Medical Microbiology:

Medically important
subcellular pathogens;
Structure of Viruses & Prions

Dr Kartini Abdul Jabar

Department of Medical Microbiology
Faculty of Medicine
University Malaya
Key learning objectives
• Historical perspective: chronology of the discovery of viruses
• Understand what is a virus
• Summarize the key properties and structural components of
viruses
• Classify viruses
• Overview of steps in replicative cycle and the outcome of viral
infections
• Briefly understand what prions are and know the associated
diseases
 Lecture outline

• What is a virus? – The history of

viruses -
• What are the properties of a
virus?
• What is the classification for
viruses?
• Viral replication – the life cycle
of a virus
• What is the outcome of viral
infections?
• Prions – a brief introduction
The Founder of Modern Medicine
Hippocrates of Kos II (~400BCE - ~370BCE)
• Hippocrates is considered the father of modern medicine.
• His work, Corpus Hippocraticum (Hippocratic Collection) include references to
infectious diseases ranging from the nature of infection, hygiene, epidemiology and
the immune response, to detailed descriptions of syndromes i.e. influenza,
poliomyelitis and hepatitis (jaundice).

This Egyptian stele (an upright stone

1224: Mesopotamian medicine carving) dating from 1403-1365 BC shows
– Documentation of rabies a priest with a walking stick and foot,
deformities characteristic of polio. The
• Man Bitten by Mad Dog disease was given its first clinical
• Illustration from an Arabic description in 1789 by the British
physician Michael Underwood, and
translation of the Materia recognised as a condition by Jakob Heine
Medica, Baghdad, Iraq, 1224 in 1840. 

Calf
Dog biting calf leg

• Rabid dog attacking a

calf. From a ruin of a 4th
century Roman
settlement in Germany
 The history of virology
Ivanovsky (1892) was first to show the agent causing tobacco mosaic
disease passed through a bacteria-retaining filter but believed that the
filter he used might have fine cracks and that small pores of a microbe
might have passed through the filter – he thought it was a toxin from a
bacterium

Beijerinck (1898) knew he was dealing with something different but

thought that the virus was an infectious liquid, not a particle. Described the
agent of mosaic disease of tobacco as a “contagium vivum fluidum”
(contagious living fluid)

• 1900: the first human virus – the yellow fever

• In 1913, Edna Steinhardt Harde, Clara Israeli, Robert
Lambert: first cultivation of a virus in a cell culture
• In 1931, Ernst Ruska, Max Knoll : Invention of the
transmission electron microscope as Ruska’s PhD
project. 8 years later, visualized tobacco mosaic virus. In
1986, shared Nobel prize with Binnig and Rohrer,
developers of scanning tunneling microscope.
SARS virus

Transmission electron microscope image on the

right shows SARS-CoV-2, the virus that causes
COVID-19, isolated from a patient in the U.S. Virus
particles are emerging from the surface of cells
cultured in the lab. The spikes on the outer edge
of the virus particles give coronaviruses their
MERS CoV name, crown-like.
Virus identification methods
• Techniques such as polymerase
chain reaction (PCR) and its
derivatives, conventional serologic
assays and culture techniques are
used for the diagnosis of many
viral diseases.
• Knowing the nucleotide
sequences and domains of many
viral structural and enzymatic
proteins of human viruses aids in
the development of new strategies
to diagnose illnesses and design
effective antiviral therapies.
Viral Diagnostic Methods, 1970-1980s
• Direct examination of clinical specimens:
Histopathology
Electron microscopy
• Detection of viral antigens
Enzyme immunoassay (EIA, ELISA)
Radioimmunoassay
Immunofluorescence
Immunochromatography
Immunohistochemistry
• Detection of viral nucleic acids
Polymerase chain reaction (PCR)
Hybridization (in-situ, Southern blot)
Oligonucleotide fingerprinting
Restriction endonuclease mapping
• Virus isolation
Cultured cells
Animals/chick embryos
• Serology
Enzyme immunoassay (EIA, ELISA)
Neutralization assay
Immunoblotting (Western blotting)
Indirect immunofluorescence assay
Haemagglutination +/- inhibition assay
Complement-fixation assay
So, what is a virus?
How small is a virus?
 Viruses are
…very small…
A virus is…
• Much smaller than bacteria – 10-400nm, clinically important viruses - 18nm-300nm
• Can possess either DNA or RNA as genomic material
• Lacks cellular machinery for self-reproduction/protein synthesis i.e. endoplasmic
reticulum, ribosomes, nucleus, mitochondria, Golgi apparatus – cannot make their
own energy or proteins
• Cannot reproduce on their own – need living cells to replicate, reproduction of
viruses occurs by assembly of the individual components rather than by binary
fission
• Not made up of cells
• A small, obligate, intracellular: nucleic acid surrounded by a protective, virus-
encoded protein coat
• Infectious, to endure in nature
Viruses are not living
organisms
Viruses exist in 2 phases
Extracellular
• Infectious particles made up
of protein and nucleic acid
Intracellular
• Replicating nucleic acids that
direct host cells to synthesize
viral components
• Assembled into particles and
released from the cell
The different shapes of viruses
• Helical
• Icosahedral
• Complex

