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(Re-) Emerging Neurotropic Viruses of Clinical Significance

(Re-) Emerging Neurotropic Viruses of Clinical Significance

(Re-) emerging neurotropic of clinical significance

Prof. Anna Papa, MD, PhD ESCMIDAristotle University eLibraryof Thessaloniki, Greece © by author What is the meaning of “emerging” ?

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 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 (improved diagnostic techniques ESCMIDand enhanced surveillance eLibrarysystems) © by author Which viruses are mainly affected by environmental factors?

1. 2. 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 (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 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 West Nile Japanese Murray Valley encephalitis Zika Usutu Togaviridae Phleboviruses (Toscana) Hendra, Nipah Picornaviridae Enteroviruses 71, D68 type 3

Bornaviridae Virus 1 ESCMIDAstroviridae eLibraryAstrovirus VA1/HMO-C Australian bat © 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 -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 (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 .

Vector: Ixodes spp. Rare but severe neuroinvasive disease with 50% of survivors displaying long-term neurological sequelae Fatality: 10% ESCMID eLibrary © by author

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 (mainly C. pipiens) Host reservoir: resident 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, 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

African -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 virus

The most important cause of 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) Host reservoirs: pigs, egrets, and herons. Groups at risk: children Fatality: 20–25% with 50% rate of severe disability amongst survivors.

The emergence of JEV can be attributed to increased population growth in endemicESCMID areas eLibrary © by author Zika virus

ZIKV is the first associated with congenital defects including microcephaly and other birth abnormalities First isolated from a sentinel febrile monkey in 1947 in Uganda. Symptoms: fever, rash, conjunctivitis, arthralgia. Fetus: ZIKV specifically attacks neural progenitor cells and causes microcephaly (also brainstem atrophy, cerebellar hypoplasia, and ventriculomegaly). Among pregnant women with ZIKV infection, birth defects are present in 7% of fetuses and infants, particularly if the maternal infection occurs during the 1st trimester. Adults: Guillain-Barré syndrome is most-infectious complication of ZIKV infection in adults. Vector: Aedes mosquitoes (A. aegypti , A. albopictus) Transmission ESCMID: mosquito bite, sexual eLibraryintercourse (of concern due to an association between ZIKV infection and adverse pregnancy and fetal outcomes) . © by author Global spread of ZIKV, 2013-2016

ZIKV expanded its geographic range from Africa and Asia to the Pacific Islands, then ESCMIDfurther to South and Central America eLibrary and the Caribbean. The first large outbreak of disease caused by Zika infection was reported from the Island of Yap (Federated States© ofby Micronesia) author in 2007. Murray Valley encephalitis virus The most serious endemic in Australia

2011: 17 encephalitis cases (3 fatal) in parts of Australia where cases had not occurred for many decades. Risk of MVEV encephalitis for the heavily populated areas of south-eastern Australia. Vector: Culex spp. mosquitoes Link between the MVEV activity and environmental factors (record rainfall, flooding). Disease: asymptomatic or mild febrile illness (occasionally with rash). Aprox. 1:150 to 1:1000 infections: encephalitis Fatality ESCMID: 15–30%, with long-term neurologicaleLibrary sequelae in 30 – 50% of survivors © by author Togaviridae

Enveloped single strand, positive sensed RNA viruses

Genus

New-world (many highly neurovirulent).

• Eastern equine encephalitis virus: eastern US • Venezuelan equine encephalitis virus: Central and S. America

Old-world alphaviruses • Chikungunya virus (CHIKV): sub-Saharan Africa, India, Southeast Asia, Western Pacific, and recent spread to the ESCMIDCaribbean and South America eLibrary © by author New World alphaviruses

EEEV - encephalitic form: infants-abrupt onset of neurological signs older patients a few days after onset of systemic disease.

North American-EEEV: the most deadly encephalitic alphavirus (40%). Patients that survive the infection may suffer from serious sequelae such as mental retardation and paralysis.

VEEV: 2–5 days after a mosquito bite.

Children are more susceptible to severe disease than adults and are more likely to suffer from permanent neurological sequelae.

Although the case fatality rate of VEE is below 1%, its association with outbreaks involving tens of thousands of human cases renders it theESCMID most important encephalitic eLibrary alphavirus. © by author Chikungunya virus

1952: First isolation from patients with fever and arthralgia in Tanzania. Chikungunya = that which bends up

Emerging global health threat with increasing incidence of neurological complications

Vectors: Aedes aegypti, A. albopictus Incubation period: 3–7 d Symptoms: high fever, headache, maculopapular rash and arthralgia.

During the outbreak in 2005–2006 on Reunion Island, neurological signs were reported in 12% of patients. Postinfectious complication: Guillain–Barré syndrome ESCMID eLibrary Astrocytes are commonly the first cells activated in brain © by author Phenuiviridae

Single-strand negative-sensed RNA viruses

Genus Phlebovirus

Vectors: sandflies, mosquitoes, ticks

Sandfly-transmitted phleboviruses Symptoms: from asymptomatic or mild disease to meningitis or encephalitis ESCMIDNeuroinvasive phleboviruseLibrary: Toscana virus © by author Toscana virus Endemic in all Mediterranean countries. The most common cause of summertime viral meningitis in central Italy Recent identification of novel strains Incubation: 3–6 days Symptoms: mild or self-limited febrile illness (fever, headache, myalgia, malaise and abnormalities in liver and hematological values, skin rash). Neurological manifestations: meningitis, paresis, or even meningoencephalitis or encephalitis.

