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Emerging Viral Infections Phleboviruses Emerging viral infections Phleboviruses © by author Anna Papa National ReferenceESCMID Centre Online for Arboviruses Lecture and Hemorrhagic Library Fever viruses Aristotle University of Thessaloniki, Greece Main vectors of phleboviruses: phlebotomine sandflies © by author Etymologia. Phlebotomus: from the Greek words phleboESCMID + tomi=opening Online a vein Lecture Library TAXONOMY Phleboviruses: arthropod-borne RNA viruses Genus Phlebovirus - Family Bunyaviridae Cause to humans symptoms ranging from short self limiting fever to encephalitis and fatal hemorrhagic fever. 70 antigenically distinct serotypes: • Sandfly Fever group – 55 serotypes (most transmitted by sandflies, few by mosquitoes, e.g. Rift Valley fever) •Uukuniemi group – 13 serotypes (transmitted by ticks). • Severe fever and thrombocytopenia syndrome (SFTS) virus (transmitted by ticks). © by author 9 antigenic complexes including 37 classified viruses. Species differentiation based on a 4-fold difference in neutralization tests. High rate of genetic reassortment of the M segment: relying only on neutralizationESCMID or hemagglutination Online Lectureinhibition assays Library is not enough. VIRION Enveloped, spherical. Diameter 80-120 nm. Glycoproteins serve as neutralizing and hemagglutinin-inhibiting antibody targets and are exposed to selective pressure. GENOME Segmented negative- stranded RNA genome. Encodes for © by author 6 proteins. S : N protein and a NSs. Uses an ambisense coding strategy ESCMIDM Online : precursor of Lecturethe viral glycoproteins Library Gn and Gc , and NSm. L : viral RNA polymerase. Phlebotomine sandflies (Psychodidae) • > 500 different species • Widely distributed in Med countries from May to September. The number increases after rainy season. • Abundant in peri-urban and rural environments, close to domestic animals and human populations. • A cool, shaded, slightly damp The sandfly becomes infected environment is ideal for the sandfly life. when biting an infected human in © by author the period between 48 h before • Active during night - silent flight - short the onset of fever and 24 h after flight range. the end of the fever, and remains infected for its lifetime ESCMID Online• Only Lecture females bite! Library Phleboviruses are of great military importance since large number of invading non-immune persons may be incapacitated at the time when they are mostly needed. © by author Sabin et al. Phlebotomus (Papatassi or sandfly) fever, a disease of military importance. Summary of existingESCMID knowledge and Online preliminary reportLecture of original investigations.Library JAMA 1944 Sandfly fever viruses: Historical perspectives 1908: Austrian military commission (Doerr et al) working on the Dalmatian coast investigated the etiology and transmission of sandfly fever. Vector: P. papatasi . Before World War I: British investigators in Malta. During World War II: 8,500 cases among US soldiers in the Sicily campaign (summer 1943), Naples outbreak (summer 1944). 1943-44: Isolation of Sicilian and Naples strains from patients in Palermo, Sicily and Naples (Sabin). August 1944: First use of DDT for the control of malaria vectors, decrease of SF cases. 1948: the largest outbreak occured© by in Serbiaauthor (>1 million cases). 1971: Isolation of TOSV from P. perniciosus in Tuscany, Italy. 1983: Association of TOSV with neurologic disease. ESCMID Online Lecture Library Although sandflies are widely distributed, most sandfly fever cases occur around the Meditteranean Basin. Meditteranean Sea © by author The incidence of SF in the Americas is relatively low. The sandflies there are sylvan and do not enter houses to bite people. ESCMID Online Lecture Library The exact epidemiology of each species is not well understood because: -asymptomatic or mild febrile cases are significantly more prevalent than previously suspected - the identity of the virus cannot be assessed with certainty (cross-reactions). Three human pathogenic phleboviruses are distributed in the Mediterranean countries : Toscana virus (TOSV) - Sandfly fever Naples virus (SFNV) - Sandfly fever Sicilian virus (SFSV). © by author SFSV and SFNV cause a transient febrile illness. TOSV is neurovirulent, leading to aseptic meningitis and meningoencephalitis. ESCMID Online Lecture Library Sandfly fever Phlebotomus fever, papataci fever, 3-day fever A few days (2-5) after the infective bite, a feeling of lassitude, abdominal distress and chills develop followed by high fever, severe frontal headaches, muscle and joint pain, flushing of the face, conjunctiva injection, and tachycardia. After 2 days the fever begins to subside and the temperature returns to normal. Fatigue, depression, bradycardia and subnormal blood pressure may persist from few days