Pox
virus

Pictures taken from CDC website and Mandell 2010

 Helical viruses
Single type of capsomer stacked around a central axis
(can be hollow) to form a helical structure

Can be short and stiff or long and bendy

RNA viruses: Rabies virus, coronavirus, measles

virus, Ebola virus, etc

Helical nucleocapsids are always enveloped for

human viruses

Measles Virus Rabies virus (bullet-

Coronavirus
 Icosahedral viruses
• Equal triangular sides Non-
enveloped
• Looks the same from all polio virus
angles
• All DNA viruses (except
poxviruses) and some RNA
viruses
• Examples: Polio virus,
Herpesvirus

Enveloped
herpes
simplex
virus

Pictures taken from CDC website

Complex virus
• Neither helical nor
icosahedral
• Examples: bacteriophage
• poxvirus

Pictures taken from CDC website and http://textbookofbacteriology.net/

Structure of a virus: definitions
• Genome: genetic material coding
for structural proteins and enzymes
needed for replication
• Capsid: protein coat made of
capsomeres – protects nucleic acid
and enable entry into host cell
• Nucleocapsid = nucleic acid +
capsid
• Envelope: derived from host cell
lipid membranes (surface, internal,
nuclear) with inserted viral
glycoproteins
• Virion: whole virus particle
(nucleocapsid and envelope, if
present)
Properties of the viral genome
• Type of nucleic acid:
• DNA vs RNA
• RNA positive-sense vs negative-sense
• RNA can be made of a single molecule of
nucleic acid or multiple discrete segments
• Viral genomes are single- or double-stranded
and circular or linear

• All DNA viruses are double-stranded except

Parvoviruses
• All RNA viruses are single-stranded except
Reoviruses
Structure of a virus
• A – non-enveloped
icosahedral virus (survive
well in outside world)
• E.g. non-enveloped viruses: DNA viruses:
Adenoviridae, Papillomaviridae
• RNA viruses: Picornaviridae, Caliciviridae,
Reoviridae

• B – enveloped helical virus

(more susceptible to
inactivation)
• E.g. enveloped viruses: DNA viruses:
Herpesviruses, poxviruses, hepadnaviruses
• RNA viruses: Flavivirus, togaviruses, coronaviruses,
orthomyxyviruses, paramyxoviruses, rhabdoviruses,
bunyaviruses, filoviruses
• Retrovirus
 Properties of the viral
envelope
Enveloped viruses more
susceptible than non-
enveloped viruses to:
change in pH eg influenza
virus
bile
detergents
lipid solvents, e.g. alcohol,
ether
drying
Other important factors:
heat/cold (temperature),
ultraviolet light

