Reported for the first time in 1955 in Malaysia, Tembusu virus (TMUV) remained, for a long time, ... more Reported 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.
Zika virus (ZIKV) is an emerging arbovirus of the Flaviviridae family that includes Dengue, West ... more Zika virus (ZIKV) is an emerging arbovirus of the Flaviviridae family that includes Dengue, West Nile, Yellow Fever and Japanese encephalitis viruses, causing a mosquito-borne disease transmitted by the Aedes genus, with recent outbreaks in the South Pacific. Here, we determine the importance of the human skin in the entry of ZIKV and its contribution to the induction of anti-viral immune responses. We show that human dermal fibroblasts, epidermal keratinocytes and immature dendritic cells are permissive to the most recent ZIKV isolate, responsible for the epidemic in French Polynesia. Several entry and/or adhesion factors, among which DC-SIGN, AXL, TYRO3, and to a lesser extent, TIM-1, permitted ZIKV entry with a major role for the TAM receptor AXL. ZIKV permissiveness of human skin fibroblasts was confirmed by the use of a neutralizing Ab and specific RNA silencing. ZIKV induced the transcription of TLR-3, RIG-I and MDA5, as well as several interferon-stimulated genes, including OAS2, ISG15 and MX1, characterized by a strongly enhanced interferon-β gene expression. ZIKV was found to be sensitive to the antiviral effect of both type I and type II interferons. Finally, infection of skin fibroblasts resulted in the formation of autophagosomes whose presence was associated with enhanced viral replication, as shown by the use of Torin 1, a chemical inducer of autophagy or the specific autophagy inhibitor 3-Methyladenine. The results presented herein permit to gain better insight in the biology of ZIKV and to devise strategies aiming to interfere with the pathology caused by this emerging Flavivirus. Zika virus (ZIKV) is an arbovirus belonging to Flaviviridae family. Vector-mediated transmission of ZIKV is initiated when a blood-feeding female Aedes mosquito injects the virus into the skin of its mammalian host, followed by infection of permissive cells via specific receptors. Indeed, skin immune cells, including dermal fibroblasts, epidermal keratinocytes and immature dendritic cells, were all found to be permissive to ZIKV infection. The results also show a major role for the phosphatidylserine receptor AXL as a ZIKV entry receptor, and cellular autophagy in enhancing ZIKV replication in permissive cells. ZIKV replication leads to activation of an antiviral innate immune response and the production of type I interferons in infected cells. Taken together, these results provide for the first time a general insight into the interaction between ZIKV and its mammalian host.
Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, Jan 3, 2015
Arboviruses represent an emerging threat to human. They are transmitted to vertebrates by the bit... more Arboviruses represent an emerging threat to human. They are transmitted to vertebrates by the bite of infected arthropods. Early transmission to vertebrates is initiated by skin puncture and deposition of virus in this organ. However, events at the bite site remain largely unknown. Here, we report that Chikungunya virus (CHIKV) and West Nile virus (WNV), despite belonging to distinct viral families, elicit a common antiviral signature in primary human dermal fibroblasts, attesting for the up regulation of interferon signalling pathways and leading to an increased expression of IFN-β, interleukins and chemokines. Remarkably, CHIKV and WNV enhance IL-1β expression and induce maturation of caspase-1, indicating the capacity of these pathogens to elicit activation of the inflammasome program in resident skin cells. CHIKV and WNV also induce the expression of the inflammasome sensor AIM2 in dermal fibroblasts, whereas inhibition of caspase-1 and AIM2 with siRNA interferes with both CHIKV...
