Consuelo Silva de Oliveira

Zika virus in the Americas: Early epidemiological and genetic findings

Zika virus genomes from Brazil The Zika virus outbreak is a major cause for concern in Brazil, where it has been linked with increased reports of otherwise rare birth defects and neuropathology. In a phylogenetic analysis, Faria et al. infer a single introduction of Zika to the Americas and estimated the introduction date to be about May to December 2013—some 12 months earlier than the virus was reported. This timing correlates with major events in the Brazilian cultural calendar associated with increased traveler numbers from areas where Zika virus has been circulating. A correlation was also observed between incidences of microcephaly and week 17 of pregnancy. Science, this issue p. 345 Virus sequencing indicates that Zika arrived in Brazil during the middle of 2013, coincident with a surge in air travelers. Brazil has experienced an unprecedented epidemic of Zika virus (ZIKV), with ~30,000 cases reported to date. ZIKV was first detected in Brazil in May 2015, and cases of microcephaly potentially associated with ZIKV infection were identified in November 2015. We performed next-generation sequencing to generate seven Brazilian ZIKV genomes sampled from four self-limited cases, one blood donor, one fatal adult case, and one newborn with microcephaly and congenital malformations. Results of phylogenetic and molecular clock analyses show a single introduction of ZIKV into the Americas, which we estimated to have occurred between May and December 2013, more than 12 months before the detection of ZIKV in Brazil. The estimated date of origin coincides with an increase in air passengers to Brazil from ZIKV-endemic areas, as well as with reported outbreaks in the Pacific Islands. ZIKV genomes from Brazil are phylogenetically interspersed with those from other South American and Caribbean countries. Mapping mutations onto existing structural models revealed the context of viral amino acid changes present in the outbreak lineage; however, no shared amino acid changes were found among the three currently available virus genomes from microcephaly cases. Municipality-level incidence data indicate that reports of suspected microcephaly in Brazil best correlate with ZIKV incidence around week 17 of pregnancy, although this correlation does not demonstrate causation. Our genetic description and analysis of ZIKV isolates in Brazil provide a baseline for future studies of the evolution and molecular epidemiology of this emerging virus in the Americas.

In situ immune response and mechanisms of cell damage in central nervous system of fatal cases microcephaly by Zika virus

Zika virus (ZIKV) has recently caused a pandemic disease, and many cases of ZIKV infection in pregnant women resulted in abortion, stillbirth, deaths and congenital defects including microcephaly, which now has been proposed as ZIKV congenital syndrome. This study aimed to investigate the in situ immune response profile and mechanisms of neuronal cell damage in fatal Zika microcephaly cases. Brain tissue samples were collected from 15 cases, including 10 microcephalic ZIKV-positive neonates with fatal outcome and five neonatal control flavivirus-negative neonates that died due to other causes, but with preserved central nervous system (CNS) architecture. In microcephaly cases, the histopathological features of the tissue samples were characterized in three CNS areas (meninges, perivascular space, and parenchyma). The changes found were mainly calcification, necrosis, neuronophagy, gliosis, microglial nodules, and inflammatory infiltration of mononuclear cells. The in situ immune response against ZIKV in the CNS of newborns is complex. Despite the predominant expression of Th2 cytokines, other cytokines such as Th1, Th17, Treg, Th9, and Th22 are involved to a lesser extent, but are still likely to participate in the immunopathogenic mechanisms of neural disease in fatal cases of microcephaly caused by ZIKV.

