Including Zika Virus Research Articles

Organotypic models of type III interferon-mediated protection from Zika virus infections at the maternal–fetal interface

Protecting the fetus from the hematogenous spread of viruses requires multifaceted layers of protection and relies heavily on trophoblasts, the fetal-derived cells that comprise the placental barrier. We showed previously that trophoblasts isolated from full-term placentas resist infection by diverse viruses, including Zika virus (ZIKV), and transfer this resistance to nonplacental cells through the activity of paracrine effectors, including the constitutive release of type III interferons (IFNs). Here, we developed 3D cell-line-based models of human syncytiotrophoblasts, cells that lie in direct contact with maternal blood, and show that these cells recapitulate the antiviral properties of primary trophoblasts through the constitutive release of type III IFNs (IFNλ1 and IFNλ2) and become resistant to ZIKV infection. In addition, using organotypic human midgestation chorionic villous explants, we show that syncytiotrophoblasts isolated from the second trimester of pregnancy also constitutively release type III IFNs and use these IFNs in autocrine and paracrine manners to restrict ZIKV infection. Collectively, these data provide important insights into the defense mechanisms used by syncytiotrophoblasts at various stages of human gestation to resist ZIKV infection and new human models to study the role of type III IFNs in the vertical transmission of ZIKV and other viruses associated with congenital disease.

Prospects for induction of CD8 T cell-mediated immunity to Zika virus infection by yellow fever virus vaccination.

The Zika virus epidemic represents an unprecedented health crisis affecting significant parts of the world 1. On February 1st 2016, the WHO declared the reported clusters of Zika-virus induced microcephaly and other neurological disorders a Public Health Emergency of International Concern (PHEIC). The epidemic is currently ongoing in Latin America and the Caribbean, with impacts of the infection already seen in large populations of Brazil, Colombia, Mexico, Peru and beyond. No specific treatment or vaccine is available, although several candidates are under development 2. This article is protected by copyright. All rights reserved.

Heat shock protein gp96-Ig vaccine induces antigen specific CD8 T cell response in the placenta

Abstract The placenta acts as a barrier against infections, due to multiple unique structural, cellular, and immune properties. The detrimental effects of congenital viruses, including Zika virus (ZIKV), on pregnancy and fetal outcomes occur in part because of impaired placental function and profound pathological changes have been observed infected placentas. Our hypothesis is that induction of appropriate vaccine-induced immune responses in the placenta are key to successful prevention of congenital viruses’ infections in developing fetus. The main goal of our study is to developed novel heat shock protein (HSP) based vaccine approach that will induce antigen-specific responses in the placenta and will lead to the prevention of the pathogen transmission to the fetus. HSP gp96 is a biological adjuvant that activates antigen-presenting cells and simultaneously delivers antigen specific peptides to MHC I for CD8 T cell activation. B6 females were mated with B6 mice and gestation day (GD) 0.5 was determined by the presence of vaginal plug. At GD 5.5, 0.5 million of OT1-gfp cells were injected in the tail vein. Two days after, 2.5 million 3T3-gp96-OVA-Ig or 3T3-gp96-Ig cells were injected subcutaneously (SC). Five days later, pregnant uteri were collected and placental and decidual single cells suspension was obtained. Frequency of OT1-gfp cells was determent by flow cytometry. We found that secreted gp96 vaccine delivered by SC route induces very high frequency of antigen specific CD8 T cells in the placenta (15%) and decidua (10%) without compromising placental or fetal viability. Our findings are highly supportive of development of novel gp96-Ig vaccine as unique systemic and placenta-homing, antigen-specific CD8 CTL vaccine strategy.

Investigation of CD8+ T Cell Immunity in Zika Virus Infection Using Mouse Models

Abstract CD8+ T cells may play a dual role in both protection against and pathogenesis of Flaviviruses, including Zika virus (ZIKV). However, virtually nothing is currently known about the role CD8+ T cells play during ZIKV infection in humans and animal models. The goal of our study is to investigate the role of CD8+ T cells during primary ZIKV infection in mice. Using LysMCre+IFNARfl/fl C57BL/6 (H-2b) mice that lack type I IFN receptor in a subset of myeloid cells, we characterized a new mouse model susceptible to infection with both East African lineage (MR766) and Asian lineage (FSS13025) ZIKV strains. A screening of 244 ZIKV epitopes predicted to bind H-2b class I molecules, defined a specific map of 26 and 15 peptides for MR766 and FSS13025 ZIKV strains, respectively. Intracellular cytokine staining confirmed the identity of these epitopes and demonstrated induction of polyfunctional ZIKV-specific CD8+ T cells. Furthermore, adoptive transfer of ZIKV-immune CD8+ T cells reduced viral burdens, whereas depletion of CD8+ T cells led to higher tissue burdens and mortality was increased in ZIKV-infected CD8−/− mice compared to Wild-type. These results demonstrate that CD8+ T cells are important mediators of protection during primary ZIKV infection and provide a H-2b mouse model for investigating ZIKV-specific CD8+ T cell responses. Based on these findings, studies are in progress towards defining the role of resident memory CD8+ T cells in protection against ZIKV infection using our recently developed mouse models of ZIKV systemic infection and sexual transmission.

