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2.  Chikungunya Virus-associated Long-term Arthralgia: A 36-month Prospective Longitudinal Study 
Background
Arthritogenic alphaviruses, including Chikungunya virus (CHIKV), are responsible for acute fever and arthralgia, but can also lead to chronic symptoms. In 2006, a Chikungunya outbreak occurred in La Réunion Island, during which we constituted a prospective cohort of viremic patients (n = 180) and defined the clinical and biological features of acute infection. Individuals were followed as part of a longitudinal study to investigate in details the long-term outcome of Chikungunya.
Methodology/Principal Findings
Patients were submitted to clinical investigations 4, 6, 14 and 36 months after presentation with acute CHIKV infection. At 36 months, 22 patients with arthralgia and 20 patients without arthralgia were randomly selected from the cohort and consented for blood sampling. During the 3 years following acute infection, 60% of patients had experienced symptoms of arthralgia, with most reporting episodic relapse and recovery periods. Long-term arthralgias were typically polyarthralgia (70%), that were usually symmetrical (90%) and highly incapacitating (77%). They were often associated with local swelling (63%), asthenia (77%) or depression (56%). The age over 35 years and the presence of arthralgia 4 months after the disease onset are risk factors of long-term arthralgia. Patients with long-term arthralgia did not display biological markers typically found in autoimmune or rheumatoid diseases. These data helped define the features of CHIKV-associated chronic arthralgia and permitted an estimation of the economic burden associated with arthralgia.
Conclusions/Significance
This study demonstrates that chronic arthralgia is a frequent complication of acute Chikungunya disease and suggests that it results from a local rather than systemic inflammation.
Author Summary
Chikungunya virus (CHIKV) is transmitted to human by mosquitoes. It is a re-emerging virus that has a risk to spread globally, given the expanding dissemination of its mosquito vectors. Chikungunya disease is characterized by acute transient febrile arthralgic illness, but can also lead to chronic incapacitating arthralgia. We have conducted a prospective longitudinal study to investigate in details long-term outcome of CHIKV infection. We found that 60% of patients experienced arthralgia 36 months after the onset of acute disease. Arthralgia affected most often multiple sites and were usually incapacitating. In addition to arthralgia, many patients suffered from myalgia and cutaneous lesions and several cognitive dysfunctions. We also showed that age over 35 years and the presence of arthralgia 4 months after the onset of disease are risk factors for long-term arthralgia. Patients with long-term arthralgia did not display biological markers typically found in autoimmune or rheumatoid diseases. This study demonstrates that chronic arthralgia is a frequent complication of acute Chikungunya disease and suggests that it results from a local rather than systemic inflammation.
doi:10.1371/journal.pntd.0002137
PMCID: PMC3605278  PMID: 23556021
3.  Mapping of Chikungunya Virus Interactions with Host Proteins Identified nsP2 as a Highly Connected Viral Component 
Journal of Virology  2012;86(6):3121-3134.
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 two-hybrid 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.
doi:10.1128/JVI.06390-11
PMCID: PMC3302312  PMID: 22258240
4.  Induction of GADD34 Is Necessary for dsRNA-Dependent Interferon-β Production and Participates in the Control of Chikungunya Virus Infection 
PLoS Pathogens  2012;8(5):e1002708.
Nucleic acid sensing by cells is a key feature of antiviral responses, which generally result in type-I Interferon production and tissue protection. However, detection of double-stranded RNAs in virus-infected cells promotes two concomitant and apparently conflicting events. The dsRNA-dependent protein kinase (PKR) phosphorylates translation initiation factor 2-alpha (eIF2α) and inhibits protein synthesis, whereas cytosolic DExD/H box RNA helicases induce expression of type I-IFN and other cytokines. We demonstrate that the phosphatase-1 cofactor, growth arrest and DNA damage-inducible protein 34 (GADD34/Ppp1r15a), an important component of the unfolded protein response (UPR), is absolutely required for type I-IFN and IL-6 production by mouse embryonic fibroblasts (MEFs) in response to dsRNA. GADD34 expression in MEFs is dependent on PKR activation, linking cytosolic microbial sensing with the ATF4 branch of the UPR. The importance of this link for anti-viral immunity is underlined by the extreme susceptibility of GADD34-deficient fibroblasts and neonate mice to Chikungunya virus infection.