Zika virus (ZIKV) is an emerging arbovirus of the Flaviviridae family that includes Dengue, West ... more Zika virus (ZIKV) is an emerging arbovirus of the Flaviviridae family that includes Dengue, West Nile, Yellow Fever and Japanese encephalitis viruses, causing a mosquito-borne disease transmitted by the Aedes genus, with recent outbreaks in the South Pacific. Here, we determine the importance of the human skin in the entry of ZIKV and its contribution to the induction of anti-viral immune responses. We show that human dermal fibroblasts, epidermal keratinocytes and immature dendritic cells are permissive to the most recent ZIKV isolate, responsible for the epidemic in French Polynesia. Several entry and/or adhesion factors, among which DC-SIGN, AXL, TYRO3, and to a lesser extent, TIM-1, permitted ZIKV entry with a major role for the TAM receptor AXL. ZIKV permissiveness of human skin fibroblasts was confirmed by the use of a neutralizing Ab and specific RNA silencing. ZIKV induced the transcription of TLR-3, RIG-I and MDA5, as well as several interferon-stimulated genes, including OAS2, ISG15 and MX1, characterized by a strongly enhanced interferon-β gene expression. ZIKV was found to be sensitive to the antiviral effect of both type I and type II interferons. Finally, infection of skin fibroblasts resulted in the formation of autophagosomes whose presence was associated with enhanced viral replication, as shown by the use of Torin 1, a chemical inducer of autophagy or the specific autophagy inhibitor 3-Methyladenine. The results presented herein permit to gain better insight in the biology of ZIKV and to devise strategies aiming to interfere with the pathology caused by this emerging Flavivirus. Zika virus (ZIKV) is an arbovirus belonging to Flaviviridae family. Vector-mediated transmission of ZIKV is initiated when a blood-feeding female Aedes mosquito injects the virus into the skin of its mammalian host, followed by infection of permissive cells via specific receptors. Indeed, skin immune cells, including dermal fibroblasts, epidermal keratinocytes and immature dendritic cells, were all found to be permissive to ZIKV infection. The results also show a major role for the phosphatidylserine receptor AXL as a ZIKV entry receptor, and cellular autophagy in enhancing ZIKV replication in permissive cells. ZIKV replication leads to activation of an antiviral innate immune response and the production of type I interferons in infected cells. Taken together, these results provide for the first time a general insight into the interaction between ZIKV and its mammalian host.
Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, Jan 3, 2015
Arboviruses represent an emerging threat to human. They are transmitted to vertebrates by the bit... more Arboviruses represent an emerging threat to human. They are transmitted to vertebrates by the bite of infected arthropods. Early transmission to vertebrates is initiated by skin puncture and deposition of virus in this organ. However, events at the bite site remain largely unknown. Here, we report that Chikungunya virus (CHIKV) and West Nile virus (WNV), despite belonging to distinct viral families, elicit a common antiviral signature in primary human dermal fibroblasts, attesting for the up regulation of interferon signalling pathways and leading to an increased expression of IFN-β, interleukins and chemokines. Remarkably, CHIKV and WNV enhance IL-1β expression and induce maturation of caspase-1, indicating the capacity of these pathogens to elicit activation of the inflammasome program in resident skin cells. CHIKV and WNV also induce the expression of the inflammasome sensor AIM2 in dermal fibroblasts, whereas inhibition of caspase-1 and AIM2 with siRNA interferes with both CHIKV...
Transmission of chikungunya virus (CHIKV) to humans is initiated by puncture of the skin by a blo... more Transmission of chikungunya virus (CHIKV) to humans is initiated by puncture of the skin by a blood-feeding Aedes mosquito. Despite the growing knowledge accumulated on CHIKV, the interplay between skin cells and CHIKV following inoculation still remains unclear. In this study we questioned the behavior of human keratinocytes, the predominant cell population in the skin, following viral challenge. We report that CHIKV rapidly elicits an innate immune response in these cells leading to the enhanced transcription of type I/II and type III interferon genes. Concomitantly, we show that despite viral particles internalization into Rab5-positive endosomes and efficient fusion of virus and cell membranes, keratinocytes poorly replicate CHIKV as attested by absence of nonstructural proteins and genomic RNA synthesis. Accordingly, human keratinocytes behave as an antiviral defense against CHIKV infection rather than as a primary targets for initial replication. This picture significantly dif...
