Dengue and Chikungunya Coinfection – The Emergence of an Underestimated Threat

Both Dengue (DENV) and Chikungunya (CHIKV) viruses can be transmitted by Aedes mosquito species and the diseases that they cause have several clinical symptoms in common. Co-circulation of DENV and CHIKV is increasing around the world and must therefore be considered as an emerging threat with an important public health concern. At present, very little is known about the clinical manifestations and biological consequences of coinfection by both viruses. Thus, numerous questions such as clinical severity and dynamics of viral replication of DENV and CHIKV coinfections, as well as vectorial competence, have yet to be addressed in this important and challenging research area. The ensuring knowledge will enhance the clinical surveillance and the development of diagnostic tools able to differentiate DENV and CHIKV in order to early detect virus invasion and local transmission, as well as to improve patient care and timely control measures. In this review, we highlight the current knowledge on DENV and CHIKV coinfections. We also discuss research perspectives and challenges in order to further understand the ecology and biology of this phenomenon

Aedesin : structure and antimicrobial activity against multidrug resistant bacterial strains

Multidrug resistance, which is acquired by both Gram-positive and Gram-negative bacteria, causes infections that are associated with significant morbidity and mortality in many clinical settings around the world. Because of the rapidly increasing incidence of pathogens that have become resistant to all or nearly all available antibiotics, there is a need for a new generation of antimicrobials with a broad therapeutic range for specific applications against infections. Aedesin is a cecropin-like anti-microbial peptide that was recently isolated from dengue virus-infected salivary glands of the Aedes aegypti mosquito. In the present study, we have refined the analysis of its structural characteristics and have determined its antimicrobial effects against a large panel of multidrug resistant bacterial strains, directly isolated from infected patients. Based the results from nuclear magnetic resonance spectroscopy analysis, Aedesin has a helix-bend-helix structure typical for a member of the family of α-helix anti-microbial peptides. Aedesin efficiently killed Gram-negative bacterial strains that display the most worrisome resistance mechanisms encountered in the clinic, including resistance to carbapenems, aminoglycosides, cephalosporins, 4th generation fluoroquinolones, folate inhibitors and monobactams. In contrast, Gram-positive strains were insensitive to the lytic effects of the peptide. The anti-bacterial activity of Aedesin was found to be salt-resistant, indicating that it is active under physiological conditions encountered in body fluids characterized by ionic salt concentrations. In conclusion, because of its strong lytic activity against multidrug resistant Gram-negative bacterial strains displaying all types of clinically relevant resistance mechanisms known today, Aedesin might be an interesting candidate for the development of alternative treatment for infections caused by these types of bacteria

Induction of a Peptide with Activity against a Broad Spectrum of Pathogens in the Aedes aegypti Salivary Gland, following Infection with Dengue Virus

The ultimate stage of the transmission of Dengue Virus (DENV) to man is strongly dependent on crosstalk between the virus and the immune system of its vector Aedes aegypti (Ae. aegypti). Infection of the mosquito's salivary glands by DENV is the final step prior to viral transmission. Therefore, in the present study, we have determined the modulatory effects of DENV infection on the immune response in this organ by carrying out a functional genomic analysis of uninfected salivary glands and salivary glands of female Ae. aegypti mosquitoes infected with DENV. We have shown that DENV infection of salivary glands strongly up-regulates the expression of genes that encode proteins involved in the vector's innate immune response, including the immune deficiency (IMD) and Toll signalling pathways, and that it induces the expression of the gene encoding a putative anti-bacterial, cecropin-like, peptide (AAEL000598). Both the chemically synthesized non-cleaved, signal peptide-containing gene product of AAEL000598, and the cleaved, mature form, were found to exert, in addition to antibacterial activity, anti-DENV and anti-Chikungunya viral activity. However, in contrast to the mature form, the immature cecropin peptide was far more effective against Chikungunya virus (CHIKV) and, furthermore, had strong anti-parasite activity as shown by its ability to kill Leishmania spp. Results from circular dichroism analysis showed that the immature form more readily adopts a helical conformation which would help it to cause membrane permeabilization, thus permitting its transfer across hydrophobic cell surfaces, which may explain the difference in the anti-pathogenic activity between the two forms. The present study underscores not only the importance of DENV-induced cecropin in the innate immune response of Ae. aegypti, but also emphasizes the broad-spectrum anti-pathogenic activity of the immature, signal peptide-containing form of this peptide

