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The Bunyavirales order comprises more than 500 viruses (generally defined as bunyaviruses) classified into 12 families. Some of these are highly pathogenic viruses infecting different hosts, including humans, mammals, reptiles, arthropods, birds, and/or plants. Host cell sensing of infection activates the innate immune system that aims at inhibiting viral replication and propagation. Upon recognition of pathogen-associated molecular patterns (PAMPs) by cellular pattern recognition receptors (PRRs), numerous signaling cascades are activated, leading to the production of interferons (IFNs). IFNs act in an autocrine and paracrine manner to establish an antiviral state by inducing the expression of hundreds of IFN-stimulated genes (ISGs). Some of these ISGs are known to restrict bunyavirus infection. Along with other constitutively expressed host cellular factors with antiviral activity, these proteins (hereafter referred to as “restriction factors”) target different steps of the viral cycle, including viral entry, genome transcription and replication, and virion egress. In reaction to this, bunyaviruses have developed strategies to circumvent this antiviral response, by avoiding cellular recognition of PAMPs, inhibiting IFN production or interfering with the IFN-mediated response. Herein, we review the current knowledge on host cellular factors that were shown to restrict infections by bunyaviruses. Moreover, we focus on the strategies developed by bunyaviruses in order to escape the antiviral state developed by the infected cells.
Solène Lerolle; Natalia Freitas; François-Loïc Cosset; Vincent Legros. Host Cell Restriction Factors of Bunyaviruses and Viral Countermeasures. Viruses 2021, 13, 784 .
AMA StyleSolène Lerolle, Natalia Freitas, François-Loïc Cosset, Vincent Legros. Host Cell Restriction Factors of Bunyaviruses and Viral Countermeasures. Viruses. 2021; 13 (5):784.
Chicago/Turabian StyleSolène Lerolle; Natalia Freitas; François-Loïc Cosset; Vincent Legros. 2021. "Host Cell Restriction Factors of Bunyaviruses and Viral Countermeasures." Viruses 13, no. 5: 784.
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne orthonairovirus that has become a serious threat to the public health. CCHFV has a single-stranded, tripartite RNA genome composed of L, M, and S segments. Cleavage of the M polyprotein precursor generates the two envelope glycoproteins (GPs) as well as three secreted nonstructural proteins GP38 and GP85 or GP160, representing GP38 only or GP38 linked to a mucin-like protein (MLD), and a double-membrane-spanning protein called NSm. Here, we examined the relevance of each M-segment non-structural proteins in virus assembly, egress and infectivity using a well-established CCHFV virus-like-particle system (tc-VLP). Deletion of MLD protein had no impact on infectivity although it reduced by 60% incorporation of GPs into particles. Additional deletion of GP38 abolished production of infectious tc-VLPs. The loss of infectivity was associated with impaired Gc maturation and exclusion from the Golgi, showing that Gn is not sufficient to target CCHFV GPs to the site of assembly. Consistent with this, efficient complementation was achieved in cells expressing MLD-GP38 in trans with increased levels of preGc to Gc conversion, co-targeting to the Golgi, resulting in particle incorporation and restored infectivity. Contrastingly, a MLD-GP38 variant retained in the ER allowed preGc cleavage but failed to rescue miss-localization or infectivity. NSm deletion, conversely, did not affect trafficking of Gc but interfered with Gc processing, particle formation and secretion. NSm expression affected N-glycosylation of different viral proteins most likely due to increased speed of trafficking through the secretory pathway. This highlights a potential role of NSm in overcoming Golgi retention and facilitating CCHFV egress. Thus, deletions of GP38 or NSm demonstrate their important role on CCHFV particle production and infectivity. GP85 is an essential viral factor for preGc cleavage, trafficking and Gc incorporation into particles, whereas NSm protein is involved in CCHFV assembly and virion secretion. Orthonairoviruses, like the lethal Crimean-Congo hemorrhagic fever virus (CCHFV), encode secreted glycoproteins, such as GP38, in addition to virion envelope glycoproteins (Gn and Gc) that are processed by internal cleavage of the viral M segment encoded polyprotein. CCHFV MLD-GP38 proteins (GP160/GP85) also include an N-terminal domain encompassing a mucin-like protein that is released from GP38 by Furin. The protective effect of non-neutralizing monoclonal antibodies targeting GP38 against lethal CCHFV challenge previously highlighted the importance of GP38 in CCHFV replication. CCHFV also encodes a double-membrane-spanning protein (NSm) of unknown function, located between the Gn and Gc on the polyprotein. To investigate the roles of these so-called accessory proteins encoded by the CCHFV M-segment in virus formation and infectivity, we generated several M-segment deletion mutants and tested them in a CCHFV transcription-entry-competent virus-like particle (tc-VLP) system. Here, we demonstrate that GP38 is crucial for Gc biogenesis, interaction with Gn and trafficking to the Golgi, and that its deletion abrogates formation of infectious particles. We also show that NSm increases the rate of protein trafficking through the secretory pathway with altered N-glycosylation profiles that are advantageous for efficient virus release. These data advanced our understanding of GP38 and NSm roles and CCHFV-host interactions.
Natalia Freitas; Margot Enguehard; Solène Denolly; Camille Levy; Gregory Neveu; Solène Lerolle; Stephanie Devignot; Friedemann Weber; Eric Bergeron; Vincent Legros; François-Loïc Cosset. The interplays between Crimean-Congo hemorrhagic fever virus (CCHFV) M segment-encoded accessory proteins and structural proteins promote virus assembly and infectivity. PLOS Pathogens 2020, 16, e1008850 .
AMA StyleNatalia Freitas, Margot Enguehard, Solène Denolly, Camille Levy, Gregory Neveu, Solène Lerolle, Stephanie Devignot, Friedemann Weber, Eric Bergeron, Vincent Legros, François-Loïc Cosset. The interplays between Crimean-Congo hemorrhagic fever virus (CCHFV) M segment-encoded accessory proteins and structural proteins promote virus assembly and infectivity. PLOS Pathogens. 2020; 16 (9):e1008850.
Chicago/Turabian StyleNatalia Freitas; Margot Enguehard; Solène Denolly; Camille Levy; Gregory Neveu; Solène Lerolle; Stephanie Devignot; Friedemann Weber; Eric Bergeron; Vincent Legros; François-Loïc Cosset. 2020. "The interplays between Crimean-Congo hemorrhagic fever virus (CCHFV) M segment-encoded accessory proteins and structural proteins promote virus assembly and infectivity." PLOS Pathogens 16, no. 9: e1008850.