Picture taken from Mandell 2010

 The Enveloped virus vs the Naked Capsid
The Naked Capsid
•Component: Protein
•Properties:
•Naked capsid viruses are
environmentally stable to temperature,
acid, proteases, detergents, drying
•Is released from cell by lysis
•Can be spread easily by fomites, hand
to hand, dust, small droplets
•Can dry out and retain infectivity
•Can survive the adverse conditions of
the gut
•Can be resistant to detergents and poor
sewage treatment
•Antibody may be sufficient for
immunoprotection
•E.g. DNA viruses: Adenoviridae*,
Papillomaviridae*
•RNA viruses: Picornaviridae*,
Caliciviridae*, Reoviridae*, Hepeviridae
The Enveloped
•Component: Membrane, lipids, proteins,
glycoproteins
•Properties:
•Environmentally labile (disrupted): Acid, detergents,
drying, heat
•Modifies cell membrane during replication
•Is released by budding and cell lysis
•Must stay wet
•Cannot survive in the gastrointestinal tract
•Spreads in large droplets, secretions, organ
transplants, blood transfusions
•Does not need to kill the cell to spread
•May need antibody and cell-mediated immune
response for protections and control
•Elicits hypersensitivity and inflammation to cause
immunopathogenesis
•E.g. DNA viruses: Herpesviruses, poxviruses,
hepadnaviruses
•RNA viruses: Flavivirus, togaviruses, coronaviruses,
orthomyxoviruses, paramyxoviruses, rhabdoviruses,
bunyaviruses, filoviruses
•Retrovirus
Properties of the viral envelope
• Lipid envelope that
surrounds the
nucleocapsid
• Acquired as the virus
particle buds from the
host cell cytoplasmic,
nuclear or
endoplasmic reticular
membrane
• Virus-encoded
proteins are inserted
into this lipid bilayer
Properties of the viral envelope
– the glycoproteins
• The virus-encoded proteins e.g.
haemagglutinin (HA) and neuraminidase
proteins of influenza virus and gp41 and
gp120 of HIV are exposed on the surface
of the virus particle
• They usually contain a hydrophilic
external portion and internal hydrophobic
domains that span the lipid membrane
and anchor into the viral envelope
• Function:
• Act as VAP (viral attachment protein) –
tissue/viral tropism
• Fusion activity
• Immunological barrier to resist evasion
by host immune system
• Determine site of budding
Properties of the viral envelope
– the matrix proteins
• Matrix protein: viral protein that
associates with the internal
(cytoplasmic) surface of the
lipid envelope where it can
interact with the domains of the
envelope glycoproteins
• Can influence cellular function
i.e. evade cellular innate
antiviral response
Properties of viruses
• In diagnostic specimens:

• Swabs in viral transport medium (VTM) containing:

• Anti-bacterials & anti-fungals for contaminants
• protein stabilizer (e.g. bovine serum albumin)
• buffer to keep pH 7.0

• Store samples in at 4°C, do not freeze

Properties of viral cultivation
• Cultured only in living cells:
• Plants, animals
• Insects
• Chick embryos (influenza)
• Cultures are the gold
standard – the virus can be
used for further research
• Cell cultures
• most widely used but not all
viruses will grow
• Types:
• Primary a.k.a. finite cell line
undergoes senescence
• Finite undergoes
transformation = immortality =
Continuous cell line
What happens in the
diagnostic virology
lab?

Left: Confluent cells

Right: Cytopathic effect
seen
 Properties of Viral Culture
• Identification of
viruses in cell
cultures:
• Cytopathic effect
• Immunofluoresence
with monoclonal
antibody
 Pictures taken from the Color Atlas of Diagnostic Microbiology

Cytopathic effect
• Viral replication results directly in cell destruction
• Changes in cell morphology caused by the infecting virus = CPE
• Cell lysis, cell fusion (multinuclear giant cells), rounding off and detachment of cells from adjacent
cells or substrate, cytoplasmic vacuoles and inclusion bodies (intracytoplasmic vs intranuclear)

