Virology 2420
Emerging & Re-Emerging Viruses Lectures:
Ebolaviruses
JASON KINDRACHUK, PhD
Assistant Professor, Canada Research Chair
Laboratory of Emerging & Re-Emerging Viruses
Department of Medical Microbiology
University of Manitoba
Email: Jason.Kindrachuk@umanitoba.ca
Twitter: @KindrachukJason
GLOBAL PREPAREDNESS FOR EMERGING
INFECTIOUS DISEASES
URGENT ACTIONS TO PREPARE THE WORLD FOR HEALTH EMERGENCIES
1.
2.
3.
4.
Heads of government must commit and invest
Countries and regional organizations must lead by example
All countries must build strong systems
Countries, donors and multilateral institutions must be prepared for the
worst
September 2019
DISEASES OF URGENCY:
• Crimean-Congo haemorrhagic
fever
• Filovirus diseases
• Emerging coronaviruses
• Lassa Fever
• Nipah
• Rift Valley Fever
• Disease X
PRIORITIZATION ELEMENTS
1. Human transmissibility
2. Severity or case fatality rate
3. Spillover potential
4. Evolutionary potential
5. Available countermeasures
6. Difficulty of detection or control
7. Public health context of the affected area(s)
8. Potential scope of outbreak (risk of international
spread)
9. Potential societal impacts
EMERGING AND RE-EMERGING ZOONOSES
• Zoonoses: diseases and infections naturally transmitted between
people and vertebrate animals (WHO)
• Emerging and re-emerging zoonoses: newly appearing or existed
previously and rapidly increasing in incidence or geographical
range
• ~60% of global emerging infectious diseases are zoonoses
– have deleterious effects on human/animal health and global economies
– SARS estimated to have lowered GDP in Canada by $1.5 billion CDN
– West African EVD cost ~$53 billion USD
Courtesy of World Health Organization
INCREASING INTEGRATION OF SOCIAL
DETERMINANTS TO ONE HEALTH
Woldehanna S, Zimicki S. Soc Sci Med. 2015. 129: 87-95.
Filoviruses
FILOVIRUSES – TAXONOMY OVERVIEW
Family Filoviridae belongs to the order Mononegavirales:
Infect primates, bats or pigs
Causes viral hemorrhagic fever in some primates
Replicates exclusively in cytoplasm
Kuhn et al., (2020) ICTV Virus Taxonomy Profile: Filoviridae, J Gen Virol, 100, 911–912
FILOVIRUS TAXONOMY
Kuhn et al., (2020) ICTV Virus Taxonomy Profile: Filoviridae, J Gen Virol, 100, 911–912
GENOME ORGANIZATION AND REPLICATION
Kuhn et al., (2020) ICTV Virus Taxonomy Profile: Filoviridae, J Gen Virol, 100, 911–912
EBOLAVIRUS SPECIES
Kuhn et al., (2020) ICTV Virus Taxonomy Profile: Filoviridae, J Gen Virol, 100, 911–912
Courtesy of US Centers for Disease
Control and Prevention
EBOLAVIRUS STRUCTURAL OVERVIEW
Ebolavirus Proteins
1. Glycoproteins (GP):
formation depends on
differential RNA editing
a.
b.
c.
d.
GP1,2
secreted GP
ssGP
Δ-peptide
2. VP24: structural; IFN
antagonism
3. VP30: RNP complex
4. VP35: RNP complex;
IFN antagonism
5. NP: RNP complex
6. VP40: structural
7. L: polymerase
EBOLAVIRUS LIFE CYCLE
FILOVIRUS-MEDIATED IMMUNE MODULATION
Viral proteins (VP24, VP35 – EBOV; VP35, VP40 – MARV) can
inhibit induction of IFN responses
Kindrachuk et al. Global Virology I. 2015.
EBOLAVIRUS TRANSMISSION
• Molecular evidence suggests that bats are reservoir for Ebola virus
• Human-to-human transmission does not occur until development of
early clinical symptoms (fever, general malaise)
EBOLAVIRUS PATHOGENESIS
Ebolaviruses
CASE FATALITY RATES
Zaire ebolavirus
(EBOV)
Sudan ebolavirus
(SUDV)
Bundibugyo ebolavirus
(BDBV)
Taï Forest ebolavirus
(TAFV)
Reston ebolavirus
(RESTV)
Baseler L et al. Annu Rev Pathol. 2017. 12:387-418
10
CLINICAL COURSE OF FILOVIRUS HEMORRHAGIC FEVER
\]]]
Courtesy of Dr. Jens H. Kuhn (NIH Integrated Research Facility)
11
CLINICAL COURSE OF NON-FATAL EBOLA VIRUS DISEASE (EVD)
Background:
•
34yr old male healthcare worker in Sierra Leone
•
Developed fever and malaise (March 2015)
•
Medevac to NIH Special Clinical Studies Unit (SCSU)
Chertow, DS et al. Ann Rev Path. 2017. 12: 387-418.
