(Re-) emerging neurotropic viruses
of clinical significance
Prof. Anna Papa, MD, PhD
Aristotle University of Thessaloniki, Greece ESCMID eLibrary
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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
What is the meaning of “emerging” virus?
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(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.
(Re-) Emerging viral diseases
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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
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Which viruses are mainly affected by environmental
factors?
1. Arboviruses
2. Enteroviruses
3. Respiratory viruses
4. Zoonotic viruses
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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
Host immune system
Virus tropism
Virus capability of spread within the CNS
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FSM
Anatomy of the Blood-Brain-Barrier (BBB)
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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)
Cho and Diamond 2012
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Early immune response is critical to limiting the neuropathogenesis of
neurotropic viruses.
Innate and adaptive immune responses
are delicately balanced and may help or harm the host
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
Immune response to neurotropic viruses
The level of viremia is correlated with the viral dissemination to the CNS
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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
Astroviridae Astrovirus VA1/HMO-C
Rhabdoviridae Australian bat lyssavirus
(Re)-emerging neurotropic viruses of clinical importance
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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 clearance in peripheral sites)
Flaviviridae
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Tick-borne encephalitis (TBE) virus
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: Diphasic illness, febrile - neurological; it can result in long-
term neurological symptoms, and even death
Fatality: European 0.5-2%, Siberian 1-3%, Far Eastern up to 35%
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.
I. ricinus
I. persulcatus
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Steps during TBEV infection
Virus transmission
from an infected tick
Replication in
regional lymph nodePrimary viremia
Secondary viremia
Crossing of the BBB
Infection of the brain
In an in vitro BBB model, TBEV crossed the BBB via a transcellularpathway without compromising the integrity of the cell monolayer (Palus et al., 2017).
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2009: first cases in Bulgaria
2014: first case in Greece
2016, first case in the Netherlands
Haditsch & Kunze, 2013
Known, unknown and emerging TBE foci
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Vector: Ixodes spp.
Rare but severe neuroinvasive disease with 50% of survivors displaying
long-term neurological sequelae
Fatality: 10%
The only North American member of the tick-borne encephalitis serogroup
of flaviviruses.
VBZ 2010
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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 paralysis, Guillain–Barré-like syndrome (probably as result of
damage to the anterior horn cells). Neurological disability in over half of
patients at 1-year follow-up.
West Nile virus
WNV is an important emerging neurotropic virus,
responsible for encephalitis outbreaks worldwide
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Schematic of WNV pathogenesis in humans
Suthar et al. Nat Rev 2013
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)
WNV infects and injures neurons within the brain stem, hippocampus, cortex, cerebellum and spinal cord
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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 whereno cases were ever reported before)
Epidemiological update: West Nile virus transmission season in Europe, 2017
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21,574 neuroinvasive disease cases
The largest epidemics of arboviral meningoencephalitis in US history,
the largest epidemics of WNV neuroinvasive disease reported to date
West Nile virus in USA, 1999-2016
Average annual incidence of WNV neuroinvasivedisease reported to CDC by state, 1999-2016
WNV neuroinvasive disease incidence reported to CDC by year, 1999-2016
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Vector: Culex spp. mosquitoes (C. pipiens)
Resevoir hosts: wild birds
2009: USUV detected in human encephalitis cases
African mosquito-borne virus closely related to WNV.
Threat of USUV emergence?
While human cases are infrequent, the potential for neuroinvasive infection
suggests a need for clinical awareness and diagnostic capability
Usutu virus
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.
Mass mortality in blackbirds (Austria 2001)
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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 endemic areas
Japanese encephalitis virus
The most important cause of viral encephalitis worldwide.
Annual encephalitis cases nearly 70,000 (half in China) - 10,000 deaths.
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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, andventriculomegaly).
Among pregnant women with ZIKV infection, birth defects are present in 7% offetuses 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: mosquito bite, sexual intercourse (of concern due to an
association between ZIKV infection and adverse pregnancy and fetal
outcomes).
Zika virus
ZIKV is the first flavivirus associated with congenital defects including
microcephaly and other birth abnormalities
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Global spread of ZIKV, 2013-2016
ZIKV expanded its geographic range from Africa and Asia to the Pacific Islands,
then further to South and Central America and the Caribbean.