Echovirus in MRC-5 cells: RSV in MRC-5 cells:

marked pyknosis syncytial formation Owl’s eye in CMV
Classification of viruses
• Based on:
• Type of nucleic acid (DNA vs RNA)
• Number of strands (ds vs ss)
• Polarity of RNA (positive sense vs negative sense)
• Symmetry of capsid
• Serological reactions
• Genetic relatedness
Classification of viruses
• Viral classification starts at the level of order and continues as follows,
with the taxon suffixes given in italics:
• Order (-virales) Eg: Herpesvirales
• Family (-viridae) Eg: Herpesviridae
• Subfamily (-virinae) Eg: betaherpesvirinae
• Genus (-virus) Eg: Cytomegalovirus

• Divided into serotypes: Enterovirus (Coxsackievirus, Echovirus,

Enterovirus, Rhinovirus, Poliovirus), Influenza A to C, DEN-1 to DEN-4
• or genotypes (HCV genotype 1 to 6)
Baltimore Classification
• Proposed by Nobel Laureate David Baltimore: based on the method of viral RNA synthesis
• A classification scheme based on:
• Type of nucleic acid (RNA or DNA)
• Type of capsid (helical, icosahedral, complex)
• Enveloped or non-enveloped
• Nature of viral genome (segmented, continuous, RNA/DNA and mechanism of mRNA synthesis)
 Class Strand Example
I dsDNA Papillomaviridae: Human papilloma virus (human warts, cervical cancers)
Polyomaviridae: Polyomavirus (BK virus, JC virus)
Adenoviridae: Mastadenovirus (human adenovirus - respiratory disease)
Herpesviridae: Alphaherpesvirinae - Herpes Simplex I (cold sores), Herpes Simplex II (genital
sores), varicella zoster (chicken pox, shingles), Betaherpesvirinae – CMV, HHV-6, HHV-7,
Gammaherpervirinae - Epstein-Barr virus (infectious mononucleosis, Burkitt’s lymphoma) &
HHV-8 (Kaposi’s sarcoma)
Poxviridae: Orthopoxvirus (Variola virus – Smallpox; Vaccinia virus – active constituent that
eradicated smallpox), Parapoxvirus (Orf virus), Molluscipoxvirus (molluscum contagiosum virus)

II ssDNA Parvoviridae: Parvovirus B19

Baltimore Classification

III dsRNA Reovirus: Rotavirus (diarrhoea)

IV (+)ssRNA: can serve as Picornaviridae: Enterovirus (Poliovirus, rhinovirus (common cold), enterovirus (A-J),
mRNA coxsackievirus, echovirus), hepatovirus (Hepatitis A)
Togaviridae: Alphavirus – Chikungunya; Rubivirus - Rubella virus
Flaviviridae: Flavivirus (Yellow fever virus, dengue virus, West Nile virus, Zika virus, JE),
Hepacivirus (Hepatitis C)
Coronaviridae: Betacoronavirus (SARS-CoV-2, SARS-CoV, MERS-CoV, other coronaviruses)
Caliciviridae: Norovirus, Sapovirus
Astroviridae: Astrovirus

V (-)ssRNA: template for Rhabdoviridae: Lyssavirus (Rabies virus)

mRNA Paramyxoviridae: Henipavirus (Hendra virus, Nipah virus), Morbilivirus (measles virus),
Respirovirus (parainfluenza 1 and 3), Rubulavirus (mumps virus, parainfluenza 2 and 4)
Orthomyxoviridae: Influenza A-D
Filoviridae: Ebolavirus, Marburgvirus
Arenaviridae: Lassa virus
Hantaviridae (order Bunyavirales): Hanta virus

VI ssRNA-RT: template for DNA Retroviridae: Lentivirus (HIV), deltaretrovirus (HTLV-1, HTLV-2))
synthesis
VII dsDNA-RT: RNA Hepadnaviridae: Orthohepadnavirus (Hepatitis B)
intermediate that is a
template for DNA synthesis
Stages in Virus-Cell Interaction
• Attachment
• Penetration
• Disassembly
• Transcription
• Translation
• Replication
• Assembly
• Release
Stages in
Virus-Cell
Interaction
(viral
replication)
• Attachment
• Penetration
• Disassembly
• Transcription
• Translation
• Replication
• Assembly
Viruses require an intact
• Release cell to replicate
Stages in
Virus-Cell
Interaction
(viral
replication)
Attachment:
• Attachment Virus particles attach to specific receptors
on the cell surface, using viral proteins
• Penetration (attachment proteins, surface
• Disassembly glycoproteins and viral capsid proteins