EBOV PERSISTENCE FOLLOWING RECOVERY
Temporal investigation of EBOV persistence in semen from an EVD survivor
• ~104 greater EBOV in semen at clinical discharge than peak viremia
• Strand-specific RT-qPCR demonstrated EBOV undergoing active replication
Barnes KG*, Kindrachuk J* et al. Clin Infect Dis. 2017. 65: 1400-1403.
FILOVIRUS TRANSMISSION CYCLE
• Molecular and serological evidence suggests that bats may be reservoir
• Marburg virus has been recovered from Rousettus aegyptiacus
Alexander KA. et al. PLoS Neg Trop Dis. 2015. 9:e0003652
PREDICTING EBOLAVIRUS ZOONOTIC DISTRIBUTION
Pigott DM. et al. eLife. 2014. 3: e04395
RESTON VIRUS IS ENDEMIC IN PHILIPPINE PIGS
• Reston virus emerged in 1989-1990:
Philippines and Reston, VA, USA
• Workers in both locations
seroconverted
• Outbreak in imported NHPs in 1996: TX,
USA
• Pigs test positive for virus in Manila, 2008
• Abattoir workers had seroconversion
Reston virus isolated
from porcine lymph
node homogenate
passaged in Vero cells
Barrette, RW. et al. Science. 2009. 325: 204-206; Sayama, Y. et al. BMC
Vet Res. 2012. 8: 82
SEROLOGICAL EVIDENCE FROM PIGS IN GUINEA
• Serological assessments by WB, IFA and VNT
• IFA of ELISA reactive sera where diluted
porcine sera incubated with Vero cells
expressing EBOV- or SUDV-GP
Fischer K. et al. Transbound Emerg Dis. 2019. Oct
18.
EBOLAVIRUSES HAVE DECIMATED GREAT APE POPULATIONS
Carcass of a chimpanzee killed by EBOV in
Republic of Congo (Walsh PD et al. Sci Rep.
2017. 7:43339
EBOV IN CENTRAL AFRICAN GREAT APES: 2001-2003
Leroy, AM. et al. Science. 2004. 303: 387-90.
SEROLOGICAL EVIDENCE IN GABONESE DOGS
Allela, L. et al. Emerg Infect Dis. 2005. 11: 385-90.
MODELING EBOLAVIRUS SPILLOVERS WITH
ENVIRONMENTAL FACTORS
• Spillover intensity increases
between wet and dry seasons
• Greatest at high (>1,000/km2)
and very low (<100/km2)
human population densities
compared with intermediate
levels
Schmidt, JP. et al. Emerg Infect Dis. 2017. 23: 415-22.
Rulli, MC. et al. Sci Rep. 2017. 7: 41613.
WEST AFRICAN EBOLA VIRUS DISEASE EPIDEMIC
Integrated Research Facility, Ft. Detrick, MD
ELWA3 (Eternal Love Winning Africa) –Médecins Sans
Frontières. Largest treatment center in Liberia during
EVD epidemic.
Liberian Institute for Biomedical Research,
Monrovia, Liberia
RESEARCH CONTAINMENT VERSUS OUTBREAK RESPONSE
EBOLA VIRUS DIAGNOSTICS IN THE FIELD
Locals bringing game to sell
to LIBR staff
Illegal taxi services resulted in close proximity to
potentially infected patients
Proximity to wildlife,
including potential
reservoirs
Virology 2420
Emerging & Re-Emerging Viruses Lectures:
Coronaviruses
JASON KINDRACHUK, PhD
Assistant Professor, Canada Research Chair
Laboratory of Emerging & Re-Emerging Viruses
Department of Medical Microbiology
University of Manitoba
Email: Jason.Kindrachuk@umanitoba.ca
Twitter: @KindrachukJason
SARS-COV-2 AND COVID-19:
A PANDEMIC IN THE AGE OF SOCIAL MEDIA
CORONAVIRUSES – A SHORT HISTORY
• Coronaviridae virus family
• RNA viruses with large genomes
• Multiple subfamily members
• Seven coronaviruses cause disease in humans
– Mild to severe respiratory illnesses
– Nosocomial transmission (SARS & MERS)
Schindell B. ACS Infect Dis. 2020
CORONAVIRUSES IN ANIMALS
Chen J et al. J Med Virol. 2020. 92: 418–423.
CORONAVIRUSES GENOME STRUCTURE
Shereen MA et al. J Adv Res. 2020. 24: 91-98
CORONAVIRUS LIFE CYCLE – SARS-COV-2
CORONAVIRUS LIFE CYCLE & THERAPEUTICS
CORONAVIRUSES IN CHINA
Latinne A. et al. BioRxiv. 2020.