Identification of Zika virus epitopes reveals immunodominant and protective roles for dengue virus cross-reactive CD8+ T cells.

CD8+ T cells play an important role in controlling Flavivirus infection, including Zika virus (ZIKV). Here, we have identified 25 HLA-B*0702-restricted epitopes and 1 HLA-A*0101-restricted epitope using interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) and intracellular cytokine staining (ICS) in ZIKV-infected IFN-α/β receptor-deficient HLA transgenic mice. The cross-reactivity of ZIKV epitopes to dengue virus (DENV) was tested using IFN-γ-ELISPOT and IFN-γ-ICS on CD8+ T cells from DENV-infected mice, and five cross-reactive HLA-B*0702-binding peptides were identified by both assays. ZIKV/DENV cross-reactive CD8+ T cells in DENV-immune mice expanded post ZIKV challenge and dominated in the subsequent CD8+ T cell response. ZIKV challenge following immunization of mice with ZIKV-specific and ZIKV/DENV cross-reactive epitopes elicited CD8+ T cell responses that reduced infectious ZIKV levels, and CD8+ T cell depletions confirmed that CD8+ T cells mediated this protection. These results identify ZIKV-specific and ZIKV/DENV cross-reactive epitopes and demonstrate both an altered immunodominance pattern in the DENV-immune setting relative to naive, as well as a protective role for epitope-specific CD8+ T cells against ZIKV. These results have important implications for ZIKV vaccine development and provide a mouse model for evaluating anti-ZIKV CD8+ T cell responses of human relevance.

Larvicidal activity of Blumea eriantha essential oil and its components against six mosquito species, including Zika virus vectors: the promising potential of (4E,6Z)-allo-ocimene, carvotanacetone and dodecyl acetate

The effective and environmentally sustainable control of mosquitoes is a challenge of essential importance. This is due to the fact that some invasive mosquitoes, with special reference to the Aedes genus, are particularly difficult to control, due to their high ecological plasticity. Moreover, the indiscriminate overuse of synthetic insecticides resulted in undesirable effects on human health and non-target organisms, as well as resistance development in targeted vectors. Here, the leaf essential oil (EO) extracted from a scarcely studied plant of ethno-medicinal interest, Blumea eriantha (Asteraceae), was tested on the larvae of six mosquitoes, including Zika virus vectors. The B. eriantha EO was analyzed by GC and GC-MS. The B. eriantha EO showed high toxicity against 3rd instar larvae of six important mosquito species: Anopheles stephensi (LC50=41.61 μg/ml), Aedes aegypti (LC50=44.82 μg/ml), Culex quinquefasciatus (LC50 =48.92 μg/ml), Anopheles subpictus (LC50=51.21 μg/ml), Ae. albopictus (LC50=56.33 μg/ml) and Culex tritaeniorhynchus (LC50=61.33 μg/ml). The major components found in B. eriantha EO were (4E,6Z)-allo-ocimene (12.8%), carvotanacetone (10.6%), and dodecyl acetate (8.9%). Interestingly, two of the main EO components, (4E,6Z)-allo-ocimene and carvotanacetone, achieved LC50 lower than 10 μg/ml on all tested mosquito species. The acute toxicity of B. eriantha EO and its major constituents on four aquatic predators of mosquito larval instars was limited, with LC50 ranging from 519 to 11.431 μg/ml. Overall, the larvicidal activity of (4E,6Z)-allo-ocimene and carvotanacetone far exceed most of the LC50 calculated in current literature on mosquito botanical larvicides, allowing us to propose both of them as potentially alternatives for developing eco-friendly mosquito control tools.

Mapping and Role of the CD8+ T Cell Response During Primary Zika Virus Infection in Mice

CD8+ T cells may play a dual role in protection against and pathogenesis of flaviviruses, including Zika virus (ZIKV). We evaluated the CD8+ T cell response in ZIKV-infected LysMCre+IFNARfl/fl C57BL/6 (H-2b) mice lacking the type I interferon receptor in a subset of myeloid cells. In total, 26 and 15 CD8+ Tcell-reactive peptides for ZIKV African (MR766) and Asian (FSS13025) lineage strains, respectively, were identified and validated. CD8+ Tcells from infected mice were polyfunctional and mediated cytotoxicity. Adoptive transfer of ZIKV-immune CD8+ Tcells reduced viral burdens, whereas their depletion led to higher tissue burdens, and CD8-/- mice displayed higher mortality with ZIKV infection. Collectively, these results demonstrate that CD8+ Tcells protect against ZIKV infection. Further, this study provides a T cell competent mouse model for investigating ZIKV-specific Tcell responses.