• Transcription
• Translation
• Replication
• Assembly
• Release
Stages in
Virus-Cell
Interaction
(viral
replication)
• Attachment
• Penetration
• Disassembly Penetration and disassembly
Fusion of viral envelope with the cell
• Transcription membrane or receptor-mediated
endocytosis for enveloped viruses
• Translation
• Replication
• Assembly
• Release
Penetration and disassembly
For non-enveloped viruses, capsid rearrangement
triggered by receptor binding, acidic pH or
proteolysis allows membrane penetration
Entry via viropexis (phagocytosis)

Waye MMY, Chor WS, Pharmaceuticals, 2010

Stages in
Virus-Cell
Interaction
(viral
replication)
• Attachment
• Penetration
• Disassembly
• Transcription
Most DNA virus (except
• Translation poxvirus) need to go to the
• Replication nucleus
Most RNA viruses stay in the
• Assembly cytoplasm

• Release
DNA viruses RNA viruses
dsDNA uses host The RNA virus genome
machinery in the must code for RNA-
nucleus (except dependent RNA
poxviruses) to make polymerases
mRNA, which is (replicases and
translated by host cell transcriptases)
ribosomes into proteins because the cell has
no means of replicating
Replication of simple RNA
DNA virus genomes
(e.g. parvoviruses, Unlike DNA viruses,
polyomaviruses, the RNA viruses must
papillomaviruses) uses also provide enzymes
host DNA-dependent for synthesis and
DNA polymerase processing of viral
mRNA
Larger, more complex
viruses (e.g. RNA degrade quickly,
adenoviruses, so most viral RNA
herpesviruses, polymerase work at
poxviruses) encode fast pace and are error
their own polymerases prone -> mutations
Murray 2016
 Positive-sense RNA viral genomes - infectious
E.g. picornaviruses, caliciviruses, coronaviruses,
flaviviruses, togaviruses
Act as mRNA, bind to ribosomes, direct protein
synthesis

The virus-encoded RNA-dependent RNA polymerase

produces a negative-sense RNA template
This template is used to generate more mRNA and to
replicate the genome
Negative-sense RNA virus
genomes – not infectious
by itself, a polymerase
must be carried into the cell
with the genome
E.g. rhabdoviruses, orthomyxoviruses,
paramyxoviruses, bunyaviruses, filoviruses
Polymerase needed to make mRNA for different viral
proteins and to generate more copies of the genome
Except for influenza virus, transcription and replication
of negative-sense RNA viruses occur in the cytoplasm
Stages in
Virus-Cell
Interaction
(viral
Assembly:
replication) Usually occurs in
cytoplasm
• Attachment Newly-made nucleic acid
and capsid are put
• Penetration together to form a new
virion
• Disassembly May have post-
translational modification
• Transcription of proteins
• Translation
• Replication
• Assembly
• Release
Stages in
Virus-Cell
Interaction
(viral
replication)
• Attachment
• Penetration
• Disassembly Viruses can be released from
cells after cell lysis, by
• Transcription exocytosis or by budding
from the plasma membrane
• Translation
• Replication
• Assembly
• Release
Retroviruses have positive-sense RNA genome but the
virus has no means for replication of the RNA in the
cytoplasm

So, the host transfer RNA (tRNA) binds to the primer

binding site and the RNA-dependent DNA polymerase
(reverse transcriptase) initiates cDNA synthesis from the
tRNA primer -> proviral DNA

The tRNA is used as a primer for synthesis of circular

complementary (cDNA) copy of the genome which is
synthesized in the cytoplasm, travels to the nucleus and is
integrated into the host chromatin, using integrase

