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(Re-) Emerging Neurotropic Viruses of Clinical Significance

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(Re-) Emerging Neurotropic Viruses of Clinical Significance (Re-) emerging neurotropic viruses of clinical significance Prof. Anna Papa, MD, PhD ESCMIDAristotle University eLibraryof Thessaloniki, Greece © by author What is the meaning of “emerging” virus? A virus that: 1. is newly discovered 2. infected new hosts 3. altered its pathogenic characteristics 4. spread into new geographic areas or reappeared in an area 5. increased recently its incidence or there is a threat to increase in the near future 6. All the above ESCMID eLibrary 5831 © by author (Re-) Emerging viral diseases (Re-) Emerging viral diseases are diseases caused by viruses that have: • been newly discovered (previously unrecognized) • infected new hosts • altered characteristics of their pathogenesis • spread into new geographic areas (like Zika virus in the Americas). • reappeared in an area • increased their incidence recently or are threatening to increase in the near future. ESCMID eLibrary © by author Factors contributing to emergence of viral diseases • Virus genetic variations • Environmental factors changing weather patterns (e.g., El Niño) damming of rivers, tropical deforestation (alter the abundance and distribution of virus vectors or hosts, exposure to new vectors) • Demographic factors Increase in the human population urbanization in developing countries intensification of agriculture speed and volume of global transportation Also: Increased capability to identify novel pathogens (improved diagnostic techniques ESCMIDand enhanced surveillance eLibrarysystems) © by author Which viruses are mainly affected by environmental factors? 1. Arboviruses 2. Enteroviruses 3. Respiratory viruses 4. Zoonotic viruses ESCMID eLibrary 5830 © by author Neurotropic viruses A neurotropic virus is a virus that is capable to infect nerve cells causing neurological manifestations. A neurotropic virus is neuroinvasive = capable of entering the nervous system (overcoming both the extraneural and neural barriers), and neurovirulent = capable of causing disease within the nervous system. Factors contributing to disease’s course and outcome Host genetics ESCMIDHost immune system eLibrary Virus tropism Virus capability of© spread by within theauthor CNS Anatomy of the Blood-Brain-Barrier (BBB) ESCMID eLibrary © by author FSM Routes of virus spread into the CNS 1. Axonal retrograde transport along motor and olfactory neurons 2. Haematogenous spread across the BBB 3. Loss of integrity of BBB (changes in endothelial cell permeability, which is regulated by vasoactive cytokines) 4. Direct infection of brain microvascular endothelial cells 5. Transport of infected macrophages or neutrophils across the BBB into the brain parenchyma (“Trojan horse” model) ESCMID eLibrary Cho and Diamond 2012 © by author Immune response to neurotropic viruses Early immune response is critical to limiting the neuropathogenesis of neurotropic viruses. Early control: Innate immune response, including cell-intrinsic antiviral defenses, the type I IFN response and innate cell-mediated responses (involving neutrophils, NK cells and γδ T cells) Late stage control: adaptive immune response, including humoral and cellural immune responses The level of viremia is correlated with the viral dissemination to the CNS ESCMIDInnate and adaptive eLibrary immune responses are delicately balanced and may help or harm the host © by author (Re)-emerging neurotropic viruses of clinical importance Viral Family Virus Flaviviridae West Nile Japanese encephalitis Murray Valley encephalitis Zika Usutu Togaviridae Chikungunya Phenuiviridae Phleboviruses (Toscana) Paramyxoviridae Hendra, Nipah Picornaviridae Enteroviruses 71, D68 Parechovirus type 3 Bornaviridae Borna Disease Virus 1 ESCMIDAstroviridae eLibraryAstrovirus VA1/HMO-C Rhabdoviridae Australian bat lyssavirus © by author Flaviviridae Single-strand positive-sensed RNA viruses Flavivirus genus includes several viruses that are etiological agents of CNS infections. Glycosylation of the envelope protein is one determinant of neuroinvasion, increasing both axonal and trans-epithelial transportation. Innate immune response is important for controlling brain infection (infection of the brain microvascular endothelium occurs after loss of effective ESCMID clearance in peripheral eLibrarysites) © by author Tick-borne encephalitis (TBE) virus I. ricinus I. persulcatus TBE is the most important arboviral disease in Europe and central and eastern Asia, causing approx. 