Publications by authors named "Cindy Kundlacz"

3 Publications

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Bluetongue Virus in France: An Illustration of the European and Mediterranean Context since the 2000s.

Viruses 2019 07 23;11(7). Epub 2019 Jul 23.

UMR Virologie, INRA, Ecole Nationale Vétérinaire d'Alfort, laboratoire de santé animale d'Alfort, ANSES, Université Paris-Est, 94700 Maisons-Alfort, France.

Bluetongue (BT) is a non-contagious animal disease transmitted by midges of the genus. The etiological agent is the BT virus (BTV) that induces a variety of clinical signs in wild or domestic ruminants. BT is included in the notifiable diseases list of the World Organization for Animal Health (OIE) due to its health impact on domestic ruminants. A total of 27 BTV serotypes have been described and additional serotypes have recently been identified. Since the 2000s, the distribution of BTV has changed in Europe and in the Mediterranean Basin, with continuous BTV incursions involving various BTV serotypes and strains. These BTV strains, depending on their origin, have emerged and spread through various routes in the Mediterranean Basin and/or in Europe. Consequently, control measures have been put in place in France to eradicate the virus or circumscribe its spread. These measures mainly consist of assessing virus movements and the vaccination of domestic ruminants. Many vaccination campaigns were first carried out in Europe using attenuated vaccines and, in a second period, using exclusively inactivated vaccines. This review focuses on the history of the various BTV strain incursions in France since the 2000s, describing strain characteristics, their origins, and the different routes of spread in Europe and/or in the Mediterranean Basin. The control measures implemented to address this disease are also discussed. Finally, we explain the circumstances leading to the change in the BTV status of France from BTV-free in 2000 to an enzootic status since 2018.
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http://dx.doi.org/10.3390/v11070672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669443PMC
July 2019

Novel Function of Bluetongue Virus NS3 Protein in Regulation of the MAPK/ERK Signaling Pathway.

J Virol 2019 08 30;93(16). Epub 2019 Jul 30.

UMR Virologie, INRA, École Nationale Vétérinaire d'Alfort, ANSES, Université Paris-Est, Maisons-Alfort, France

Bluetongue virus (BTV) is an arbovirus transmitted by blood-feeding midges to a wide range of wild and domestic ruminants. In this report, we showed that BTV, through its nonstructural protein NS3 (BTV-NS3), is able to activate the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway, as assessed by phosphorylation levels of ERK1/2 and the translation initiation factor eukaryotic translation initiation factor 4E (eIF4E). By combining immunoprecipitation of BTV-NS3 and mass spectrometry analysis from both BTV-infected and NS3-transfected cells, we identified the serine/threonine-protein kinase B-Raf (BRAF), a crucial player in the MAPK/ERK pathway, as a new cellular interactor of BTV-NS3. BRAF silencing led to a significant decrease in the MAPK/ERK activation by BTV, supporting a model wherein BTV-NS3 interacts with BRAF to activate this signaling cascade. This positive regulation acts independently of the role of BTV-NS3 in counteracting the induction of the alpha/beta interferon response. Furthermore, the intrinsic ability of BTV-NS3 to bind BRAF and activate the MAPK/ERK pathway is conserved throughout multiple serotypes/strains but appears to be specific to BTV compared to other members of genus. Inhibition of MAPK/ERK pathway with U0126 reduced viral titers, suggesting that BTV manipulates this pathway for its own replication. Altogether, our data provide molecular mechanisms that unravel a new essential function of NS3 during BTV infection. Bluetongue virus (BTV) is responsible of the arthropod-borne disease bluetongue (BT) transmitted to ruminants by blood-feeding midges. In this report, we found that BTV, through its nonstructural protein NS3 (BTV-NS3), interacts with BRAF, a key component of the MAPK/ERK pathway. In response to growth factors, this pathway promotes cell survival and increases protein translation. We showed that BTV-NS3 enhances the MAPK/ERK pathway, and this activation is BRAF dependent. Treatment of MAPK/ERK pathway with the pharmacologic inhibitor U0126 impairs viral replication, suggesting that BTV manipulates this pathway for its own benefit. Our results illustrate, at the molecular level, how a single virulence factor has evolved to target a cellular function to increase its viral replication.
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http://dx.doi.org/10.1128/JVI.00336-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675888PMC
August 2019

Nonstructural Protein NSs of Schmallenberg Virus Is Targeted to the Nucleolus and Induces Nucleolar Disorganization.

J Virol 2017 Jan 16;91(1). Epub 2016 Dec 16.

ANSES, UMR1161 Virologie, Laboratory for Animal Health, Maisons-Alfort, France

Schmallenberg virus (SBV) was discovered in Germany in late 2011 and then spread rapidly to many European countries. SBV is an orthobunyavirus that causes abortion and congenital abnormalities in ruminants. A virus-encoded nonstructural protein, termed NSs, is a major virulence factor of SBV, and it is known to promote the degradation of Rpb1, a subunit of the RNA polymerase II (Pol II) complex, and therefore hampers global cellular transcription. In this study, we found that NSs is mainly localized in the nucleus of infected cells and specifically appears to target the nucleolus through a nucleolar localization signal (NoLS) localized between residues 33 and 51 of the protein. NSs colocalizes with nucleolar markers such as B23 (nucleophosmin) and fibrillarin. We observed that in SBV-infected cells, B23 undergoes a nucleolus-to-nucleoplasm redistribution, evocative of virus-induced nucleolar disruption. In contrast, the nucleolar pattern of B23 was unchanged upon infection with an SBV recombinant mutant with NSs lacking the NoLS motif (SBVΔNoLS). Interestingly, unlike wild-type SBV, the inhibitory activity of SBVΔNoLS toward RNA Pol II transcription is impaired. Overall, our results suggest that a putative link exists between NSs-induced nucleolar disruption and its inhibitory function on cellular transcription, which consequently precludes the cellular antiviral response and/or induces cell death.

Importance: Schmallenberg virus (SBV) is an emerging arbovirus of ruminants that spread in Europe between 2011 and 2013. SBV induces fetal abnormalities during gestation, with the central nervous system being one of the most affected organs. The virus-encoded NSs protein acts as a virulence factor by impairing host cell transcription. Here, we show that NSs contains a nucleolar localization signal (NoLS) and induces disorganization of the nucleolus. The NoLS motif in the SBV NSs is absolutely necessary for virus-induced inhibition of cellular transcription. To our knowledge, this is the first report of nucleolar functions for NSs within the Bunyaviridae family.
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http://dx.doi.org/10.1128/JVI.01263-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5165206PMC
January 2017