Author Summary
Nucleic acids detection by multiple molecular sensors results in type-I interferon production, which protects cells and tissues from viral infections. At the intracellular level, the detection of double-stranded RNA by one of these sensors, the dsRNA-dependent protein kinase also leads to the profound inhibition of protein synthesis. We describe here that the inducible phosphatase 1 co-factor Ppp1r15a/GADD34, a well known player in the endoplasmic reticulum unfolded protein response (UPR), is activated during double-stranded RNA detection and is absolutely necessary to allow cytokine production in cells exposed to poly I:C or Chikungunya virus. Our data shows that the cellular response to nucleic acids can reveal unanticipated connections between innate immunity and fundamental stress pathways, such as the ATF4 branch of the UPR.
doi:10.1371/journal.ppat.1002708
PMCID: PMC3355096  PMID: 22615568
5.  Type I IFN controls chikungunya virus via its action on nonhematopoietic cells 
Chikungunya virus (CHIKV) is the causative agent of an outbreak that began in La Réunion in 2005 and remains a major public health concern in India, Southeast Asia, and southern Europe. CHIKV is transmitted to humans by mosquitoes and the associated disease is characterized by fever, myalgia, arthralgia, and rash. As viral load in infected patients declines before the appearance of neutralizing antibodies, we studied the role of type I interferon (IFN) in CHIKV pathogenesis. Based on human studies and mouse experimentation, we show that CHIKV does not directly stimulate type I IFN production in immune cells. Instead, infected nonhematopoietic cells sense viral RNA in a Cardif-dependent manner and participate in the control of infection through their production of type I IFNs. Although the Cardif signaling pathway contributes to the immune response, we also find evidence for a MyD88-dependent sensor that is critical for preventing viral dissemination. Moreover, we demonstrate that IFN-α/β receptor (IFNAR) expression is required in the periphery but not on immune cells, as IFNAR−/−→WT bone marrow chimeras are capable of clearing the infection, whereas WT→IFNAR−/− chimeras succumb. This study defines an essential role for type I IFN, produced via cooperation between multiple host sensors and acting directly on nonhematopoietic cells, in the control of CHIKV.
doi:10.1084/jem.20090851
PMCID: PMC2822618  PMID: 20123960
6.  Multidisciplinary Prospective Study of Mother-to-Child Chikungunya Virus Infections on the Island of La Réunion 
PLoS Medicine  2008;5(3):e60.
Background
An outbreak of chikungunya virus affected over one-third of the population of La Réunion Island between March 2005 and December 2006. In June 2005, we identified the first case of mother-to-child chikungunya virus transmission at the Groupe Hospitalier Sud-Réunion level-3 maternity department. The goal of this prospective study was to characterize the epidemiological, clinical, biological, and radiological features and outcomes of all the cases of vertically transmitted chikungunya infections recorded at our institution during this outbreak.
Methods and Findings
Over 22 mo, 7,504 women delivered 7,629 viable neonates; 678 (9.0%) of these parturient women were infected (positive RT-PCR or IgM serology) during antepartum, and 61 (0.8%) in pre- or intrapartum. With the exception of three early fetal deaths, vertical transmission was exclusively observed in near-term deliveries (median duration of gestation: 38 wk, range 35–40 wk) in the context of intrapartum viremia (19 cases of vertical transmission out of 39 women with intrapartum viremia, prevalence rate 0.25%, vertical transmission rate 48.7%). Cesarean section had no protective effect on transmission. All infected neonates were asymptomatic at birth, and median onset of neonatal disease was 4 d (range 3–7 d). Pain, prostration, and fever were present in 100% of cases and thrombocytopenia in 89%. Severe illness was observed in ten cases (52.6%) and mainly consisted of encephalopathy (n = 9; 90%). These nine children had pathologic MRI findings (brain swelling, n = 9; cerebral hemorrhages, n = 2), and four evolved towards persistent disabilities.
Conclusions
Mother-to-child chikungunya virus transmission is frequent in the context of intrapartum maternal viremia, and often leads to severe neonatal infection. Chikungunya represents a substantial risk for neonates born to viremic parturients that should be taken into account by clinicians and public health authorities in the event of a chikungunya outbreak.
In a prospective study on the island of La Réunion, Marc Lecuit and colleagues find frequent transmission of Chikungunya virus by viremic mothers giving birth during an outbreak, resulting in serious infant illness.
Editors' Summary
Background.
Chikungunya virus, an emerging infectious agent that is transmitted by day-biting mosquitoes, was first isolated from a patient in Tanzania in the early 1950s. Since then, major outbreaks of chikungunya fever have occurred throughout sub-Saharan Africa and in Southeast Asia, India, and the Western Pacific, usually at intervals of about 7–8 years. The virus causes fever, rash, severe joint and muscle pains, and sometimes arthritis (joint inflammation). These symptoms develop within 3–7 days of being bitten by an infected mosquito. Most people recover fully within a few weeks, but joint pain can sometimes continue for years. There is no treatment for chikungunya fever, but the symptoms can be eased with anti-inflammatory drugs. Preventative measures include covering arms and legs and using insecticides to avoid insect bites and depriving the mosquitoes of their breeding sites by draining standing water from man-made containers near human dwellings.
