Persistent Replication of a Chikungunya Virus Replicon in Human Cells Is Associated with Presence of Stable Cytoplasmic Granules Containing Nonstructural Protein 3

Remenyi, Roland; Gao, Yanni; Hughes, Ruth E; Curd, Alistair; Zothner, Carsten; Peckham, Michelle; Merits, Andres; Harris, Mark

doi:10.1128/jvi.00477-18

Cited by 38 publications

(33 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, although viral material (RNA and/or protein) can be detected, researchers have been unable to isolate infectious (replication competent) virus from the joint tissues of patients with subacute or chronic disease 112,114,116 or from mice 2 weeks after CHIKV infection 91 . A number of possibilities could explain this apparent discrepancy: levels of infectious virus might simply be too low to be isolated; defective viral RNA could continue to replicate as replicons without being able to produce infectious (replication-competent) virus 165 , with viral proteins being translated from replicon RNA, and/or residual inactive viral material is only slowly cleared 91 , with large amounts accumulating during the acute infection 90 .…”

Section: Chronic Arthropathymentioning

confidence: 99%

Rheumatic manifestations of chikungunya: emerging concepts and interventions

Suhrbier

2019

Nat Rev Rheumatol

145

View full text Add to dashboard Cite

Chikungunya virus (CHIKV) is a member of a group of globally distributed, mosquito-transmitted arthritogenic alphaviruses that cause sporadic outbreaks of primarily rheumatic disease every 2-50 years 1-4. The largest epidemic of CHIKV disease (hereafter simply referred to as chikungunya) ever recorded began on Lamu Island, Kenya, in 2004 (Fig. 1). The epidemic expanded across four continents, with cases still being reported in 2019 (Fig. 1; Supplementary Table 1). Three major genotypes of CHIKV are now recognized-the Asian, the West African and the Asian and East-Central South African (ECSA) genotypes 5-but a new lineage, the Indian Ocean Lineage (IOL), also emerged from the ECSA genotype during the 2004-2019 epidemic 6. The epidemic reached >100 countries (Supplementary Table 1), caused >10 million cases (Supplementary Table 2), and might arguably be called a pandemic. An estimated 1.3 billion people are at risk of chikungunya 7. Climate change modelling suggests that many more areas of the world (including parts of China, sub-Saharan Africa, South America and the United States) might become able to accommodate transmission of CHIKV in the future 8,9. Chikungunya was previously often viewed as (and for many patients remains) a relatively benign and selflimiting rheumatic disease. However, a considerably more complex spectrum of less common atypical and severe manifestations is now recognized in subgroups of patients, with chikungunya often complicated by comorbidities and co-infections. Hospitalization rates for chikun gunya range from 0.6% to 13% 10-14 and estimates of chikungunya-related mortality range from 0.024% to 0.7% 10,12,15-17. In addition, many patients develop protracted rheumatic disease lasting many months, occasionally years, with a number of sequelae now also recognized 18-22. Estimates for the total economic costs (direct and indirect) of chikungunya have ranged from a median of US$67 for adults and $258 for children in Columbia 23 , to a mean of $150 per outpatient and $3,300 per inpatient in 2006 in Réunion Island 11. In a large study of a chikungunya outbreak in Bangladesh in 2017, >10 days of productivity were lost in ~30% of patients with chikung unya because of severe arthropathy 24. Such costs might be viewed as relatively modest by Western standards; however, the occasionally high attack rate of chikungunya, with up to 30-75% of a given population affected by chikungunya disease at any one time 1,25 , can result in a substantial economic burden, especially in resource-poor communities that are often affected by the disease 26. Considerable research in patients and animal models has now provided extensive insights into the complex Pandemic An epidemic of disease that has spread across a large region; for instance, multiple continents, or even worldwide. Attack rate The total number of new cases of a disease divided by the total population (that is, the percentage of a defined population that is affected by a disease).

show abstract

Section: Chronic Arthropathymentioning

confidence: 99%

Rheumatic manifestations of chikungunya: emerging concepts and interventions

Suhrbier

2019

Nat Rev Rheumatol

145

View full text Add to dashboard Cite

show abstract

“…4A) and could not be observed either in mock-infected cells or in nsP3-mCherry-negative cells in CHIKV-infected cultures. In Old World alphaviruses, including CHIKV, nsP3 binds the GTPase-activating protein (SH3 domain)-binding protein 1 (G3BP), an essential stress granule component (37,38,42,43). We exploited this by overexpressing a G3BP-GFP protein to investigate DHX9 relocalization with respect to this known nsP3-binding partner.…”

Section: Resultsmentioning

confidence: 99%

The Host DHX9 DExH-Box Helicase Is Recruited to Chikungunya Virus Replication Complexes for Optimal Genomic RNA Translation