Once integrated into the CD4 cell DNA, the machinery in

the cell is used to make more HIV

New HIV proteins and RNA move to the surface

Newly formed immature (noninfectious) HIV pushes itself

out of the host CD4 cell

Protease is released and acts to break the long protein

chains into smaller proteins to form mature, infectious HIV
Viral replication
• Viral infection can affect cellular processes i.e. protein and nucleic acid
synthesis, maintenance of cytoskeletal architecture and preservation of
membrane integrity – can also induce apoptosis of host cells

• In DNA virus replication:

• Occurs usually in host nucleus (except poxviruses)
• May use host DNA polymerases
• Some (eg herpesviruses) have mRNA encoding for viral DNA polymerase

• In RNA replication:
• There is no proof-reading or correction like DNA
• Lots of errors -> mutations may occur (advantage: antiviral resistance,
disadvantage: not viable), can exist as genetic variants in a host (quasispecies)
• Eg, influenza antigenic drift
Outcome of viral infection
• Failed infection (abortive infection)
• Cell death (lytic infection)
• Replication without cell death (persistent infection)
• Presence of virus without virus production but with potential for
reactivation (latent or recurrent infection)
Viral infection outcome

Virus Site of Latency Cancer

Herpes simplex 1 & 2 Neurons (dorsal root No
ganglia)
Varicella-zoster virus No

Epstein-Barr virus B cells Nasopharyngeal

carcinoma, Burkitt’s
lymphoma, Hodgkin’s
lymphoma
Hepatitis B & C Hepatocytes Hepatocellular carcinoma
Papillomavirus Epithelial cells Cervical cancer
HIV T-cells, macrophages Kaposi sarcoma
 Antigenic
drift

Antigenic shift

Recombination
Genetic variation

Recombination: eg DNA Reassortment: segmented

virus (herpesvirus) RNA viruses (influenza –
antigenic shift)
Human Bird
influenza influenza
18 HA subtypes
11 NA subtypes
Outcome of viral infection
System/Disease Causative viruses

GIT-Diarrhoea Rotavirus, norovirus, adenovirus, astrovirus

Adenoviruses, coronaviruses (SARS-CoV-2, SARS-CoV, MERS-

Respiratory tract-
CoV), rhinoviruses, orthomyxoviruses (influenza),
URT/LRT infection
paramyxoviruses (RSV, parainfluenza)
Musculoskeletal-Skin Measles, rubella, parvovirus B19, herpesviruses (HSV 1, HSV 2,
/exanthema (rash), VZV, CMV, EBV, HHV-6, HHV-7), enteroviruses, poxviruses
myalgia (smallpox), HFMD-enterovirus EV A71, Chikungunya
Enteroviruses (EV A71, polio), herpesviruses (HSV-1 & 2, VZV),
CNS- meningitis,
Rhabdoviruses (rabies), measles, HIV, flaviviruses (Japanese
encephalitis
encephalitis), Nipah

GIT-Hepatitis Hepatitis A, B ,C-E & G viruses, herpesviruses (CMV, EBV)

Malignancy EBV, Hepatitis B & C, HIV, papillomaviruses

Dengue, filoviruses (Ebola, Marburg), bunyaviruses (Lassa,

Haemorrhagic fever
 Prions

• “Because the novel properties of the scrapie

agent distinguish it from viruses, plasmids, and
viroids, a new term "prion" is proposed to denote
a small proteinaceous infectious particle, which
is resistant to inactivation by most procedures
that modify nucleic acids.”
• Stanley B. Prusiner, 1982
• Neurologist, biochemist, Nobel Prize Laureate (1997)
Prion diseases to-date

Human Prion Diseases Animal Prion Diseases

• Creutzfeld-Jakob Disease • Bovine Spongiform Encephalopahy
(CJD) (BSE)
• Chronic Wasting Disease
• Variant Creutzfeld-Jakob
Disease (vCJD) • Scrapie
• Transmissible mink encephalopathy
• Gerstmann-Straussler-
• Feline spongiform encephalopathy
Scheinker Syndrome (GSS)
• Ungulate spongiform
• Fatal Familial Insomnia encephalopathy
• Kuru
Prion protein gene PRNP, encodes for cellular prion protein (PrPC)
Mature PrPC has 209 amino acids. Properly assembled, the tertiary structure composes of
three α-helices and two antiparallel β-sheets.
In prion disease, α-helix-rich PrPC undergoes conformational transition to β-sheet-rich PrPSc

