Chikungunya triggers an autophagic process which promotes viral replication

Krejbich-Trotot, Pascale; Gay, Bernard; Li-Pat-Yuen, Ghislaine; Hoarau, Jean-Jacques; Jaffar‐Bandjee, Marie‐Christine; Briant, Laurence; Gasque, Philippe; Denizot, Mélanie

doi:10.1186/1743-422x-8-432

Cited by 103 publications

(95 citation statements)

References 24 publications

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“…More recently, UBQLN1 has also been involved in autophagy, mediating protein targeting to autophagosomes by its interaction with LC3 (44). Thus, the nsP2 interaction with UBQLN4 could be either involved in the negative regulation of antiviral mechanisms through the degradation of cellular factors like p53 or participate in the hijacking of cellular process like autophagy to the benefit of CHIKV replication, as previously shown for several positive-strand RNA viruses, including CHIKV (28,31). Indeed, although autophagy was recently shown to protect mice from SINV infection of the central nervous system (38), this cellular process is hijacked by numerous positivestrand RNA viruses to produce multimembrane structures involved in viral replication and assembly (31).…”

Section: Discussionmentioning

confidence: 88%

Mapping of Chikungunya Virus Interactions with Host Proteins Identified nsP2 as a Highly Connected Viral Component

Bouraï

Lucas‐Hourani

Gad

et al. 2012

J Virol

102

111

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h Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that has been responsible for an epidemic outbreak of unprecedented magnitude in recent years. Since then, significant efforts have been made to better understand the biology of this virus, but we still have poor knowledge of CHIKV interactions with host cell components at the molecular level. Here we describe the extensive use of high-throughput yeast two-hybrid (HT-Y2H) assays to characterize interactions between CHIKV and human proteins. A total of 22 high-confidence interactions, which essentially involved the viral nonstructural protein nsP2, were identified and further validated in protein complementation assay (PCA). These results were integrated to a larger network obtained by extensive mining of the literature for reports on alphavirus-host interactions. To investigate the role of cellular proteins interacting with nsP2, gene silencing experiments were performed in cells infected by a recombinant CHIKV expressing Renilla luciferase as a reporter. Collected data showed that heterogeneous nuclear ribonucleoprotein K (hnRNP-K) and ubiquilin 4 (UBQLN4) participate in CHIKV replication in vitro. In addition, we showed that CHIKV nsP2 induces a cellular shutoff, as previously reported for other Old World alphaviruses, and determined that among binding partners identified by yeast twohybrid methods, the tetratricopeptide repeat protein 7B (TTC7B) plays a significant role in this activity. Altogether, this report provides the first interaction map between CHIKV and human proteins and describes new host cell proteins involved in the replication cycle of this virus.

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Section: Discussionmentioning

confidence: 88%

Mapping of Chikungunya Virus Interactions with Host Proteins Identified nsP2 as a Highly Connected Viral Component

Bouraï

Lucas‐Hourani

Gad

et al. 2012

J Virol

102

111

View full text Add to dashboard Cite

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“…The enhanced activation of autophagy by rapidly replicating bacteria such as wBm during larval development and in adult worm populations and induced by wMelPop in Drosophila also may influence the successful infection and transmission of viruses. For example, the requirement of arboviruses (Dengue and Chikungunya) for an intact host autophagy system and their use of autophagosomes for successful replication and transmission (34,35) may be blocked by Wolbachia-mediated manipulation of autophagosomal maturation, a hypothesis we are testing currently.…”

Section: Discussionmentioning

confidence: 99%

Autophagy regulates Wolbachia populations across diverse symbiotic associations

Voronin

Cook

Steven

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

114

117

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Wolbachia are widespread and abundant intracellular symbionts of arthropods and filarial nematodes. Their symbiotic relationships encompass obligate mutualism, commensalism, parasitism, and pathogenicity. A consequence of these diverse associations is that Wolbachia encounter a wide range of host cells and intracellular immune defense mechanisms of invertebrates, which they must evade to maintain their populations and spread to new hosts. Here we show that autophagy, a conserved intracellular defense mechanism and regulator of cell homeostasis, is a major immune recognition and regulatory process that determines the size of Wolbachia populations. The regulation of Wolbachia populations by autophagy occurs across all distinct symbiotic relationships and can be manipulated either chemically or genetically to modulate the Wolbachia population load. The recognition and activation of host autophagy is particularly apparent in rapidly replicating strains of Wolbachia found in somatic tissues of Drosophila and filarial nematodes. In filarial nematodes, which host a mutualistic association with Wolbachia, the use of antibiotics such as doxycycline to eliminate Wolbachia has emerged as a promising approach to their treatment and control. Here we show that the activation of host nematode autophagy reduces bacterial loads to the same magnitude as antibiotic therapy; thus we identify a bactericidal mode of action targeting Wolbachia that can be exploited for the development of chemotherapeutic agents against onchocerciasis, lymphatic filariasis, and heartworm.Brugia malayi | innate immunity | chemotherapy | helminth | endosymbiont W olbachia is a widespread and abundant endosymbiotic bacterium of arthropods and filarial nematodes that resides in vacuoles of host germline and somatic cells. Wolbachia show a diverse variety of symbiotic associations with their host, ranging from obligate mutualism in filarial nematodes to commensal, parasitic, or pathogenic associations in insects and other arthropod hosts (1-5).In filarial nematodes Wolbachia is obligatory for normal larval growth and development, embryogenesis, and survival of adult worms (1). Although the molecular basis of this mutualistic relationship remains unknown, a comparison of host and bacterial genomes suggests that intact biosynthetic pathways for haem, nucleotides, riboflavin, and FAD may be among the contributions of the bacteria to the biology of the nematode host (6-8). The biological processes most sensitive to Wolbachia loss include larval growth and development and embryogenesis in adult females. These processes have a high metabolic demand because of the rapid growth, development, and organogenesis of the nematode and are associated with the rapid expansion of Wolbachia populations following larval infection of mammalian hosts and in reproductively active adult females (9). Loss of Wolbachia results in extensive apoptosis of germline and somatic cells of embryos, microfilariae, and fourth-stage (L4) larvae, presumably because of the lack of provision of ...

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“…CHIKV nsP2 and nsP3 display activities that counteract some of these antiviral responses (94). Authophagy is proposed to play a global pro-CHIKV function in human cells, possibly by limiting apoptosis, and may be a pathogenesis determinant (95)(96)(97). Although some additional proviral host factors have been identified (70, 74, 78, 98-100), specific host pathways and mechanisms that promote replication of to a week and may occur in a biphasic manner (2,120).…”

Section: Disease Mechanisms and Host Immune Responsesmentioning

confidence: 99%