Zika virus epidemic in Brazil. I. Fatal disease in adults: Clinical and laboratorial aspects

BACKGROUND Zika virus (ZIKV) was first detected in Brazil in May 2015 and the country experienced an explosive epidemic. However, recent studies indicate that the introduction of ZIKV occurred in late 2013. Cases of microcephaly and deaths associated with ZIKV infection were identified in Brazil in November, 2015. OBJECTIVES To determine the etiology of three fatal adult cases. STUDY DESIGN Here we report three fatal adult cases of ZIKV disease. ZIKV infection in these patients was confirmed by cells culture and/or real-time reverse transcriptase polymerase chain reaction (RT-qPCR) and by antigen detection using immunohistochemical assay. Samples of brain and other selected organs taken at autopsy from three patients were also analyzed by histopathological and immunohistological examination. RESULTS The first patient, a 36-year-old man with lupus and receiving prednisone therapy, developed a fulminant ZIKV infection. At autopsy, RT-qPCR of blood and tissues was positive for ZIKV RNA, and the virus was cultured from an organ homogenate. The second patient, a previously healthy female, 16 years of age, presented classic symptoms of Zika fever, but later developed severe thrombocytopenia, anemia and hemorrhagic manifestations and died. A blood sample taken on the seventh day of her illness was positive RT-PCR for ZIKV RNA and research in the serum was positive for antinuclear factor fine speckled (1/640), suggesting Evans syndrome (hemolytic anemia an autoimmune disorder with immune thrombocytopenic purpura) secondary to ZIKV infection. The third patient was a 20-year-old woman hospitalized with fever, pneumonia and hemorrhages, who died on 13days after admission. Histopathological changes were observed in all viscera examined. ZIKV antigens were detected by immunohistochemistry in viscera specimens of patients 1 and 3. These three cases demonstrate other potential complications of ZIKV infection, in addition to microcephaly and Guillain-Barre syndrome (GBS), and they suggest that individuals with immune suppression and/or autoimmune disorders may be at higher risk of developing severe disease, if infected with ZIKV.

Chikungunya risk for Brazil

This study aimed to show, based on the literature on the subject, the potential for dispersal and establishment of the chikungunya virus in Brazil. The chikungunya virus, a Togaviridae member of the genus Alphavirus, reached the Americas in 2013 and, the following year, more than a million cases were reported. In Brazil, indigenous transmission was registered in Amapa and Bahia States, even during the period of low rainfall, exposing the whole country to the risk of virus spreading. Brazil is historically infested by Ae. aegypti and Ae. albopictus, also dengue vectors. Chikungunya may spread, and it is important to take measures to prevent the virus from becoming endemic in the country. Adequate care for patients with chikungunya fever requires training general practitioners, rheumatologists, nurses, and experts in laboratory diagnosis. Up to November 2014, more than 1,000 cases of the virus were reported in Brazil. There is a need for experimental studies in animal models to understand the dynamics of infection and the pathogenesis as well as to identify pathophysiological mechanisms that may contribute to identifying effective drugs against the virus. Clinical trials are needed to identify the causal relationship between the virus and serious injuries observed in different organs and joints. In the absence of vaccines or effective drugs against the virus, currently the only way to prevent the disease is vector control, which will also reduce the number of cases of dengue fever.

Microcephaly and Zika virus

The original isolation of the Zika virus (ZIKV), a Flavivirus member of the Flaviviridae family, was obtained in 1947 from the blood of a febrile rhesus monkey exposed at the Zika forest near Lake Victoria, in the outskirts of Entebbe, the capital of Uganda. ZIKV was also isolated from wild mosquitoes in the same area and later periodic human febrile cases were attributed to ZIKV in Uganda and other countries in West and East Africa. Later, in the 1960s, ZIKV was detected in Asia and the virus was isolated from Aedes aegypti mosquitoes, initially in Malaysia and, subsequently, in several countries in Asia, showing that this arbovirus also occurred outside the African continent. This new facet of ZIKV, i.e., ability to cause epidemic disease transmitted by Aedes aegypti, disclosed a new milestone in the epidemiology of this arbovirus infection. It was clear that ZIKV had managed to adapt to an old acquaintance of humans, Aedes aegypti mosquitoes, transmitters of urban yellow fever, four serotypes of dengue fever, chikungunya virus, and other arboviruses in Asia and Africa. Since the 1960s, sporadic cases of ZIKV infection have been reported in humans; due to its sporadic occurrence

In situ inflammasome activation results in severe damage to the central nervous system in fatal Zika virus microcephaly cases

HighlightsZIKV induce activation inflammasome in situ in fatal cases of microcephaly.Recognition of the ZIKV PAMPs by NLRP1, NLRP3, and AIM2 provoke release of caspase 1.Caspase 1 activation converts cytokines IL‐1&bgr;, IL‐18, and IL‐33 to bioactive form.Response induced by Caspase 1, iNOS, and cytokines enhance neuroinflammatory process. Abstract 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‐1&bgr;, 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.

