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      Inflammatory Cytokine Expression Is Associated with Chikungunya Virus Resolution and Symptom Severity


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          The Chikungunya virus infection zones have now quickly spread from Africa to parts of Asia, North America and Europe. Originally thought to trigger a disease of only mild symptoms, recently Chikungunya virus caused large-scale fatalities and widespread economic loss that was linked to recent virus genetic mutation and evolution. Due to the paucity of information on Chikungunya immunological progression, we investigated the serum levels of 13 cytokines/chemokines during the acute phase of Chikungunya disease and 6- and 12-month post-infection follow-up from patients of the Italian outbreak. We found that CXCL9/MIG, CCL2/MCP-1, IL-6 and CXCL10/IP-10 were significantly raised in the acute phase compared to follow-up samples. Furthermore, IL-1β, TNF-α, Il-12, IL-10, IFN-γ and IL-5 had low initial acute phase levels that significantly increased at later time points. Analysis of symptom severity showed association with CXCL9/MIG, CXCL10/IP-10 and IgG levels. These data give insight into Chikungunya disease establishment and subsequent convalescence, which is imperative to the treatment and containment of this quickly evolving and frequently re-emerging disease.

          Author Summary

          Chikungunya virus (CHIKV) is transmitted by mosquitoes and causes a human disease clinically characterized by sudden appearance of high fever, rash, headache, nausea, and severe joint pain (the defining symptom). Chikungunya was identified in Africa and the word Chikungunya means that which bends up, describing the bent posture of CHIKV patients while in severe pain. CHIKV, a current problem in Africa, Indian Ocean region, and Southeast Asia, is now spreading to temperate regions of North America, France and Italy. Presently, the immune response for CHIKV infection remains largely uninvestigated and no treatment is available. We investigated cytokine profiles at diagnosis and follow-up of CHIKV infected patients during the Italian 2007 outbreak and associated cytokine levels with antibody level and symptom severity. Cytokines, important immune mediators, are often drug targets. Since CHIKV symptoms can persist for months or years following infection it is important to investigate possible drug targets to alleviate discomfort. We found cytokine profiles that describe the initial infection and recovery phase. We determined the cytokines CXCL9/MIG and CXCL10/IP-10 as well as antibody levels were associated with symptom severity. These results reflect previously unreported cytokine profiles which may be important for the development of future therapeutics for CHIKV outbreaks.

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          Two Chikungunya Isolates from the Outbreak of La Reunion (Indian Ocean) Exhibit Different Patterns of Infection in the Mosquito, Aedes albopictus

          Background A Chikungunya (CHIK) outbreak hit La Réunion Island in 2005–2006. The implicated vector was Aedes albopictus. Here, we present the first study on the susceptibility of Ae. albopictus populations to sympatric CHIKV isolates from La Réunion Island and compare it to other virus/vector combinations. Methodology and Findings We orally infected 8 Ae. albopictus collections from La Réunion and 3 from Mayotte collected in March 2006 with two Chikungunya virus (CHIKV) from La Réunion: (i) strain 05.115 collected in June 2005 with an Alanine at the position 226 of the glycoprotein E1 and (ii) strain 06.21 collected in November 2005 with a substitution A226V. Two other CHIKV isolates and four additional mosquito strains/species were also tested. The viral titer of the infectious blood-meal was 107 plaque forming units (pfu)/mL. Dissemination rates were assessed by immunofluorescent staining on head squashes of surviving females 14 days after infection. Rates were at least two times higher with CHIKV 06.21 compared to CHIKV 05.115. In addition, 10 individuals were analyzed every day by quantitative RT-PCR. Viral RNA was quantified on (i) whole females and (ii) midguts and salivary glands of infected females. When comparing profiles, CHIKV 06.21 produced nearly 2 log more viral RNA copies than CHIKV 05.115. Furthermore, females infected with CHIKV 05.115 could be divided in two categories: weakly susceptible or strongly susceptible, comparable to those infected by CHIKV 06.21. Histological analysis detected the presence of CHIKV in salivary glands two days after infection. In addition, Ae. albopictus from La Réunion was as efficient vector as Ae. aegypti and Ae. albopictus from Vietnam when infected with the CHIKV 06.21. Conclusions Our findings support the hypothesis that the CHIK outbreak in La Réunion Island was due to a highly competent vector Ae. albopictus which allowed an efficient replication and dissemination of CHIKV 06.21.
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            Type 1/Type 2 immunity in infectious diseases.