to several weeks. Recovery is usually complete. © by author Similar symptoms to dengue fever, but without rash. ESCMID Online Lecture Library Toscana virus infections - Asymptomatic - Influenza-like syndrome - Meningitis or meningoencephalitis in summer May to October, with peak in August. Central Italy: 80% of acute CNS viral infections in children and 50% of cases in adults during summer. Central Anatolia, Turkey: 15.7% of aseptic meningitis. Portugal: 5.6% of meningitis cases. Seroprevalence varies among countries and among regions of a country. Italy: 3% in northern Italy (Torino), to© 16% by in Umbriaauthor and 22% in central Italy. Spain: 5% to 26%. France (south-eastern ):12% in blood from donors. Turkey: 17.8% Cyprus: 20%,ESCMID Greece 50% in OnlineIonian islands Lecture Library TOSV genotypes S segment Italian – Spanish group 13.2% at nt level Spanish group French strains © by author Italian group * TOSV detectedESCMID in central Anatolia,Online Turkey, Lecture clusters in the Library Italian group Laboratory diagnosis of phleboviral infections Virus isolation RT-PCR (only in the first 1-2 days after symptom onset and before the IgM detection). Serology (cross reactions exist within the antigenic complex). Neutralization assays on early convalescent sera are the reference method to identify the viruses or to assess the antibody response specificity. © by author * The patient has lifelong immunity to the infecting phlebovirus but not to heterologous serotypes. ESCMID Online Lecture Library Prevention Prevention of sandfly bites (insect repellents) Control of sandflies and their breeding grounds with insecticides © by author Ordinary mosquito nets and screening are not sufficient to prevent sandfly bites: unfed female flies can pass through. ESCMID Online Lecture Library SF outbreak in Cyprus, 2002 Time: May to September 2002 Place: Cyprus, Athalassa National Forest Park, 5km SE of Nicosia Patients: 256/581 (44%) soldiers of the Greek Army forces, 17-22 y. Signs and Symptoms: high fever (39-41oC), headache, rigors, arthralgia, myalgia, lower back pain. Duration of symptoms: 60-72 h. Post infectious asthenia sydrome (2 weeks) Laboratory findings: leucopenia, monocytosis, 2X elevated transaminases (mainly ALAT) © by author Laboratory diagnosis: Genetic detection of a SFSV-like strain (Cyprus virus) Isolation in Vero E6 cells ESCMIDSerological Online cross-reactivity Lecture for phleboviruses Library Cyprus virus isolated from patient’s blood on the 1st day of illness 0 24h 48h © by author δ=100 nm ESCMID Online Lecture Library Phylogenetic tree including Cyprus virus (partial L segment) Cyprus – Sicilian: 6.7% at nt level © by author1.5% at aa level ESCMID Online Lecture Library Turkey Summer of 2007 and 2008 Turkey in Kozan and Izmir in Med Turkey, and Ankara in central Turkey. © by author A SFSV-like strain was isolated (SFTV) highly homologous to Cyprus virus. ESCMID Online Lecture Library France Massilia virus MASV has been isolated from P. (L.) perniciosus in 2005 in two localities in SE France. It is most closely related to viruses in the SFNV complex. So far there are no reports of human disease from this virus. © by author ESCMID Online Lecture Library Algeria July 2006. 460 sandflies. 1/24 pools phlebo-positive. P. ariasi. Closer to Cyprus virus. July 2007. 785 sandflies. 3/40 pools phlebo-positive. © by authorTwo sequences from P. longicuspis closer to Poona virus of SFNV. One from P. papatasi in Kabylia closer to Cyprus virus rather than the Algerian strain from P. ariasi ESCMID Online Lecturediscovered Library in 2006. Tunesia SFN-like virus SFS-like virus Sandfliy collection from two sites, Utique and Felta, corresponding to different bioclimatic zones © by author 1489 sandflies (75 pools) 10/75 pools contained phlebovirus RNA Overall ESCMIDprevalence of phlebovirus Online infection Lecture 0.67% Library (10/1489). Punique virus: member of the SFNV complex, most closely related to MASV. Genetic distance of Punique virus and all other members of the SFNV complex: 25–29 %. Sandflies of the subgenus Larroussius (P. perniciosus, P. perfiliewi and P. longicuspis) Mostly in sandflies from the subgenus Larroussius (P. perniciosus, P. longicuspis and © by author P. major) Mostly in P. papatasi (subgenus Phlebotomus) ESCMID Online Lecture Library Granada virus (GRV), was isolated from female sandflies collected in June 2004 in Alfacar, Granada, SE Spain. GRV infects humans (detection of neutralizing antibodies). Not known whether it can be implicated in human disease. Likely to be a natural reassortant of MASV(donor of the L and S segments) with a yet unidentified phlebovirus (donor of the M segment). © by author ESCMID Online Lecture Library New phleboviruses in the Americas Aguacate virus: 10th serogroup or species in
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