Why Was This Study Done?
In 2005, chikungunya fever appeared for the first time on several islands in the Indian Ocean. On La Réunion Island, the disease affected 300,000 people—more than one-third of the population—between March 2005 and December 2006. In June 2005, clinicians identified the first case of mother-to-child chikungunya virus transmission (vertical transmission). Public-health officials and clinicians need to know more about how often vertical transmission occurs and its clinical implications to help them prepare for future chikungunya fever outbreaks. In this study, the researchers identify and characterize all the cases of vertical chikungunya virus transmission that occurred at the largest hospital on La Réunion Island during the 2005–6 outbreak.
What Did the Researchers Do and Find?
The researchers enrolled all 7,504 women who gave birth at the hospital during the outbreak and their 7,629 children into their study. They then used “RT-PCR” (which detects the genome of virus particles during an active infection) and “IgM serology” (which looks for an immune response to recent infection) to determine which women had been infected with chikungunya virus during their pregnancy. 678 of the new mothers had been infected sometime between conception and a week before delivery, 22 mothers had been infected between 7 and 3 days before delivery, and 39 had been infected 2 days either side of delivery (the “intrapartum” period). Except for three early fetal deaths that were associated with chikungunya virus infections, vertical transmission was seen only in babies born to mothers infected with the virus intrapartum. 19 of the babies born to these women were infected with the virus—a vertical transmission rate of nearly 50%. The women who transmitted the virus to their offspring had more virus in their placenta than those who did not transmit the infection. Delivery by emergency cesarean section did not prevent transmission. All the infected babies were born healthy but developed fever, weakness, and pain within 3–7 days. In many of them, the number of platelets (clot-forming particles) in their blood also dropped dramatically. Ten babies became seriously ill—nine of them developed brain swelling; two had bleeding into their brain. Four children had lasting disabilities at the end of the study.
What Do These Findings Mean?
These findings show that mother-to-child transmission of chikungunya virus occurs frequently when women are infected with the virus at the time of delivery and that newborn children infected by this route can become very ill. Although these results do not find that cesarean section reduces infection rates, 90% of cesarean sections involving infected infants were performed urgently, rather than planned. The study also provides no information about whether delaying delivery, provided that no fetal distress is observed, until the mother's viral load has decreased might be beneficial. More studies are needed to provide a complete description of both the short-term and long-term effects of chikungunya virus infection in newborn babies, but it is clear that clinicians should monitor babies exposed to chikungunya virus during delivery for a week after their birth. Most importantly, clinicians and public-health officials will need to take account of the threat that the chikungunya virus poses to newborn children whenever and wherever it emerges.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050060.
Read the related PLoS Medicine 10.1371/journal.pmed.0050068
The World Health Organization provides information about chikungunya fever and a brief description of the recent chikungunya outbreak in the Indian Ocean (in English, French, Spanish, Arabic, Chinese, and Russian)
The US Centers for Disease Control and Prevention has a fact sheet on chikungunya fever
The UK Health Protection Agency also provides information about chikungunya virus, including news on recent outbreaks
The French Institut de Veille Sanitaire (Institute for Public Health Surveillance) has a Web page on chikungunya (in French)
The Institut Pasteur has a Web page on chikungunya research (in French and English)
doi:10.1371/journal.pmed.0050060
PMCID: PMC2267812  PMID: 18351797
7.  A Mouse Model for Chikungunya: Young Age and Inefficient Type-I Interferon Signaling Are Risk Factors for Severe Disease 
PLoS Pathogens  2008;4(2):e29.
Chikungunya virus (CHIKV) is a re-emerging arbovirus responsible for a massive outbreak currently afflicting the Indian Ocean region and India. Infection from CHIKV typically induces a mild disease in humans, characterized by fever, myalgia, arthralgia, and rash. Cases of severe CHIKV infection involving the central nervous system (CNS) have recently been described in neonates as well as in adults with underlying conditions. The pathophysiology of CHIKV infection and the basis for disease severity are unknown. To address these critical issues, we have developed an animal model of CHIKV infection. We show here that whereas wild type (WT) adult mice are resistant to CHIKV infection, WT mouse neonates are susceptible and neonatal disease severity is age-dependent. Adult mice with a partially (IFN-α/βR+/−) or totally (IFN-α/βR−/−) abrogated type-I IFN pathway develop a mild or severe infection, respectively. In mice with a mild infection, after a burst of viral replication in the liver, CHIKV primarily targets muscle, joint, and skin fibroblasts, a cell and tissue tropism similar to that observed in biopsy samples of CHIKV-infected humans. In case of severe infections, CHIKV also disseminates to other tissues including the CNS, where it specifically targets the choroid plexuses and the leptomeninges. Together, these data indicate that CHIKV-associated symptoms match viral tissue and cell tropisms, and demonstrate that the fibroblast is a predominant target cell of CHIKV. These data also identify the neonatal phase and inefficient type-I IFN signaling as risk factors for severe CHIKV-associated disease. The development of a permissive small animal model will expedite the testing of future vaccines and therapeutic candidates.