Identified >700 new bat-origin coronavirus
sequences in China
Showed that 3% of villagers in Yunnan province
were seropositive for bat coronaviruses
THE START (?) OF A PANDEMIC –
DECEMBER 31, 2019
Atypical Pneumonia Cases in Hubei Province, China
Initial reports of a “SARS-like” illness in
China – late December
Potential link to Huanan Seafood
Wholesale Market
SARS-COV-2 EMERGENCE
• Increasing likelihood that
the virus spilled over from
a bat host
• RaTG13 (Rhinolophus
affinis)
• ~96% identical to
SARS-CoV-2
Lu R. et al. Lancet. 2020. 395: P565-574
• Similarity in RBD to
pangolin CoVs
(intermediate?)
• Human-to-cat
transmission
• Human-to-mink
transmission
De Witt, E. et al. Nat Rev Micro. 2016. 14:523-533
CORONAVIRUS DISEASE 2019 PATHOGENESIS
Cevik M, Kuppalli K, Kindrachuk J, Peiris M. BMJ. 2020 [accepted]
SARS-COV-2/COVID-19 – WHAT WE KNOW
Comparing SARS-CoV-2 & SARS-CoV
1. Differences in viral load kinetics and duration of infectivity
2. ↑ infectivity of SARS-CoV-2
-URT cells and conjunctiva: ACE2 receptor binding and affinity
SARS-CoV-2 >> SARS-CoV
Unknowns
• Infectious dose?
• Estimations of 100s to 1000s of particles for SARS-CoV
• Diversity of clinical presentation and outcomes?
• What factors contribute to superspreader events?
COVID-19 CLINICAL DISEASE SPECTRUM
Gandhi RT, Lynch JB, del Rio C. N Engl J Med. 2020. 383: 1757-1766
CDC COVID-19 PLANNING SCENARIOS
COVID-19 DIAGNOSTICS
Courtesy of BioRender
DELAYS BETWEEN DIAGNOSIS AND ONSET
OF SYMPTOMS
De Witt, E. et al. Nat Rev Micro. 2016. 14:523-533
COVID-19 AND INFLUENZA
COVID-19 AND INFLUENZA
HOSPITALIZATIONS VS AGE GROUPS
Courtesy of US Centers for Disease Control and Prevention
De Witt, E. et al. Nat Rev Micro. 2016. 14:523-533
CURRENT GAPS IN KNOWLEDGE
1.
2.
3.
4.
5.
Aerosol transmission during daily activities (e.g. talking, coughing, etc) and medical
procedures (e.g. intubation)
Infectious aerosol generation in asymptomatic and presymptomatic infections
Impact of infection in vulnerable populations (age, comorbidities)
Biological characteristics underlying superspreading events
Disinfection and ventilation procedures
Santarpia JL et al. Sci Rep. 2020. 10: 12732
Richard M et al. Nat Comm. 2020. 11: 3496
WHEN DID SARS-COV-2 EMERGE?
Data remains inconclusive but suggests virus was likely spreading earlier than December
Huang C. et al. Lancet. 2020. 395: 497-506.
SEROPREVALENCE INVESTIGATIONS
• Duration of IgG for at
least 120 days
(Icelandic population)
• Stronger induction
related to disease
severity and age
• Human data remains
variable
Gubdjartsson DF. et al. NEJM. 2020.
DOES REINFECTION OCCUR?
Rhesus macaques
protected from reinfection
following recovery
Bao L. et al. bioRxiv. 2020.
RT-qPCR sensitivity issues
at LOD in clinical samples
Wolfel R. et al. Nature. 2020.
THE RACE TO FIND TREATMENTS
Tay MZ. et al. Nat Rev Immunol. 2020. 20: 363-374.
THE RACE TO FIND TREATMENTS
Cevik M, Kuppalli K, Kindrachuk J, Peiris M. BMJ. 2020 [accepted]
Current FDA approvals and emergency use authorizations:
1. Remdesivir (Veklury) – virus replication inhibitor
• not recommended by WHO
2. Bamlanivimab – monoclonal antibody
• Mild to moderate Covid-19 only
3. Casirivimab & Imdevimab – monoclonal antibody cocktail
• Mild to moderate Covid-19 only
4. Baricitinib & Remdesivir – target JAK (inflammation) and viral replication
• Severe Covid-19 treatment
LIGHT AT THE END OF A LONG TUNNEL
Courtesy of The New York
Times
LIGHT AT THE END OF A LONG TUNNEL
Krammer F. Nature. 2020. 586: 516-527
LIGHT AT THE END OF A LONG TUNNEL
Krammer F. Nature. 2020. 586: 516-527
LIGHT AT THE END OF A LONG TUNNEL
Krammer F. Nature. 2020. 586: 516-527
VARIANTS OF CONCERN
B.1.1.7 transmission across UK Nov-Dec 2020
Compilation of SARS-CoV-2 spike mutations
occurring in humas and animals
Courtesy of RF Garry (virological.org)