Reported for the first time in 1955 in Malaysia, Tembusu virus (TMUV) remained, for a long time, ... more Reported 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.
Zika virus (ZIKV) is an emerging arbovirus of the Flaviviridae family that includes Dengue, West ... more Zika virus (ZIKV) is an emerging arbovirus of the Flaviviridae family that includes Dengue, West Nile, Yellow Fever and Japanese encephalitis viruses, causing a mosquito-borne disease transmitted by the Aedes genus, with recent outbreaks in the South Pacific. Here, we determine the importance of the human skin in the entry of ZIKV and its contribution to the induction of anti-viral immune responses. We show that human dermal fibroblasts, epidermal keratinocytes and immature dendritic cells are permissive to the most recent ZIKV isolate, responsible for the epidemic in French Polynesia. Several entry and/or adhesion factors, among which DC-SIGN, AXL, TYRO3, and to a lesser extent, TIM-1, permitted ZIKV entry with a major role for the TAM receptor AXL. ZIKV permissiveness of human skin fibroblasts was confirmed by the use of a neutralizing Ab and specific RNA silencing. ZIKV induced the transcription of TLR-3, RIG-I and MDA5, as well as several interferon-stimulated genes, including OAS2, ISG15 and MX1, characterized by a strongly enhanced interferon-β gene expression. ZIKV was found to be sensitive to the antiviral effect of both type I and type II interferons. Finally, infection of skin fibroblasts resulted in the formation of autophagosomes whose presence was associated with enhanced viral replication, as shown by the use of Torin 1, a chemical inducer of autophagy or the specific autophagy inhibitor 3-Methyladenine. The results presented herein permit to gain better insight in the biology of ZIKV and to devise strategies aiming to interfere with the pathology caused by this emerging Flavivirus. Zika virus (ZIKV) is an arbovirus belonging to Flaviviridae family. Vector-mediated transmission of ZIKV is initiated when a blood-feeding female Aedes mosquito injects the virus into the skin of its mammalian host, followed by infection of permissive cells via specific receptors. Indeed, skin immune cells, including dermal fibroblasts, epidermal keratinocytes and immature dendritic cells, were all found to be permissive to ZIKV infection. The results also show a major role for the phosphatidylserine receptor AXL as a ZIKV entry receptor, and cellular autophagy in enhancing ZIKV replication in permissive cells. ZIKV replication leads to activation of an antiviral innate immune response and the production of type I interferons in infected cells. Taken together, these results provide for the first time a general insight into the interaction between ZIKV and its mammalian host.
Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, Jan 3, 2015
Arboviruses represent an emerging threat to human. They are transmitted to vertebrates by the bit... more Arboviruses represent an emerging threat to human. They are transmitted to vertebrates by the bite of infected arthropods. Early transmission to vertebrates is initiated by skin puncture and deposition of virus in this organ. However, events at the bite site remain largely unknown. Here, we report that Chikungunya virus (CHIKV) and West Nile virus (WNV), despite belonging to distinct viral families, elicit a common antiviral signature in primary human dermal fibroblasts, attesting for the up regulation of interferon signalling pathways and leading to an increased expression of IFN-β, interleukins and chemokines. Remarkably, CHIKV and WNV enhance IL-1β expression and induce maturation of caspase-1, indicating the capacity of these pathogens to elicit activation of the inflammasome program in resident skin cells. CHIKV and WNV also induce the expression of the inflammasome sensor AIM2 in dermal fibroblasts, whereas inhibition of caspase-1 and AIM2 with siRNA interferes with both CHIKV...