The Unifying Effects of Maternal-Placental-Fetal Axis Dysregulation on Neurodevelopment Following Infectious and Toxic In Utero Insults

Homeostasis during pregnancy and in the in utero environment is essential for prenatal development. Prenatal maturation is hallmarked by an orchestrated and rigorous developmental program characterized by critical cascades in multiple organ systems. During these critical periods of development, however, potential vulnerability to injury exists throughout pregnancy. Indeed, the developing central nervous system (CNS) is extremely vulnerable to environmental insults throughout the entirety of gestation. These insults can adversely affect the developing brain and spinal cord, and permanently alter the neurodevelopmental trajectory. Specifically, in utero insults and dysregulation of the maternal-placental-fetal axis can change molecular, cellular, structural, and functional development of the CNS, culminating in adverse outcomes and neurological disorders throughout postnatal life. In this review, we will discuss common infectious and toxin-induced in utero insults that have recently garnered attention, including Zika virus, prenatal opioid and alcohol exposure, and chorioamnionitis. The goals are to identify common pathophysiological mechanisms, to emphasize the urgent need for new diagnostic tools, and to promote a broader understanding of the diverse array of neurological outcomes presenting in these children throughout their lifespan. With an increasing number of infants exposed to in utero infections and toxins, and the expanding public health awareness of the consequences of Zika infection, the opioid crisis, alcohol consumption during pregnancy, and the frequency of preterm birth in the United States, familiarity with the underlying mechanisms of each of these insults is paramount to improve the diagnosis and treatment for this exceedingly vulnerable patient population.

Personal Actions to Minimize Mosquito-Borne Illnesses, Including Zika Virus.

Several mosquito-transmitted viral diseases, including dengue, chikungunya, and now Zika, have recently become substantial health threats in the Americas. Population-level actions, such as mosquito...

Genetic dissection of Flaviviridae host factors through genome-scale CRISPR screens.

SummaryThe Flaviviridae are a family of viruses that cause severe human diseases. For example, dengue virus (DENV) is a rapidly emerging pathogen causing an estimated 100 million symptomatic infections annually worldwide1. No approved antivirals are available to date and clinical trials with a tetravalent dengue vaccine showed disappointingly low protection rates2. Also hepatitis C virus (HCV) remains a major medical problem with 160 million chronically infected patients and only expensive treatment on the market3. Despite distinct differences in pathogenesis and mode of transmission, the two viruses share common replication strategies4. A detailed understanding of the host functions that determine viral infection is lacking. Here, we utilized a pooled CRISPR genetic screening strategy5,6 to comprehensively dissect host factors required for these two highly important Flaviviridae members. For DENV, we identified ER-associated multi-protein complexes involved in signal sequence recognition, N-linked glycosylation and ER associated degradation. Dengue virus replication was nearly completely abrogated in cells deficient in the oligosaccharyltransferase (OST) complex. Mechanistic studies pinpointed viral RNA replication and not entry or translation as critical step requiring the OST complex. Moreover, we showed that viral non-structural proteins bind to the OST complex. The identified ER-associated protein complexes were also important for other mosquito-borne flaviviruses including Zika virus, an emerging pathogen causing severe birth defects7. In contrast, the most significant genes identified in the HCV screen were distinct and included viral receptors, RNA binding proteins and enzymes involved in metabolism. We discovered an unexpected link between intracellular FAD levels and HCV replication. This study shows remarkable divergence in host dependency factors between DENV and HCV and illuminates novel host targets for antiviral therapy.

Deeper understanding of Flaviviruses including Zika virus by using Apriori Algorithm and Decision Tree

Zika virus is spreaded by mosquito. There is high probability of Microcephaly. In 1947, the virus was first found from Uganda, but it has broken outall around world, specially North and south America. So, apriori algorithm and decision tree were used to compare polyprotein sequences of zika virus among other flavivirus; Yellow fever, West Nile virus, Dengue virus, Tick borne encephalitis. By this, dissimilarity and similarity about them were found.

Quoi de neuf en dermatologie clinique?

Significant advances have been performed in cutaneous adverse reactions leading to primary prevention strategy and implication of new signaling pathways. Histological features of DRESS and methotrexate toxicity are detailed. New emerging infectious agents are reported including Zika Virus, an arbovirus which can be confused with dengue or chikungunya, a new cowpox virus transmitted by domestic cat leading to lymphadenitis, Spirurina type X larva transmitted in Japan by eating raw squid or fish.Malignancies in pemphigus and pemphigoid are emphasized. Expert recommandations are developped on definitions, diagnosis and disease activity of mucous membrane pemphigoid, bubllous pemphigoid and pemphigus. Psoriasis and cardiometabolic association are discussed. This risk association appears higher in hidradenitis suppurativa, which seems more frequent in patients of African ancestry. IgG4-related disease is an immune mediated entity characterized by fibroinflammatory lesions often misdiagnosed. Pruritus, heat sensations, numbness could be recognized as a small-fiber neuropathy symptoms. Burden impact in common dermatosis is demonstrated and should be integrated in our daily practice.