Energy Resolution Performance of the CMS Electromagnetic Calorimeter

The energy resolution performance of the CMS lead tungstate crystal electromagnetic calorimeter is presented. Measurements were made with an electron beam using a fully equipped supermodule of the calorimeter barrel. Results are given both for electrons incident on the centre of crystals and for electrons distributed uniformly over the calorimeter surface. The electron energy is reconstructed in matrices of 3 times 3 or 5 times 5 crystals centred on the crystal containing the maximum energy. Corrections for variations in the shower containment are applied in the case of uniform incidence. The resolution measured is consistent with the design goals

Biology of zika virus in human skin cells and astrocytes

Le virus Zika (ZIKV), virus découvert pour la première fois à la fin des années quarante, est un arbovirus émergent récemment arrivé sous le feu des projecteurs à l’occasion d’une pandémie rapide à l’échelle mondiale. Appartenant à la famille des Flaviviridae, ce flavivirus est transmis par les moustiques du genre Aedes. Alors qu’on le croyait relativement peu pathogène, ce virus se révèle être la cause probable d’une vague de complications neurologiques, incluant l’apparition de microcéphalies et de syndromes de Guillain-Barré. De plus, il n’existe à l’heure actuelle ni vaccins ni traitements spécifiques, la lutte contre le virus se résumant largement à la mise en place de mesures de prévention contre la piqûre de moustiques et la lutte anti-vectorielle.Une meilleure connaissance de l’ensemble de la biologie du virus, depuis les modalités d’entrée dans l’organisme, en particulier au niveau cutanée, jusqu’aux mécanismes moléculaires intimes de la réplication du virus s’avère nécessaire. Par des approches moléculaires et cellulaires, nous avons mis en évidence le tropisme du virus, identifié ses récepteurs et déterminé les réponses cellulaires induites par ce dernier. Nos travaux ont également identifié un potentiel mécanisme d’évasion mise en place par le ZIKV. Nous avons également entrepris un travail original sur un mécanisme moléculaire favorisant la pathogénicité des flavivirus. Une meilleure connaissance de ce mécanisme pourrait déboucher sur l’identification de potentiels cibles thérapeutiques. Enfin, le tropisme neuronal avéré du ZIKV nous a amené à travailler sur la réponse immune des astrocytes humain. En effet, les astrocytes forment une population cellulaire très importante dans le système nerveux central qui est fortement impliquée dans les mécanismes de neurogénèse dans le cerveau des fœtus.The Zika virus (ZIKV) was first isolated from non-human primates the late 1940s. This emerging arbovirus has recently been under the spotlight due to a rapid world pandemic. Belonging to the Flaviviridae family, this flavivirus is transmitted by Aedes’ genus mosquitoes. Historically low pathogenic, a new major concern is the possible association of ZIKV with diverse of neurological complications, including the development of microcephaly and Guillain-Barré syndrome, particularly in newborns of infected mothers. In addition, there is currently no vaccine or specific treatment to cure the disease, so the main preventive measures to fight the spreading of the virus are to prevent mosquitoes’ bites and to plan an effective vector control. A better understanding of the biology of the virus, from the entry in the body, especially at the skin level, to the molecular mechanisms of viral replication, is therefore necessary.Using different molecular and cellular strategies, we investigated the tropism of the virus, identified cell surface receptors and determined the cell’s responses to the infection. Our work also permitted to identify a potential mechanism by which ZIKV evades the host immune system to facilitated his own replication. We also have undertaken original work on a molecular mechanism increasing the pathogenicity of flavivirus. A better knowledge of this mechanism may lead to the identification of potential therapeutic targets. Finally, considering the neuronal tropism of the ZIKV, we studied the immune response of human astrocytes, a very important cell population in the central nervous system, playing a major role in the mechanisms of neurogenesis during the fetus’ brain development

Mayaro Virus Pathogenesis and Transmission Mechanisms

International audienceMayaro virus (MAYV), isolated for the first time in Trinidad and Tobago, has captured the attention of public health authorities worldwide following recent outbreaks in the Americas. It has a propensity to be exported outside its original geographical range, because of the vast distribution of its vectors. Moreover, most of the world population is immunologically naïve with respect to infection with MAYV which makes this virus a true threat. The recent invasion of several countries by Aedes albopictus underscores the risk of potential urban transmission of MAYV in both tropical and temperate regions. In humans, the clinical manifestations of MAYV disease range from mild fever, rash, and joint pain to arthralgia. In the absence of a licensed vaccine and clinically proven therapeutics against Mayaro fever, prevention focuses mainly on household mosquito control. However, as demonstrated for other arboviruses, mosquito control is rather inefficient for outbreak management and alternative approaches to contain the spread of MAYV are therefore necessary. Despite its strong epidemic potential, little is currently known about MAYV. This review addresses various aspects of MAYV, including its epidemiology, vector biology, mode of transmission, and clinical complications, as well as the latest developments in MAYV diagnosis

