects on the corresponding female gonads have not been evaluated. Methods In this study, we assessed the effects of ZIKV on the ovary in nonpregnant mice. Results During the acute phase, ZIKV productively infected the ovary causing accumulation of CD4+ and virus-specific CD8+ T cells. T cells protected against ZIKV infection in the ovary, as higher viral burden was measured in CD8−/− and TCRβδ−/− mice. Increased cell death and tissue inflammation in the ovary was observed during the acute phase of infection, but this normalized over time. Conclusions In contrast to that observed with males, minimal persistence and no long-term consequences of ZIKV infection on ovarian follicular reserve or fertility were demonstrated in this model. Thus, although ZIKV replicates in cells of the ovary and causes acute oophoritis, there is rapid resolution and no long-term effects on fertility, at least in mice.

scholarly journals The Cellular NMD Pathway Restricts Zika Virus Infection and Is Targeted by the Viral Capsid Protein

mBio ◽  
2018 ◽  
Vol 9 (6) ◽  
Author(s):  
Krystal A. Fontaine ◽  
Kristoffer E. Leon ◽  
Mir M. Khalid ◽  
Sakshi Tomar ◽  
David Jimenez-Morales ◽  
...  
Keyword(s):  
Capsid Protein ◽  
Zika Virus ◽  
Neurological Disorders ◽  
Mrna Decay ◽  
Neural Progenitor ◽  
Viral Capsid ◽  
Zikv Infection ◽  
Viral Capsid Protein ◽  
Quality Control Process ◽  
Nonsense Mediated Mrna Decay

ABSTRACT Zika virus (ZIKV) infection of neural progenitor cells (NPCs) in utero is associated with neurological disorders, such as microcephaly, but a detailed molecular understanding of ZIKV-induced pathogenesis is lacking. Here we show that in vitro ZIKV infection of human cells, including NPCs, causes disruption of the nonsense-mediated mRNA decay (NMD) pathway. NMD is a cellular mRNA surveillance mechanism that is required for normal brain size in mice. Using affinity purification-mass spectrometry, we identified multiple cellular NMD factors that bind to the viral capsid protein, including the central NMD regulator up-frameshift protein 1 (UPF1). Endogenous UPF1 interacted with the ZIKV capsid protein in coimmunoprecipitation experiments, and capsid expression posttranscriptionally downregulated UPF1 protein levels, a process that we confirmed occurs during ZIKV infection. Cellular fractionation studies show that the ZIKV capsid protein specifically targets nuclear UPF1 for degradation via the proteasome. A further decrease in UPF1 levels by RNAi significantly enhanced ZIKV infection in NPC cultures, consistent with a model in which NMD restricts ZIKV infection in the fetal brain. We propose that ZIKV, via the capsid protein, has evolved a strategy to lower UPF1 levels and dampen antiviral activities of NMD, which in turn contributes to neuropathology in vivo. IMPORTANCE Zika virus (ZIKV) is a significant global health threat, as infection has been linked to serious neurological complications, including microcephaly. Using a human stem cell-derived neural progenitor model system, we find that a critical cellular quality control process called the nonsense-mediated mRNA decay (NMD) pathway is disrupted during ZIKV infection. Importantly, disruption of the NMD pathway is a known cause of microcephaly and other neurological disorders. We further identify an interaction between the capsid protein of ZIKV and up-frameshift protein 1 (UPF1), the master regulator of NMD, and show that ZIKV capsid targets UPF1 for degradation. Together, these results offer a new mechanism for how ZIKV infection can cause neuropathology in the developing brain.

scholarly journals Persistence and Intra-Host Genetic Evolution of Zika Virus Infection in Symptomatic Adults: A Special View in the Male Reproductive System

Viruses ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 615 ◽  
Author(s):  
Danielle Oliveira ◽  
Giuliana Durigon ◽  
Érica Mendes ◽  
Jason Ladner ◽  
Robert Andreata-Santos ◽  
...  
Keyword(s):  
Reproductive System ◽  
Zika Virus ◽  
Male Reproductive System ◽  
Genetic Evolution ◽  
Single Nucleotide Variants ◽  
Zikv Infection ◽  
Initial Symptoms ◽  
Host Genetic ◽  
Male Patients

We followed the presence of Zika virus (ZIKV) in four healthy adults (two men and two women), for periods ranging from 78 to 298 days post symptom onset. The patients were evaluated regarding the presence of the virus in different body fluids (blood, saliva, urine and semen), development of immune responses (including antibodies, cytokines and chemokines), and virus genetic variation within samples collected from semen and urine during the infection course. The analysis was focused primarily on the two male patients who shed the virus for up to 158 days after the initial symptoms. ZIKV particles were detected in the spermatozoa cytoplasm and flagella, in immature sperm cells and could also be isolated from semen in cell culture, confirming that the virus is able to preserve integrity and infectivity during replication in the male reproductive system (MRS). Despite the damage caused by ZIKV infection within the MRS, our data showed that ZIKV infection did not result in infertility at least in one of the male patients. This patient was able to conceive a child after the infection. We also detected alterations in the male genital cytokine milieu, which could play an important role in the replication and transmission of the virus which could considerably increase the risk of ZIKV sexual spread. In addition, full genome ZIKV sequences were obtained from several samples (mainly semen), which allowed us to monitor the evolution of the virus within a patient during the infection course. We observed genetic changes over time in consensus sequences and lower frequency intra-host single nucleotide variants (iSNV), that suggested independent compartmentalization of ZIKV populations in the reproductive and urinary systems. Altogether, the present observations confirm the risks associated with the long-term replication and shedding of ZIKV in the MRS and help to elucidate patterns of intra-host genetic evolution during long term replication of the virus.

scholarly journals Hepatic and Cardiac Complications Related to Zika Virus Infection

2019 ◽  
Vol 1 (2) ◽  
Author(s):  
Hassan S. Naji
Keyword(s):  
Liver Injury ◽  
Virus Infection ◽  
Zika Virus ◽  
Neurological Disorders ◽  
Cardiovascular Complications ◽  
Cardiac Complications ◽  
Coagulation Disorders ◽  
Severe Liver ◽  
Zikv Infection ◽  
Review Study

Major global concerns regarding Zika virus (ZIKV) infection, include microcephaly in neonates and Guillain-Barre syndrome in adults. However, there is evidence for the involvement of other body organs along with neurological disorders. Recent studies indicate that ZIKV like other arboviruses can cause cardiovascular complications, severe liver injury, and coagulation disorders. These possible threats must not be overlooked, and clinicians should be aware of compatible symptoms in patients, so they can manage them properly. The purpose of this review study is to characterize hepato-cardiac complications of Zika virus.

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