Matkovic

Bernard

Fontanel

et al. 2019

J Virol

Self Cite

View full text Add to dashboard Cite

Beyond their role in cellular RNA metabolism, DExD/H-box RNA helicases are hijacked by various RNA viruses in order to assist replication of the viral genome. Here, we identify the DExH-box RNA helicase 9 (DHX9) as a binding partner of chikungunya virus (CHIKV) nsP3 mainly interacting with the C-terminal hypervariable domain. We show that during early CHIKV infection, DHX9 is recruited to the plasma membrane, where it associates with replication complexes. At a later stage of infection, DHX9 is, however, degraded through a proteasome-dependent mechanism. Using silencing experiments, we demonstrate that while DHX9 negatively controls viral RNA synthesis, it is also required for optimal mature nonstructural protein translation. Altogether, this study identifies DHX9 as a novel cofactor for CHIKV replication in human cells that differently regulates the various steps of CHIKV life cycle and may therefore mediate a switch in RNA usage from translation to replication during the earliest steps of CHIKV replication. IMPORTANCE The reemergence of chikungunya virus (CHIKV), an alphavirus that is transmitted to humans by Aedes mosquitoes, is a serious global health threat. In the absence of effective antiviral drugs, CHIKV infection has a significant impact on human health, with chronic arthritis being one of the most serious complications. The molecular understanding of host-virus interactions is a prerequisite to the development of targeted therapeutics capable to interrupt viral replication and transmission. Here, we identify the host cell DHX9 DExH-Box helicase as an essential cofactor for early CHIKV genome translation. We demonstrate that CHIKV nsP3 protein acts as a key factor for DHX9 recruitment to replication complexes. Finally, we establish that DHX9 behaves as a switch that regulates the progression of the viral cycle from translation to genome replication. This study might therefore have a significant impact on the development of antiviral strategies.

show abstract

“…Apart from RNA intermediates, studies have reported the persistence of CHIKV specific proteins in host cells over an extended period of time. CHIKV-nsP3 was found to be present as granules along the cell membrane in cells in persistent infection (33), while in another study, CHIKV-capsid proteins were evident in CHIKV infected mice as late as 60 days post-infection, suggesting the active translation of viral proteins during the chronic phase of CHIKD (25).…”

Section: Chronic Phasementioning

confidence: 85%

“…At the same time, components of adaptive immunity have been reported to be instrumental in mounting the severity of the disease and resulting in the chronic arthritic condition that could last for years (26,31,32). Recent research has attributed several viral factors that could also contribute to alleviated chronic conditions, such as persistence of defective viral particles in the host (33) and prolonged infection of synovial macrophages (24).…”

Section: Introductionmentioning

confidence: 99%

Disease Resolution in Chikungunya—What Decides the Outcome?

et al. 2020

View full text Add to dashboard Cite

Chikungunya disease (CHIKD) is a viral infection caused by an alphavirus, chikungunya virus (CHIKV), and triggers large outbreaks leading to epidemics. Despite the low mortality rate, it is a major public health concern owing to high morbidity in affected individuals. The complete spectrum of this disease can be divided into four phases based on its clinical presentation and immunopathology. When a susceptible individual is bitten by an infected mosquito, the bite triggers inflammatory responses attracting neutrophils and initiating a cascade of events, resulting in the entry of the virus into permissive cells. This phase is termed the pre-acute or the intrinsic incubation phase. The virus utilizes the cellular components of the innate immune system to enter into circulation and reach primary sites of infection such as the lymph nodes, spleen, and liver. Also, at this point, antigen-presenting cells (APCs) present the viral antigens to the T cells thereby activating and initiating adaptive immune responses. This phase is marked by the exhibition of clinical symptoms such as fever, rashes, arthralgia, and myalgia and is termed the acute phase of the disease. Viremia reaches its peak during this phase, thereby enhancing the antigen-specific host immune response. Simultaneously, T cell-mediated activation of B cells leads to the formation of CHIKV specific antibodies. Increase in titres of neutralizing IgG/IgM antibodies results in the clearance of virus from the bloodstream and marks the initiation of the post-acute phase. Immune responses mounted during this phase of the infection determine the degree of disease progression or its resolution. Some patients may progress to a chronic arthritic phase of the disease that may last from a few months to several years, owing to a compromised disease resolution. The present review discusses the immunopathology of CHIKD and the factors that dictate disease progression and its resolution.

show abstract

Persistent Replication of a Chikungunya Virus Replicon in Human Cells Is Associated with Presence of Stable Cytoplasmic Granules Containing Nonstructural Protein 3

Cited by 38 publications

References 87 publications

Rheumatic manifestations of chikungunya: emerging concepts and interventions

Rheumatic manifestations of chikungunya: emerging concepts and interventions

The Host DHX9 DExH-Box Helicase Is Recruited to Chikungunya Virus Replication Complexes for Optimal Genomic RNA Translation

Disease Resolution in Chikungunya—What Decides the Outcome?

Contact Info

Product

Resources

About