Project #14680
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#14680 : Modulation of cellular pathways involved in neuropathology of rabies infection
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Name of Applicant : Florence LARROUS
Date of application : 13-01-2020
Unit : Lyssavirus Dynamics and Host Adaptation
Location : Bat. Lwoff, &st floor
Phone : 3927
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Project context and summary :

Viruses have evolved powerful countermeasures to evade host innate immunity, which produces immediate, but non-specific, immune response during infection. Among viruses possessing RNA genomes, the order of negative-single-strand viruses (Mononegavirales) encompasses many human and animal pathogens that cause severe disease, including measles virus, mumps virus and rabies virus. Rabies virus is known for its neurotropic retrograde progression from the site of transmission to brain parenchyma, and towards salivary glands, different organs linked through parasympathetic nervous system. In the cases of human infection, the exhibited symptoms such as hallucination, diplopia, hydrophobia, unsteadiness or paralysis all indicate that there is causality between rabies virus infection and dysfunction of neural activity. However, lack of pathological brain lesions observed at the point of autopsy or noncytolytic propagation devoid of apoptosis suggest that rabies virus possesses mechanisms to evade or delay immune responses and cell death at least for the duration of replication and transmission. Even though the details in molecular perspective of these discoveries are well laid out now, how these proteins work in coordination or if there are hidden components which connect them all together leading toward deterioration of neural cells on the benefit of virus is largely unclear. Moreover, considering the complexity of brain cell composition and how important the neighboring cells are to shape one neuron’s specialization and dependency onto others in homeostasis, which result in the astounding heterogeneity of gene expression, an integrated and holistic approach is mandatory to get a fully comprehensive view of the mechanisms involved. Consequently, we performed an RNASeq analysis in human interneuron cells derived from induced pluripotent stem cells and infected by two recombinant rabies viruses (Tha virus, isolated from a dog in Thailand and Th4M, a less pathogenic virus which is mutated on 4 different residues of the M gene; this virus can no longer escape the NF-KB pathway) in order to obtain transcriptome data by comparison with uninfected cells, and to have an overview of the temporal dynamics of the genes expression.

Related team publications :
3: Sonthonnax F, Besson B, Bonnaud E, Jouvion G, Merino D, Larrous F, Bourhy H. Lyssavirus matrix protein cooperates with phosphoprotein to modulate the Jak-Stat pathway. Sci Rep. 2019 Aug 21;9(1):12171. doi: 10.1038/s41598-019-48507-4. PubMed PMID: 31434934; PubMed Central PMCID: PMC6704159.
3: Besson B, Kim S, Kim T, Ko Y, Lee S, Larrous F, Song J, Shum D, Grailhe R, Bourhy H. Kinome-Wide RNA Interference Screening Identifies Mitogen-Activated Protein Kinases and Phosphatidylinositol Metabolism as Key Factors for Rabies Virus Infection. mSphere. 2019 May 22;4(3). pii: e00047-19. doi: 10.1128/mSphere.00047-19. PubMed PMID: 31118297; PubMed Central PMCID: PMC6531879.
Ben Khalifa Y, Luco S, Besson B, Sonthonnax F, Archambaud M, Grimes JM, Larrous F, Bourhy H. The matrix protein of rabies virus binds to RelAp43 to modulate NF-κB-dependent gene expression related to innate immunity. Sci Rep. 2016 Dec 21;6:39420. doi: 10.1038/srep39420. PubMed PMID: 28000711; PubMed Central PMCID: PMC5175135.
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Project Type : Medium
Status : Closed
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