Normal: α-helices > β-sheets

Abnormal: α-helices < β-sheets Sponge-like lesions in the brain
tissue of a classic CJD patient
-> forms aggregates, form amyloid fibrils
-> part of the fibrils can break off and act as template for the recruitment of additional PrP C
molecules
Induce abnormal unfolding of normal cellular proteins (prion proteins) in the brain
Aggregates extracellularly within the central nervous system to form plaques (amyloid) which
disrupt normal tissue structure – results in spongy architecture due to vacuole formation in
the neurons
Prion diseases to-date

Human Prion Diseases Animal Prion Diseases

• Creutzfeld-Jakob Disease • Bovine Spongiform Encephalopahy
(CJD) (BSE)
• Chronic Wasting Disease
• Variant Creutzfeld-Jakob
Disease (vCJD) • Scrapie
• Transmissible mink encephalopathy
• Gerstmann-Straussler-
• Feline spongiform encephalopathy
Scheinker Syndrome (GSS)
• Ungulate spongiform
• Fatal Familial Insomnia encephalopathy
• Kuru
 Clinical and Pathologic Characteristics
Distinguishing Classic CJD from Variant CJD
Characteristic Classic CJD Variant CJD
Median age at death 68 years 28 years
Median duration of illness 4-5 months 13-14 months
Clinical signs and symptoms Dementia; early Prominent psychiatric/behavioral
neurologic signs symptoms; painful dyesthesiasis;
delayed neurologic signs
Periodic sharp waves on electroencephalogram Often present Often absent

“Pulvinar sign” on MRI* Not reported Present in >75% of cases

*An abnormal signal in the
posterior thalami on T2- and
diffusion-weighted images and
fluid-attenuated inversion
recovery sequences on brain
magnetic resonance imaging
(MRI); in the appropriate clinical
context, this signal is highly
specific for vCJD.

Presence of “florid plaques” on neuropathology Rare or absent Present in large numbers

