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  1. Article ; Online: Lyssavirus matrix protein cooperates with phosphoprotein to modulate the Jak-Stat pathway

    Florian Sonthonnax / Benoit Besson / Emilie Bonnaud / Grégory Jouvion / David Merino / Florence Larrous / Hervé Bourhy

    Scientific Reports, Vol 9, Iss 1, Pp 1-

    2019  Volume 13

    Abstract: Abstract Phosphoprotein (P) and matrix protein (M) cooperate to undermine the immune response to rabies virus (RABV) infections. While P is involved in the modulation of the Jak-Stat pathway through the cytoplasmic retention of interferon (IFN)-activated ...

    Abstract Abstract Phosphoprotein (P) and matrix protein (M) cooperate to undermine the immune response to rabies virus (RABV) infections. While P is involved in the modulation of the Jak-Stat pathway through the cytoplasmic retention of interferon (IFN)-activated STAT1 (pSTAT1), M interacts with the RelAp43-p105-ABIN2-TPL2 complex, to efficiently inhibit the nuclear factor-κB (NF-κB) pathway. Using transfections, protein-complementation assays, reverse genetics and DNA ChIP, we identified a role of M protein in the control of Jak-Stat signaling pathway, in synergy with the P protein. In unstimulated cells, both M and P proteins were found to interact with JAK1. Upon type-I IFN stimulation, the M switches toward pSTAT1 interaction, which results in an enhanced capacity of P protein to interact with pSTAT1 and restrain it in the cytoplasm. Furthermore, the role for M-protein positions 77, 100, 104 and 110 was also demonstrated in interaction with both JAK1 and pY-STAT1, and confirmed in vivo. Together, these data indicate that M protein cooperates with P protein to restrain in parallel, and sequentially, NF-κB and Jak-Stat pathways.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2019-08-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: A combination of two human monoclonal antibodies cures symptomatic rabies

    Guilherme Dias de Melo / Florian Sonthonnax / Gabriel Lepousez / Grégory Jouvion / Andrea Minola / Fabrizia Zatta / Florence Larrous / Lauriane Kergoat / Camille Mazo / Carine Moigneu / Roberta Aiello / Angela Salomoni / Elise Brisebard / Paola De Benedictis / Davide Corti / Hervé Bourhy

    EMBO Molecular Medicine, Vol 12, Iss 11, Pp n/a-n/a (2020)

    2020  

    Abstract: Abstract Rabies is a neglected disease caused by a neurotropic Lyssavirus, transmitted to humans predominantly by the bite of infected dogs. Rabies is preventable with vaccines or proper post‐exposure prophylaxis (PEP), but it still causes about 60,000 ... ...

    Abstract Abstract Rabies is a neglected disease caused by a neurotropic Lyssavirus, transmitted to humans predominantly by the bite of infected dogs. Rabies is preventable with vaccines or proper post‐exposure prophylaxis (PEP), but it still causes about 60,000 deaths every year. No cure exists after the onset of clinical signs, and the case‐fatality rate approaches 100% even with advanced supportive care. Here, we report that a combination of two potent neutralizing human monoclonal antibodies directed against the viral envelope glycoprotein cures symptomatic rabid mice. Treatment efficacy requires the concomitant administration of antibodies in the periphery and in the central nervous system through intracerebroventricular infusion. After such treatment, recovered mice presented good clinical condition, viral loads were undetectable, and the brain inflammatory profile was almost normal. Our findings provide the unprecedented proof of concept of an antibody‐based therapeutic approach for symptomatic rabies.
    Keywords immunotherapeutics ; monoclonal antibody therapy ; neglected diseases ; neuroinfectious diseases ; rabies virus ; Medicine (General) ; R5-920 ; Genetics ; QH426-470
    Language English
    Publishing date 2020-11-01T00:00:00Z
    Publisher Wiley
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Regulation of NF-κB by the p105-ABIN2-TPL2 complex and RelAp43 during rabies virus infection.

    Benoit Besson / Florian Sonthonnax / Magalie Duchateau / Youcef Ben Khalifa / Florence Larrous / Hyeju Eun / Véronique Hourdel / Mariette Matondo / Julia Chamot-Rooke / Regis Grailhe / Hervé Bourhy

    PLoS Pathogens, Vol 13, Iss 10, p e

    2017  Volume 1006697

    Abstract: At the crossroad between the NF-κB and the MAPK pathways, the ternary complex composed of p105, ABIN2 and TPL2 is essential for the host cell response to pathogens. The matrix protein (M) of field isolates of rabies virus was previously shown to disturb ... ...

    Abstract At the crossroad between the NF-κB and the MAPK pathways, the ternary complex composed of p105, ABIN2 and TPL2 is essential for the host cell response to pathogens. The matrix protein (M) of field isolates of rabies virus was previously shown to disturb the signaling induced by RelAp43, a NF-κB protein close to RelA/p65. Here, we investigated how the M protein disturbs the NF-κB pathway in a RelAp43-dependant manner and the potential involvement of the ternary complex in this mechanism. Using a tandem affinity purification coupled with mass spectrometry approach, we show that RelAp43 interacts with the p105-ABIN2-TPL2 complex and we observe a strong perturbation of this complex in presence of M protein. M protein interaction with RelAp43 is associated with a wide disturbance of NF-κB signaling, involving a modulation of IκBα-, IκBβ-, and IκBε-RelAp43 interaction and a favored interaction of RelAp43 with the non-canonical pathway (RelB and p100/p52). Monitoring the interactions between host and viral proteins using protein-fragment complementation assay and bioluminescent resonance energy transfer, we further show that RelAp43 is associated to the p105-ABIN2-TPL2 complex as RelAp43-p105 interaction stabilizes the formation of a complex with ABIN2 and TPL2. Interestingly, the M protein interacts not only with RelAp43 but also with TPL2 and ABIN2. Upon interaction with this complex, M protein promotes the release of ABIN2, which ultimately favors the production of RelAp43-p50 NF-κB dimers. The use of recombinant rabies viruses further indicates that this mechanism leads to the control of IFNβ, TNF and CXCL2 expression during the infection and a high pathogenicity profile in rabies virus infected mice. All together, our results demonstrate the important role of RelAp43 and M protein in the regulation of NF-κB signaling.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2017-10-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

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