The large form of human 2′,5′-Oligoadenylate Synthetase (OAS3) exerts antiviral effect against Chikungunya virus

AbstractChikungunya virus (CHIKV) becomes one of the most important mosquito-borne alphavirus in the medical field. CHIKV is highly sensitive to antiviral activity of Type-I interferons (IFN-α/β). Here, we investigated the role of IFN-induced 2′,5′-Oligoadenylate Synthetase (OAS) family in innate immunity to CHIKV. We established inducible human epithelial HeLa cell lines expressing either the large form of human OAS, OAS3, or the genetic variant OAS3-R844X which is predicted to lack about 20% of the OAS3 protein from the carboxy terminus. HeLa cells respond to ectopic OAS3 expression by efficiently inhibiting CHIKV growth. The characteristic of the antiviral effect was a blockade in early stages of virus replication. Thus, OAS3 pathway may represent a novel antialphaviral mechanism by which IFN-α/β controls CHIKV growth. HeLa cells expressing the truncated form of OAS3 were less resistant to CHIKV infection, raising the question on the involvement of OAS3 genetic polymorphism in human susceptibility to alphavirus infection

The growth of arthralgic Ross River virus is restricted in human monocytic cells

International audienceAlphaviruses such as Chikungunya and Ross River (RRV) viruses are associated with persistent arthritisand arthralgia in humans. Monocytes and macrophages are believed to play an important role in alphaviralarthritides. In this study, we evaluated RRV permissiveness of the human acute leukemia MM6 cellline. Viral growth analysis showed that RRV infection of MM6 cells resulted in a very low virus progenyproduction with daily output. Using recombinant RRV expressing the reporter gene Renilla luciferase, aweak viral replication level was detected in infected cells at the early stages of infection. The infectionrestriction was not associated with type-I interferon and pro-inflammatory cytokines release. Apoptosishallmarks (i.e. mitochondrial BAX localisation and PARP cleavage) were observed in infected MM6cells indicating that RRV can trigger apoptosis at late infection times. The long-term persistence of RRVgenomic RNA in surviving MM6 cells identifies human monocytic cells as potential cellular reservoirs ofviral material within the infected host

The Israeli strain IS-98-ST1 of West Nile virus as viral model for West Nile encephalitis in the Old World

West Nile virus (WNV) recently became a major public health concern in North America, the Middle East, and Europe. In contrast with the investigations of the North-American isolates, the neurovirulence properties of Middle-Eastern strains of WNV have not been extensively characterized. Israeli WNV strain IS-98-ST1 that has been isolated from a white stork in 1998, was found to be highly neuroinvasive in adult C57BL/6 mice. Strain IS-98-ST1 infects primary neuronal cells from mouse cortex, causing neuronal death. These results demonstrate that Israeli strain IS-98-ST1 provides a suitable viral model for WNV-induced disease associated with recent WNV outbreaks in the Old World

Reconfigurable IMA platform: from safety assessment to test scenarios on the SCARLETT demonstrator

International audienceThe next generation of IMA platforms should include reconfiguration capabilities in order to limit the effect of some hardware failures on aircraft operational reliability. The contribution of this paper is to describe the safety assessment process from the safety assessment on the preliminary design of a reconfigurable IMA architecture to the execution of the failure scenarios on the SCARLETT demonstrator

Replication properties of a contemporary Zika virus from West Africa

Zika virus (ZIKV) has become a global health problem over the past decade due to the extension of the geographic distribution of the Asian/American genotype. Recent epidemics of Asian/American ZIKV have been associated with developmental disorders in humans. There is mounting evidence that African ZIKV may be associated with increased fetal pathogenicity necessitating to pay a greater attention towards currently circulating viral strains in sub-Saharan Africa. Here, we generated an infectious molecular clone GUINEA-18 of a recently transmitted human ZIKV isolate from West Africa, ZIKV-15555. The available infectious molecular clone MR766MC of historical African ZIKV strain MR766-NIID was used for a molecular clone-based comparative study. Viral clones GUINEA-18 and MR766MC were compared for their ability to replicate in VeroE6, A549 and HCM3 cell lines. There was a lower replication rate for GUINEA-18 associated with weaker cytotoxicity and reduced innate immune system activation compared with MR766MC. Analysis of chimeric viruses between viral clones stressed the importance of NS1 to NS4B proteins, with a particular focus of NS4B on GUINEA-18 replicative properties. ZIKV has developed strategies to prevent cytoplasmic stress granule formation which occurs in response to virus infection. GUINEA-18 was greatly efficient in inhibiting stress granule assembly in A549 cells subjected to a physiological stressor, with NS1 to NS4B proteins also being critical in this process. The impact of these GUINEA-18 proteins on viral replicative abilities and host-cell responses to viral infection raises the question of the role of nonstructural proteins in the pathogenicity of currently circulating ZIKV in sub-Saharan Africa