Chikungunya and Zika Viruses : Co-Circulation and the Interplay between Viral Proteins and Host Factors

International audienceChikungunya and Zika viruses, both transmitted by mosquito vectors, have globally re-emerged over for the last 60 years and resulted in crucial social and economic concerns. Presently, there is no specific antiviral agent or vaccine against these debilitating viruses. Understanding viral–host interactions is needed to develop targeted therapeutics. However, there is presently limited information in this area. In this review, we start with the updated virology and replication cycle of each virus. Transmission by similar mosquito vectors, frequent co-circulation, and occurrence of co-infection are summarized. Finally, the targeted host proteins/factors used by the viruses are discussed. There is an urgent need to better understand the virus–host interactions that will facilitate antiviral drug development and thus reduce the global burden of infections caused by arboviruses

Monitoring arbovirus in Thailand : surveillance of dengue, chikungunya and zika virus, with a focus on coinfections

Infections caused by arboviruses such as dengue virus (DENV), chikungunya virus (CHIKV), and Zika virus (ZIKV) frequently occur in tropical and subtropical regions. These three viruses are transmitted by Aedes (Ae.) aegypti and Ae. albopictus. In Thailand, the highest incidence of arbovirus infection and the high circulation of Aedes mosquito mainly occurs in the Southern provinces of the country. Few studies have focused on the incidence of co-infection of arboviruses in this region. In the present study, a cross-sectional study was conducted on a cohort of 182 febrile patients from three hospitals located in Southern Thailand. Surveillance of DENV, CHIKV and ZIKV was conducted from May to October 2016 during the rainy season. The serological analysis and molecular detection of arboviruses were performed by ELISA and multiplex RT-PCR respectively. The results demonstrated that 163 cases out of 182 patients (89.56%) were infected with DENY, with a predominance of DENV-2. Among these DENY positive cases, a co-infection with CHIKV for 6 patients (3.68%) and with ZIKV for 1 patient (0.61%) were found. 19 patients out of 182 were negative for arboviruses. This study provides evidence of co-infection of arboviruses in Southern Thailand and highlight the importance of testing DENV and other medically important arboviruses, such as CHIKV and ZIKV simultaneously

Dengue virus replication in infected human keratinocytes leads to activation of antiviral innate immune responses

Dengue virus (DENV) infection is the most prevalent mosquito-borne viral diseases in the world. Vector-mediated transmission of DENV is initiated when a blood-feeding female Aedes mosquito injects saliva, together with the virus, into the skin of its mammalian host. Understanding the role of skin immune cells in the activation of innate immunity to DENV at the early times of infection is a critical issue that remains to be investigated. The purpose of our study was to assess the contribution of human keratinocytes as potential host cells to DENV in the activation of immune responses at the anatomical site of mosquito bite. We show that primary keratinocytes support DENV replication with the production of negative-stranded viral RNAs inside the infected cells. In the course of DENV life cycle, we observed the activation of host genes involved in the antiviral immune responses such as intracellular RNA virus sensors Toll-Like Receptor-3, Retinoic Acid Inducible Gene-I, Melanoma Differentiation Associated gene-5 and the RNA-dependent protein kinase R. DENV infection of primary keratinocytes also resulted in up-regulation of the expression of the antiviral Ribonuclease L gene, which subsequently led to enhanced production of IFN-beta and IFN-gamma. Depending on stages of viral replication, we observed the activation of host genes encoding the antimicrobial proteins beta-defensin and RNase 7 in infected keratinocytes. Our data demonstrate for the first time the permissiveness of human epidermal keratinocytes to DENV infection. Remarkably, DENV replication in keratinocytes contributes to the establishment of antiviral innate immunity that might occur in the early times after the bite of mosquito

New Insights into the Biology of the Emerging Tembusu Virus

International audienceReported for the first time in 1955 in Malaysia, Tembusu virus (TMUV) remained, for a long time, in the shadow of flaviviruses with human health importance such as dengue virus or Japanese encephalitis virus. However, since 2010 and the first large epidemic in duck farms in China, the threat of its emergence on a large scale in Asia or even its spillover into the human population is becoming more and more significant. This review aims to report current knowledge on TMUV from viral particle organization to the development of specific vaccines and therapeutics, with a particular focus on host-virus interactions