Papa et al. EID 2014 ESCMID eLibrary © by author Paramyxoviridae enveloped single-stranded negative-sensed RNA viruses Genus . Nipah and Hendra viruses

Nipah virus The most frequent henipavirus

1998: first detection in pig farmers in Malaysia Host reservoir: fruit bats Transmission: from human to human via respiratory droplets. 8% of acute encephalitic patients have relapsing encephalitis Fatality: 30%.

Main site of infection: endothelium of blood vessels in the CNS (andESCMID lungs, kidneys) eLibrary © by author Zoonotic transmission cycles of in Malaysia and Bangladesh

Zoonotic transmission Direct transmission via the consumption through an intermediate, of date palm sap contaminated with NiV ESCMIDamplifying host eLibraryby fruit bats and further human -to - human transmission © by author J Pathol 2015

Hendra virus infection is an emerging of horses and humans in Australia.

First identified in meningitis and encephalitis deaths of a few Australian individuals who had been in close contact with horses. Host reservoir: fruit bat. Amplifying hosts: horses able to transmit the virus to humans who work closely with infected animals Incubation: 5–14 days

ESCMIDVirus eLibrary transmission to horses © by author Picornaviridae

small, non-enveloped single-strand positive-sensed RNA viruses

• Genus : and the non- enteroviruses • Genus Parechovirus: human parechovirus

Symptoms: to life-threatening infections, such as encephalitis and myocarditis. ESCMID eLibrary © by author Enteroviruses

CNS infections are most often caused by EVs

EVs classification into species: • EV-A, containing EV71 and several Coxsackie A viruses (CV-A) • EV-B including coxsackie B viruses (CVB) 1–6 and all echoviruses • EV-C with the (PVs) 1–3 and several CVAs • EV-D containing EV-68

Enteroviruses 71, D-68 and C105 can cause polio-like paralysis They are considered a critical emerging public health threat ESCMID eLibrary © by author Enterovirus 71

It continues to expand its geographic range and has caused numerous outbreaks in Southeast Asia and Australia

Typically associated with hand-foot and-mouth disease Up to 30% of patients demonstrate neurologic complications ranging from meningitis, encephalitis to a poliomyelitis syndrome in infants and young children. Symptoms: fever, mouth ulcers, reduced consciousness, and irritability and cough, coryza, and vomiting. Most patients with flaccid paralysis only partially recover, and some of them show persistent weakness.

Transmission is through the fecal-oral route, through contact with contaminated ESCMID secretions and surfaces eLibrary © by author Human parechovirus type 3

First reported in 2004, is exceptional because it can provoke sepsis and meningoencephalitis leading to neurological sequelae, and even death, in neonates and young infants

Incubation: 1-12 days Transmission: fecal-oral route. Respiratory transmission is also possible

J Pediatric Infect Dis Soc. 2017

• PeV3 can cause severe neurologic illness in neonates. • Y oungerESCMID infants are more likely to requireeLibrary intensive care. PeV3 should be considered along with HSV and other pathogens when evaluating young infants with sepsis -©like illness by or meningitis. author

single-stranded negative-sensed RNA viruses

Borna Disease virus

BoDV-1: causes neurological disease mainly in horses and sheep (i.e. chronic progressive meningoencephalitis). Highest incidence in central Europe. Reservoir: shrews (in Germany Crocidura leucodon).

On 7 March 2018, Germany reported 4 human cases (3 organ recipients from the same donor) of acute encephalitis linked to BoDV- 1, speciesESCMIDMammalian 1 Bornavirus eLibrary). This is the first time that BoDV-1 has been confirmed in humans © by author Astroviridae

Etiologic agent of encephalitis, at least in the context of immunosuppression

EID 2010

CID 2015

Astrovirus VA1/HMO-C: highly divergent from the classic human ESCMID; prototype of a distinct eLibraryevolutionary clade of astroviruses © by author Rhabdoviridae

Australian bat lyssavirus

The only virus known to be transmissible to humans directly from bats without an intermediate host

Zoonotic virus closely related to virus

Three cases of ABLV in humans have been confirmed in Queensland, all of them fatal. Reservoir: fruit and insectivorous bats Transmission: bite or scratch of bats ESCMID eLibrary © by author Diagnosis of emerging CNS infections: the syndromic approach

Collection and analysis of all available meta-data

• Demographic data • Clinical signs and symptoms • Days after onset of the symptoms • Place of residence, living conditions, occupation, recreational activities • Underlying diseases/disorders / comorbidities • Recent transfusion/ transplantation • Immune status • Vaccination history • Recent ESCMID travel in endemic areas eLibrary • Vector bite history © by author The facts

Emerging neurotropic viruses are associated with increased morbidity and mortality in humans worldwide, representing a real and evolving threat to human health.

It is expected that more novel pathogens will be identified in the near future (broader application of NGS)

Early recognition of the causative agent of unexplained acute CNS infections will enable specific interventions to prevent outbreaks ESCMIDthat threaten public eLibraryhealth. © by author Actions needed

• Clinicians should be aware of emerging CNS infections and include them to the differential diagnosis

• Microbiologists should have ready lab protocols for prompt and correct diagnosis (EQAs are helpful)

• Awareness of the public (living in or travelers to endemic areas - special attention to pregnant women and ZIKV transmission).

• There is need for effective surveillance and control and for ESCMIDdrugs and vaccine design. eLibrary © by author ESCMID eLibrary © by author

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