A Mouse Model for Chikungunya: Young Age and Inefficient Type-I Interferon Signaling Are Risk Factors for Severe Disease

Chikungunya virus (CHIKV) is a re-emerging arbovirus responsible for a massive outbreak currently afflicting the Indian Ocean region and India. Infection from CHIKV typically induces a mild disease in humans, characterized by fever, myalgia, arthralgia, and rash. Cases of severe CHIKV infection involving the central nervous system (CNS) have recently been described in neonates as well as in adults with underlying conditions. The pathophysiology of CHIKV infection and the basis for disease severity are unknown. To address these critical issues, we have developed an animal model of CHIKV infection. We show here that whereas wild type (WT) adult mice are resistant to CHIKV infection, WT mouse neonates are susceptible and neonatal disease severity is age-dependent. Adult mice with a partially (IFN-α/βR+/−) or totally (IFN-α/βR−/−) abrogated type-I IFN pathway develop a mild or severe infection, respectively. In mice with a mild infection, after a burst of viral replication in the liver, CHIKV primarily targets muscle, joint, and skin fibroblasts, a cell and tissue tropism similar to that observed in biopsy samples of CHIKV-infected humans. In case of severe infections, CHIKV also disseminates to other tissues including the CNS, where it specifically targets the choroid plexuses and the leptomeninges. Together, these data indicate that CHIKV-associated symptoms match viral tissue and cell tropisms, and demonstrate that the fibroblast is a predominant target cell of CHIKV. These data also identify the neonatal phase and inefficient type-I IFN signaling as risk factors for severe CHIKV-associated disease. The development of a permissive small animal model will expedite the testing of future vaccines and therapeutic candidates

Understanding the role of contrasting urban contexts in healthy aging: an international cohort study using wearable sensor devices (the CURHA study protocol).

BACKGROUND: Given the challenges of aging populations, calls have been issued for more sustainable urban re-development and implementation of local solutions to address global environmental and healthy aging issues. However, few studies have considered older adults' daily mobility to better understand how local built and social environments may contribute to healthy aging. Meanwhile, wearable sensors and interactive map-based applications offer novel means for gathering information on people's mobility, levels of physical activity, or social network structure. Combining such data with classical questionnaires on well-being, physical activity, perceived environments and qualitative assessment of experience of places opens new opportunities to assess the complex interplay between individuals and environments. In line with current gaps and novel analytical capabilities, this research proposes an international research agenda to collect and analyse detailed data on daily mobility, social networks and health outcomes among older adults using interactive web-based questionnaires and wearable sensors. METHODS/DESIGN: Our study resorts to a battery of innovative data collection methods including use of a novel multisensor device for collection of location and physical activity, interactive map-based questionnaires on regular destinations and social networks, and qualitative assessment of experience of places. This rich data will allow advanced quantitative and qualitative analyses in the aim to disentangle the complex people-environment interactions linking urban local contexts to healthy aging, with a focus on active living, social networks and participation, and well-being. DISCUSSION: This project will generate evidence about what characteristics of urban environments relate to active mobility, social participation, and well-being, three important dimensions of healthy aging. It also sets the basis for an international research agenda on built environment and healthy aging based on a shared and comprehensive data collection protocol

Characterization of Reemerging Chikungunya Virus

An unprecedented epidemic of chikungunya virus (CHIKV) infection recently started in countries of the Indian Ocean area, causing an acute and painful syndrome with strong fever, asthenia, skin rash, polyarthritis, and lethal cases of encephalitis. The basis for chikungunya disease and the tropism of CHIKV remain unknown. Here, we describe the replication characteristics of recent clinical CHIKV strains. Human epithelial and endothelial cells, primary fibroblasts and, to a lesser extent, monocyte-derived macrophages, were susceptible to infection and allowed viral production. In contrast, CHIKV did not replicate in lymphoid and monocytoid cell lines, primary lymphocytes and monocytes, or monocyte-derived dendritic cells. CHIKV replication was cytopathic and associated with an induction of apoptosis in infected cells. Chloroquine, bafilomycin-A1, and short hairpin RNAs against dynamin-2 inhibited viral production, indicating that viral entry occurs through pH-dependent endocytosis. CHIKV was highly sensitive to the antiviral activity of type I and II interferons. These results provide a general insight into the interaction between CHIKV and its mammalian host