Normal
CJD
Sponge-like lesions in the brain
tissue of a classic CJD patient
Pulminar and ‘hockey stick’ sign on MRI for vCJD
Neuropathological destruction pattern in variant Creutzfeldt-
Jakob disease (vCJD) Accumulations of florid plaques
surrounded by confluent vacuoles in a vCJD case.
Donald A. Collie, et al. Diagnosing Variant Creutzfeldt-Jakob Disease with the Pulvinar Sign: MR Imaging
Findings in 86 Neuropathologically Confirmed Cases. American Journal of Neuroradiology September
2003, 24 (8) 1560-1569;
Mark M. Bahn, Piero Parchi, Abnormal Diffusion-Weighted Magnetic Resonance Images in Creutzfeldt-Jakob
Disease. Arch Neurol. 1999;56(5):577-583. doi:10.1001/archneur.56.5.577
CDC’s Diagnostic Criteria for Creutzfeldt-Jakob Disease (CJD), 2018
1. Sporadic CJD
Definite:
Diagnosed by standard neuropathological techniques; and/or immunocytochemically; and/or Western blot confirmed protease-
resistant PrP; and /or presence of scrapie-associated fibrils.
Probable:
Neuropsychiatric disorder plus positive real-time quaking-induced conversion (RT-QuIC) in cerebrospinal fluid (CSF) or other
tissues
OR
Rapidly progressive dementia; and at least two out of the following four clinical features:
Myoclonus
Visual or cerebellar signs
Pyramidal/extrapyramidal signs
Akinetic mutism
AND a positive result on at least one of the following laboratory tests
a typical EEG (periodic sharp wave complexes) during an illness of any duration; and/or
a positive 14-3-3 CSF assay in patients with a disease duration of less than 2 years
Magnetic resonance imaging (MRI) high signal abnormalities in caudate nucleus and/or putamen on diffusion-weighted imaging
(DWI) or fluid attenuated inversion recovery (FLAIR)
AND without routine investigations indicating an alternative diagnosis.
Possible:
Progressive dementia; and at least two out of the following four clinical features:
Myoclonus
Visual or cerebellar signs
Pyramidal/extrapyramidal signs
Akinetic mutism
AND the absence of a positive result for any of the four tests above that would classify a case as “probable”
AND duration of illness less than two years
AND without routine investigations indicating an alternative diagnosis.
2. Iatrogenic CJD
Progressive cerebellar syndrome in a recipient of human cadaveric-derived pituitary hormone;  or sporadic CJD with a recognized
exposure risk, e.g., antecedent neurosurgery with dura mater implantation.
3. Familial CJD
Definite or probable CJD plus definite or probable CJD in a first degree relative; and/or Neuropsychiatric disorder plus disease-
specific PrP gene mutation.
Diagnostic Criteria vCJD
Definite Variant CJD
Neuropathologic examination of brain tissue is required to confirm a diagnosis of variant CJD. The following
confirmatory features should be present.
Numerous widespread kuru-type amyloid plaques surrounded by vacuoles in both the cerebellum and
cerebrum – florid plaques.
Spongiform change and extensive prion protein deposition shown by immunohistochemistry throughout the
cerebellum and cerebrum.
Suspected Variant CJD
Current age or age at death <55 years (a brain autopsy is recommended, however, for all physician-diagnosed
CJD cases).
Psychiatric symptoms at illness onset and/or persistent painful sensory symptoms (frank pain and/or
dysesthesia).
Dementia, and development ≥4 months after illness onset of at least two of the following five neurologic signs:
poor coordination, myoclonus, chorea, hyperreflexia, or visual signs. (If persistent painful sensory symptoms
exist, ≥4 months delay in the development of the neurologic signs is not required).
A normal or an abnormal EEG, but not the diagnostic EEG changes often seen in classic CJD.
Duration of illness of over 6 months.
Routine investigations of the patient do not suggest an alternative, non-CJD diagnosis.
No history of receipt of cadaveric human pituitary growth hormone or a dura mater graft.
No history of CJD in a first degree relative or prion protein gene mutation in the patient.
Note
If a patient has the typical bilateral pulvinar high signal on MRI scan, a suspected diagnosis of variant CJD
requires the presence of a progressive neuropsychiatric disorder, d, e, f and g of the above criteria, and four of
the following five criteria: 1) early psychiatric symptoms (anxiety, apathy, delusions, depression, withdrawal); 2)
persistent painful sensory symptoms (frank pain and/or dysesthesia); 3) ataxia; 4) myoclonus or chorea or
dystonia; and 5) dementia.
A history of possible exposure to bovine spongiform encephalopathy (BSE) such as residence or travel to a
BSE-affected country after 1980 increases the index of suspicion for a variant CJD diagnosis.
Infection Control and Biosafety in CJD
• WHO developed guidelines
• Stringent chemical and autoclave sterilization methods to reprocess
heat-resistant instruments that come in contact with high infectivity
tissues (brain, spinal cord, and eyes) and low infectivity tissues
(cerebrospinal fluid, kidneys, liver, lungs, lymph nodes, spleen,
olfactory epithelium, and placenta) of patients with suspected or
confirmed CJD.
• For lab: Safety practices
• Treatment: supportive
 Learning objectives

Understand and define what is a virus


Know the main properties and structural components of a virus


Able to relate the differences between viruses with other pathogens


Know how viruses are classified


Understand briefly the virus life cycle and outcome of viral infections


Know some examples of the medically important viruses
(especially in Malaysia ) and the associated diseases


Briefly understand what prions are and know the associated diseases


At the end of the Medical Program (on graduation), students should be able to apply:

To describe organisation and function of RNA viruses, DNA viruses and Prions.