Zika virus (ZIKV) is an emerging arbovirus of the Flaviviridae family that includes Dengue, West ... more Zika virus (ZIKV) is an emerging arbovirus of the Flaviviridae family that includes Dengue, West Nile, Yellow Fever and Japanese encephalitis viruses, causing a mosquito-borne disease transmitted by the Aedes genus, with recent outbreaks in the South Pacific. Here, we determine the importance of the human skin in the entry of ZIKV and its contribution to the induction of anti-viral immune responses. We show that human dermal fibroblasts, epidermal keratinocytes and immature dendritic cells are permissive to the most recent ZIKV isolate, responsible for the epidemic in French Polynesia. Several entry and/or adhesion factors, among which DC-SIGN, AXL, TYRO3, and to a lesser extent, TIM-1, permitted ZIKV entry with a major role for the TAM receptor AXL. ZIKV permissiveness of human skin fibroblasts was confirmed by the use of a neutralizing Ab and specific RNA silencing. ZIKV induced the transcription of TLR-3, RIG-I and MDA5, as well as several interferon-stimulated genes, including OAS2, ISG15 and MX1, characterized by a strongly enhanced interferon-β gene expression. ZIKV was found to be sensitive to the antiviral effect of both type I and type II interferons. Finally, infection of skin fibroblasts resulted in the formation of autophagosomes whose presence was associated with enhanced viral replication, as shown by the use of Torin 1, a chemical inducer of autophagy or the specific autophagy inhibitor 3-Methyladenine. The results presented herein permit to gain better insight in the biology of ZIKV and to devise strategies aiming to interfere with the pathology caused by this emerging Flavivirus. Zika virus (ZIKV) is an arbovirus belonging to Flaviviridae family. Vector-mediated transmission of ZIKV is initiated when a blood-feeding female Aedes mosquito injects the virus into the skin of its mammalian host, followed by infection of permissive cells via specific receptors. Indeed, skin immune cells, including dermal fibroblasts, epidermal keratinocytes and immature dendritic cells, were all found to be permissive to ZIKV infection. The results also show a major role for the phosphatidylserine receptor AXL as a ZIKV entry receptor, and cellular autophagy in enhancing ZIKV replication in permissive cells. ZIKV replication leads to activation of an antiviral innate immune response and the production of type I interferons in infected cells. Taken together, these results provide for the first time a general insight into the interaction between ZIKV and its mammalian host.
Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, Jan 3, 2015
Arboviruses represent an emerging threat to human. They are transmitted to vertebrates by the bit... more Arboviruses represent an emerging threat to human. They are transmitted to vertebrates by the bite of infected arthropods. Early transmission to vertebrates is initiated by skin puncture and deposition of virus in this organ. However, events at the bite site remain largely unknown. Here, we report that Chikungunya virus (CHIKV) and West Nile virus (WNV), despite belonging to distinct viral families, elicit a common antiviral signature in primary human dermal fibroblasts, attesting for the up regulation of interferon signalling pathways and leading to an increased expression of IFN-β, interleukins and chemokines. Remarkably, CHIKV and WNV enhance IL-1β expression and induce maturation of caspase-1, indicating the capacity of these pathogens to elicit activation of the inflammasome program in resident skin cells. CHIKV and WNV also induce the expression of the inflammasome sensor AIM2 in dermal fibroblasts, whereas inhibition of caspase-1 and AIM2 with siRNA interferes with both CHIKV...
Transmission of chikungunya virus (CHIKV) to humans is initiated by puncture of the skin by a blo... more Transmission of chikungunya virus (CHIKV) to humans is initiated by puncture of the skin by a blood-feeding Aedes mosquito. Despite the growing knowledge accumulated on CHIKV, the interplay between skin cells and CHIKV following inoculation still remains unclear. In this study we questioned the behavior of human keratinocytes, the predominant cell population in the skin, following viral challenge. We report that CHIKV rapidly elicits an innate immune response in these cells leading to the enhanced transcription of type I/II and type III interferon genes. Concomitantly, we show that despite viral particles internalization into Rab5-positive endosomes and efficient fusion of virus and cell membranes, keratinocytes poorly replicate CHIKV as attested by absence of nonstructural proteins and genomic RNA synthesis. Accordingly, human keratinocytes behave as an antiviral defense against CHIKV infection rather than as a primary targets for initial replication. This picture significantly dif...
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Papers by Rodolphe Hamel