Author Summary
Chikungunya virus (CHIKV) is transmitted by mosquito bites. CHIKV has recently re-emerged and is responsible for a massive outbreak in the Indian Ocean region and India. It has also reached Italy, indicating that CHIKV has a great potential to spread globally. Infection from CHIKV typically induces a mild disease in humans, characterized by a flu-like syndrome associated with muscle and joint pain and rash. Cases of severe infection involving the central nervous system (CNS) have recently been described, notably in neonates. We have developed the first animal model for CHIKV infection and studied the pathophysiology of the resulting disease. We show here that mouse neonates are susceptible to CHIKV and neonatal disease severity is age-dependent. Adult mice with a partial or complete defect in type-I interferon pathway develop a mild or severe infection, respectively. In mice with a mild infection, CHIKV primarily targets muscle, joint and skin fibroblasts, a cell and tissue tropism similar to that observed in biopsy samples of CHIKV-infected humans. In case of severe infections, CHIKV also disseminates to the CNS. Our work indicates that CHIKV-associated symptoms perfectly match viral tissue and cell tropisms, and demonstrate that the fibroblast is a prominent target cell of CHIKV. It also identifies the neonatal phase and inefficient type-I interferon signaling as risk factors for severe CHIKV-associated disease. The development of a permissive small animal model will expedite the testing of future vaccines and therapeutic candidates.
doi:10.1371/journal.ppat.0040029
PMCID: PMC2242832  PMID: 18282093
8.  Poliovirus-Induced Apoptosis Is Reduced in Cells Expressing a Mutant CD155 Selected during Persistent Poliovirus Infection in Neuroblastoma Cells 
Journal of Virology  2003;77(1):790-798.
Poliovirus (PV) can establish persistent infections in human neuroblastoma IMR-32 cells. We previously showed that during persistent infection, specific mutations were selected in the first extracellular domain of the PV receptor (CD155) of these cells (N. Pavio, T. Couderc, S. Girard, J. Y. Sgro, B. Blondel, and F. Colbère-Garapin, Virology 274:331-342, 2000). These mutations included the Ala 67 → Thr substitution, corresponding to a previously described allelic form of the PV receptor. The mutated CD155Thr67 and the nonmutated IMR-32 CD155 (CD155IMR) were expressed independently in murine LM cells lacking the CD155 gene. Following infection of the cells with PV, we analyzed the death of cells expressing these two forms of CD155. Levels of DNA fragmentation, caspase activity, and cytochrome c release were lower in LM-CD155Thr67 cells than in LM-CD155IMR cells. Thus, the level of apoptosis was lower in cells expressing mutated CD155 selected during persistent PV infection in IMR-32 than in cells expressing the wild-type receptor.
doi:10.1128/JVI.77.1.790-798.2003
PMCID: PMC140570  PMID: 12477887
9.  Poliovirus Induces Apoptosis in the Mouse Central Nervous System 
Journal of Virology  1999;73(7):6066-6072.
Poliovirus (PV) is the etiological agent of human paralytic poliomyelitis. Paralysis results from the destruction of motoneurons, a consequence of PV replication. However, the PV-induced process leading to the death of motoneurons is not well known. We investigated whether PV-induced central nervous system (CNS) injury is associated with apoptosis by using mice as animal models. Transgenic mice expressing the human PV receptor were infected intracerebrally with either the neurovirulent PV-1 Mahoney strain or a paralytogenic dose of the attenuated PV-1 Sabin strain. Nontransgenic mice were infected with a mouse-adapted PV-1 Mahoney mutant. DNA fragmentation was demonstrated in CNS tissue from paralyzed mice by visualization of DNA oligonucleosomal laddering and by enzyme-linked immunosorbent assay. Viral antigens and DNA fragmentation detected by the in situ terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end-labeling technique were colocalized in neurons of spinal cords from paralyzed mice. In addition, morphological changes characteristic of cells undergoing apoptosis were observed in motoneurons by electron microscopy. Thus, we show that PV multiplication and CNS injury during paralytic poliomyelitis are associated with apoptosis.
PMCID: PMC112668  PMID: 10364359

Results 1-9 (9)