The first large outbreak of disease caused by Zika infection was reported from the
Island of Yap (Federated States of Micronesia) in 2007.
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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: 15–30%, with long-term neurological sequelae in 30–50% of
survivors
Murray Valley encephalitis virus
The most serious endemic arbovirus in Australia
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Togaviridae
Enveloped single strand, positive sensed RNA viruses
New-world alphaviruses (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
Caribbean and South America
Genus alphavirus
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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.
New World alphaviruses
Although the case fatality rate of VEE is below 1%, its association
with outbreaks involving tens of thousands of human cases renders
it the most important encephalitic alphavirus. ESCMID eLibrary
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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
Chikungunya virus
Astrocytes are commonly the first cells activated in brain
Emerging global health threat with increasing incidence of neurological
complications
1952: First isolation from patients with fever and arthralgia
in Tanzania.
Chikungunya = that which bends up
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Phenuiviridae
Single-strand negative-sensed RNA viruses
Sandfly-transmitted phleboviruses
Symptoms: from asymptomatic or mild disease to
meningitis or encephalitis
Neuroinvasive phlebovirus: Toscana virus
Genus Phlebovirus
Vectors: sandflies, mosquitoes, ticks
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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.
Toscana virus
Endemic in all Mediterranean countries.
The most common cause of summertime viral meningitis in central Italy
Recent identification of novel strains
Papa et al. EID 2014
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Paramyxoviridae
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%.
enveloped single-stranded negative-sensed RNA viruses
Genus Henipavirus. Nipah and Hendra viruses
Main site of infection: endothelium of blood vessels in the CNS (and lungs, kidneys) ESCMID eLibrary
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Zoonotic transmission cycles of Nipah virus in Malaysia and Bangladesh
J Pathol 2015
Zoonotic transmission
through an intermediate,
amplifying host
Direct transmission via the consumption
of date palm sap contaminated with NiV
by fruit bats and further human-to-
human transmission
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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
Hendra virus
Hendra virus infection is an emerging viral disease of horses and humans
in Australia.
Virus transmission
to horses
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small, non-enveloped single-strand positive-sensed RNA viruses
• Genus Enterovirus: poliovirus and the non-polio enteroviruses
• Genus Parechovirus: human parechovirus
Symptoms: common cold to life-threatening infections, such as
encephalitis and myocarditis.
Picornaviridae
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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 polioviruses (PVs) 1–3 and several CVAs
• EV-D containing EV-68
Enteroviruses
Enteroviruses 71, D-68 and C105 can cause polio-like paralysis
They are considered a critical emerging public health threat
CNS infections are most often caused by EVs
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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 secretions and surfaces
Enterovirus 71
It continues to expand its geographic range and has caused
numerous outbreaks in Southeast Asia and Australia
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Incubation: 1-12 days
Transmission: fecal-oral route. Respiratory transmission is also possible
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
J Pediatric Infect Dis Soc. 2017
• PeV3 can cause severe neurologic illness in neonates. • Younger infants are more likely to require intensive care. PeV3 should be considered along with HSV and other pathogens when evaluating young infants with sepsis-like illness or meningitis.
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single-stranded negative-sensed RNA viruses
Bornaviridae
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, species Mammalian 1 Bornavirus).
This is the first time that BoDV-1 has been confirmed in humans
Borna Disease virus
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Astrovirus VA1/HMO-C: highly divergent from the classic human
astroviruses; prototype of a distinct evolutionary clade of astroviruses
EID 2010
CID 2015
Astroviridae
Etiologic agent of encephalitis, at least in the context of immunosuppression
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Australian bat lyssavirus
The only virus known to be transmissible to humans directly from bats
without an intermediate host
Zoonotic virus closely related to rabies 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
Rhabdoviridae
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Collection and analysis of all available meta-data
Diagnosis of emerging CNS infections:
the syndromic approach
• 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 travel in endemic areas
• Vector bite history
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Emerging neurotropic viruses are associated with increasedmorbidity and mortality in humans worldwide, representing areal and evolving threat to human health.
It is expected that more novel pathogens will be identified inthe near future (broader application of NGS)
Early recognition of the causative agent of unexplained acuteCNS infections will enable specific interventions to preventoutbreaks that threaten public health.
The facts
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• 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
drugs and vaccine design.
Actions needed
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