Correlation between Apoptosis and in Situ Immune Response in Fatal Cases of Microcephaly Caused by Zika Virus

Zika virus (ZIKV) is a single-stranded positive-sense RNA flavivirus that possesses a genome approximately 10.7 Kb in length. Although pro-inflammatory and anti-inflammatory cytokines and apoptotic markers belonging to the extrinsic and intrinsic pathways are suggested to be involved in fatal cases of ZIKV-induced microcephaly, their exact roles and associations are unclear. To address this, brain tissue samples were collected from 10 individuals, five of whom were diagnosed as ZIKV positive with microcephaly and a further five were flavivirus-negative controls that died because of other causes. Examination of material from the fatal cases of microcephaly revealed lesions in the cerebral cortex, edema, vascular proliferation, neuronal necrosis, gliosis, neuronophagy, calcifications, apoptosis, and neuron loss. The expression of various apoptosis markers in the neural parenchyma, including FasL, FAS, BAX, BCL2, and caspase 3 differed between ZIKV-positive cases and controls. Further investigation of type 1 and 2 helper T-cell cytokines confirmed a greater anti-inflammatory response in fatal ZIKV-associated microcephaly cases. Finally, an analysis of the linear correlation between tumor necrosis factor-α, IL-1β, IL-4, IL-10, transforming growth factor-β, and IL-33 expression and various apoptotic markers suggested that the immune response may be associated with the apoptotic phenomenon observed in ZIKV-induced microcephaly.

Acompanhamento de gestantes com confirmação laboratorial de infecção pelo vírus Zika na região metropolitana de Belém, Estado do Pará, Brasil: dados preliminares

El virus Zika es un arbovirus emergente y desde su confirmacion en el nordeste de Brasil, en mayo de 2015, se disemino rapidamente a la mayoria de los paises de America Latina y del Caribe. La mayoria de las personas infectadas con el virus Zika son asintomaticas, sin embargo, en mujeres embarazadas la infeccion puede causar graves complicaciones al feto. En la investigacion de 60 embarazadas con exantema y con media de edad gestacional de 20 semanas hubo confirmacion de laboratorio para el virus Zika (biologia molecular y/o serologia) y hasta el momento sin coinfeccion y ningun registro de alteracion ultrasonografica o desenlaces con microcefalia u otra malformacion

Microcefalia e vírus Zika

The original isolation of the Zika virus (ZIKV), a Flavivirus member of the Flaviviridae family, was obtained in 1947 from the blood of a febrile rhesus monkey exposed at the Zika forest near Lake Victoria, in the outskirts of Entebbe, the capital of Uganda. ZIKV was also isolated from wild mosquitoes in the same area and later periodic human febrile cases were attributed to ZIKV in Uganda and other countries in West and East Africa. Later, in the 1960s, ZIKV was detected in Asia and the virus was isolated from Aedes aegypti mosquitoes, initially in Malaysia and, subsequently, in several countries in Asia, showing that this arbovirus also occurred outside the African continent. This new facet of ZIKV, i.e., ability to cause epidemic disease transmitted by Aedes aegypti, disclosed a new milestone in the epidemiology of this arbovirus infection. It was clear that ZIKV had managed to adapt to an old acquaintance of humans, Aedes aegypti mosquitoes, transmitters of urban yellow fever, four serotypes of dengue fever, chikungunya virus, and other arboviruses in Asia and Africa. Since the 1960s, sporadic cases of ZIKV infection have been reported in humans; due to its sporadic occurrence