            T helper type 1 (Th1) lymphocytes secrete secrete interleukin (IL)-2, interferon-gamma, and lymphotoxin-alpha and stimulate type 1 immunity, which is characterized by intense phagocytic activity. Conversely, Th2 cells secrete IL-4, IL-5, IL-9, IL-10, and IL-13 and stimulate type 2 immunity, which is characterized by high antibody titers. Type 1 and type 2 immunity are not strictly synonymous with cell-mediated and humoral immunity, because Th1 cells also stimulate moderate levels of antibody production, whereas Th2 cells actively suppress phagocytosis. For most infections, save those caused by large eukaryotic pathogens, type 1 immunity is protective, whereas type 2 responses assist with the resolution of cell-mediated inflammation. Severe systemic stress, immunosuppression, or overwhelming microbial inoculation causes the immune system to mount a type 2 response to an infection normally controlled by type 1 immunity. In such cases, administration of antimicrobial chemotherapy and exogenous cytokines restores systemic balance, which allows successful immune responses to clear the infection.
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              Outbreak of chikungunya on Reunion Island: early clinical and laboratory features in 157 adult patients.

              Chikungunya is a reemerging disease. In 2005-2006, a severe outbreak occurred on Reunion Island in the southwestern part of the Indian Ocean. Other islands in this area were affected during the same period. Adult patients with acute chikungunya (defined as onset of fever and/or polyarthralgia in the 5 days preceding consultation) and laboratory-confirmed chikungunya who were referred to Groupe Hospitalier Sud Reunion during the period from March 2005 through April 2006 were included in this retrospective study. Their clinical and laboratory features are reported. Laboratory-confirmed acute chikungunya was documented in 157 patients. The mean age of patients was 57.9 years, and the ratio of male to female patients was 1.24 : 1. Sixty percent of patients had at least 1 comorbidity. Ninety-seven patients (61.8%) were hospitalized, and 60 (38.2%) were treated as outpatients. Five fatalities were reported. One hundred fifty-one patients (96.1%) experienced polyarthralgia, and 129 (89%) experienced fever. Gastrointestinal symptoms were reported by 74 patients (47.1%), and skin rash was reported by 63 (40.1%). Hemorrhagic signs were rare. Lymphopenia and hypocalcemia were the prominent laboratory findings. Severe thrombocytopenia was rarely observed. Chikungunya virus can be responsible for explosive outbreaks of disease. Polyarthralgia and fever are the 2 main clinical features. In this era of travel and globalization, chikungunya should be considered in the differential diagnosis of febrile polyarthralgia with an abrupt onset.

                Author and article information

                Role: Editor
                PLoS Negl Trop Dis
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, USA )
                August 2011
                16 August 2011
                : 5
                : 8
                : e1279
                [1 ]Sardinia Research and Development (SaRD), University di Sassari, Sassari, Italy
                [2 ]Immune Diagnostics and Research (IDR), Toronto Medical Discovery Tower (TDMT), Toronto, Ontario, Canada
                [3 ]Experimental Therapeutics, University Health Network (UHN), Toronto, Ontario, Canada
                [4 ]Dipartimento di Sanità Pubblica, Azienda Usl di Ravenna, Ferrara, Italy
                [5 ]Agenzia Sanitaria e Sociale Regione Emilia-Romagna, Bologna, Italy
                [6 ]Department of Hematology and Oncology, Alma Mater Studiorum - University of Bologna, Bologna, Italy
                [7 ]National Centre of Influenza, Hospital Clínico Universitario de Valladolid, Valladolid, Spain
                [8 ]Unidad de Investigación en Infección e Inmunidad - Microbiology Service, Hospital Clínico Universitario de Valladolid - Instituto de Estudios de Ciencias de la Salud de Castilla y León (IECSCYL), Valladolid, Spain
                [9 ]Faculty of Medicine, Institute of Medical Science (IMS), University of Toronto, Toronto, Ontario, Canada
                [10 ]Dipartimento di Scienze Biomediche, University di Sassari, Sassari, Italy
                [11 ]PhD School in Biomolecular and Biotechnology Sciences, University of Sassari, Sassari, Italy
                Centers for Disease Control and Prevention, United States of America
                Author notes

                Conceived and designed the experiments: AAK DB DJK VS SR. Performed the experiments: DB SGP LX AD AF IB. Analyzed the data: AAK MJC JFB-M. Contributed reagents/materials/analysis tools: GS MLM NS PG FC AP GR DJK VS SR. Wrote the paper: AAK.

                Kelvin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                : 18 October 2010
                : 5 July 2011
                Page count
                Pages: 12
                Research Article
                Molecular Cell Biology
                Clinical Immunology
                Diagnostic Medicine
                Drugs and Devices
                Global Health
                Infectious Diseases
                Public Health

                Infectious disease & Microbiology
                Infectious disease & Microbiology


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