13,000 hospitalizations each year. TBE is an emerging disease due to its rising incidence and the expansion in new areas. Transmission: tick bite Ixodes ricinus and I. persulcatus ticks (in Europe), consumption of unpasteurized dairy products from infected livestock, needle stick Reservoir hosts: rodents, insectivores Incubation period: 7 -14 d after a tick bite, 3–5 d after consumption of infected milk Subtypes: European, Siberian, Far-Eastern Symptoms ESCMID: Diphasic illness, febrile eLibrary - neurological; it can result in long - term neurological symptoms, and even death Fatality: European 0.5 -©2%, Siberian by 1 -3%,author Far Eastern up to 35% Steps during TBEV infection Infection of the brain Virus transmission from an infected tick Crossing of the BBB Replication in Primary viremia regional lymph node Secondary viremia In an in vitro BBB model, TBEV crossed the BBB via a transcellular pathway ESCMID without compromising theeLibrary integrity of the cell monolayer (Palus et al., 2017). © by author Known, unknown and emerging TBE foci 2009: first cases in Bulgaria 2014: first case in Greece 2016, first case in the Netherlands ESCMIDHaditsch & Kunze , 2013eLibrary © by author VBZ 2010 The only North American member of the tick-borne encephalitis serogroup of flaviviruses. Vector: Ixodes spp. Rare but severe neuroinvasive disease with 50% of survivors displaying long-term neurological sequelae Fatality: 10% ESCMID eLibrary © by author West Nile virus WNV is an important emerging neurotropic virus, responsible for encephalitis outbreaks worldwide Originally isolated in in the West Nile province of Uganda in 1937 Vectors: Culex mosquitos (mainly C. pipiens) Host reservoir: resident birds 7 genetic lineages; lineages 1 and 2 are responsible for the major epidemics in humans. Incubation period: 3–14 d. Viremia occurs within 1–3 d and can last up to 11 d. Groups at risk: elderly, immunocompromised, patients with diabetes, hypertension, and chronic kidney disease. Symptoms: most asymptomatic - approx. 20% flu-like illness, maculopapular rash - <1% neuroinvasive disease: encephalitis (mental status change, Parkinsonian movement disorders), meningitis or acute flaccid ESCMID paralysis, Guillain–Barré-like eLibrary syndrome (probably as result of damage to the anterior horn cells). Neurological disability in over half of patients at 1 -year follow -©up. by author Schematic of WNV pathogenesis in humans WNV replicates in keratinocytes, skin-resident dermal dendritic cells (DCs) and Langerhans cells Infected DCs migrate to the regional lymph node leading to viraemia Subsequent infection of peripheral organs (e.g. spleen, kidney and liver). By day 4, viral replication peaks in the spleen and serum. Between days 6 and 8, WNV is detected within the brain and spinal cord (via multiple routes of entrance) ESCMIDWNV infectseLibrary and injures neurons within the brain stem, hippocampus, cortex, cerebellum and spinal cord Suthar et al. Nat Rev © 2013 by author Epidemiological update: West Nile virus transmission season in Europe, 2017 In the European Union, 204 human WNF cases have been reported: Romania (66 cases), Italy (57), Greece (48), Hungary (21), Austria (5), Croatia (5), France (1) and Bulgaria (1). In the neighbouring countries, 84 cases were reported: Serbia (49), Israel (28) and Turkey (7). Many countries reported cases in newly affected areas (areas where noESCMIDcases were ever reported before eLibrary) © by author West Nile virus in USA, 1999-2016 21,574 neuroinvasive disease cases The largest epidemics of arboviral meningoencephalitis in US history, the largest epidemics of WNV neuroinvasive disease reported to date Average annual incidence of WNV neuroinvasive WNV neuroinvasive disease incidence disease reported to CDC by state, 1999-2016 reported to CDC by year, 1999-2016 ESCMID eLibrary © by author Usutu virus African mosquito-borne virus closely related to WNV. Vector: Culex spp. mosquitoes (C. pipiens) Mass mortality in blackbirds Resevoir hosts: wild birds (Austria 2001) 2009: USUV detected in human encephalitis cases Italy, retrospective study published in 2017: USUV was the cause of previously unexplained encephalitis suggesting that neurological cases associated to USUV may be more common than previously thought. Deleterious effect of Usutu virus on human neural cells (Salinas et al. PNTD 2017). USUV efficiently infects neurons, astrocytes, microglia and human neuronal stem cells. When compared to ZIKV, USUV led to a higher infection rate, viral production, and stronger cell death and antiviral response. Threat of USUV emergence? While ESCMIDhuman cases are infrequent, eLibrarythe potential for neuroinvasive infection suggests a need for clinical awareness and diagnostic capability © by author Japanese encephalitis virus The most important cause of viral encephalitis worldwide. Annual encephalitis cases nearly 70,000 (half in China) - 10,000 deaths. First identified in Japan in the 19th century. Currently in China, Southeast Asia, India, New Guinea, and Australia. Continues to expand its geographic range. Vector: Culex mosquitoes (mainly C. tritaeniorhynchus)
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