Download Viruses

Viruses
are sub-microscopic, obligate intracellular
parasites
 Viroids are small (200-400nt), circular RNA molecules with a
rod-like secondary structure which possess no capsid or
envelope which are associated with certain plant diseases.
Their replication strategy like that of viruses - they are obligate
intracellular parasites.
 Virusoids are satellite, viroid-like molecules, somewhat
larger than viroids (e.g. approximately 1000nt) which are
dependent on the presence of virus replication for
multiplication (hence 'satellite'), they are packaged into virus
capsids as passengers.
 Prions are rather ill-defined infectious agents believed to
consist of a single type of protein molecule with no nucleic
acid component. Confusion arises from the fact that the prion
protein & the gene which encodes it are also found in normal
'uninfected' cells. These agents are associated with diseases
such as Creutzfeldt-Jakob disease in humans, scrapie in
sheep & bovine spongiform encephalopathy (BSE) in cattle.
The first written record of a virus infection
consists of a heiroglyph from Memphis,
the capital of ancient Egypt, drawn in
approximately 3700 BC, which depicts a
temple priest called Ruma showing typical
clinical signs of paralytic poliomyelitis .
The Year 1193 BC
The Pharaoh Siptah rules Egypt from 1200-1193 BC
when he dies suddenly at the age of about 20.
FOOT
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His mummified body lays undisturbed in his tomb in
the Valley of the Kings until 1905 when the tomb
was excavated.
The mummy shows that his left leg was withered
and his foot was rigidly extended like a horse's
hoof - classic paralytic poliomyelitis
.
Ramesses V's preserved mummy shows that he
died of smallpox at about the age of 35 in 1143
BC.
The pustular lesions on the face
of the mummy are very similar
to those of more recent patients
Mesopotanian laws concerning rabid dogs date
from 1000 BC. People who let rabid dogs run free
were fined.
Smallpox is endemic in China by
1000BC. In response, the practice of
variolation is developed.
Recognizing that survivors of smallpox
outbreaks are protected from subsequent
infection, variolation involves inhalation
of the dried crusts from smallpox lesions
like snuff, or in later modifications,
inoculation of the pus from a lesion into
a scratch on the forearm
The Year 1520
Smallpox , which had reached Europe from the East in 710
A.D., was transferred to the Americas by Hernando
Cortez.
3,500,000 Aztecs died in the next 2 years - effectively the
end of the Aztec empire .
Lady Mary
Wortley Montagu
introduced
Variolation to
England
The Year 1796
On 14th May 1796, Edward Jenner
vaccinated an 8 year old boy, James
Phipps, with material from a cowpox
lesion on the hand of a milkmaid,
Sarah
Nelmes.
James, who had never had smallpox,
developed a small lesion at the site
of vaccination which healed in 2
weeks.
On 1st July 1796, Jenner challenged
the boy by deliberately inoculating
him with material from a real case of
smallpox !
The Year 1886
Louis Pasteur tested a rabies vaccine. This depended on deliberate,
experimental production of the vaccine by serial passage of infectious
virus in rabbit spinal cords.
The next vaccines for yellow fever and influenza did not appear until
the 1930s.
The Year 1892
On 12th February, Dmitri Iwanowski, a Russian botanist,
presents a paper to the St. Petersburg Academy of Science
which shows that extracts from diseased tobacco plants can
transmit disease to other plants after passage through ceramic
filters fine enough to retain the smallest known bacteria.
This is generally recognised as the beginning of Virology.
Unfortunately, neither Iwanowski nor the scientific
community fully realize the significance of these results.
The Birth of Virology
*Adolph Mayer-1883. Inoculated plants
with agent that he named Tobacco
mosaic virus. Showed that the agent
was soluble and could not be grown in
culture. Thought that the pathogen
might be a small bacterium.
*Martinus Beijerinck-1897
Found that the agent could reproduce only in the host
and was not inactivated by alcohol. Called the agent a
“contagium vivum fluidum” or a “contageous living
liquid”. Clearly stated that the agent was not a bacterium,
fungus or other culturable pathogen. He is known as the
“Father of Virology”.
Walter Reed (1851-1902)
Through experimental transmission to mice,
in 1900 Walter Reed demonstrated that
yellow fever was caused by a virus, spread
by mosquitoes.
Karl Landsteiner (1868-1943)
Karl Landsteiner (1868-1943) and Erwin
Popper proved that poliomyelitis was caused
by a virus. Landsteiner and Popper were the
first to prove that viruses could infect
humans as well as animals.
Francis Peyton Rous (1879-1970)
Francis
Peyton
Rous
(1879-1970)
demonstrated that a virus (Rous sarcoma
virus) can cause cancer in chickens. (For this
work, he was eventually awarded the Nobel
Prize, in 1966.
Rous is the first person to show that a virus
could cause cancer in animals (see also 1981).
Frederick Twort (1915)
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First to isolate viruses that infect bacteria
(bacteriophages)
Felix d'Herelle (1873-1949)
Following Frederick Twort's work, Felix
d'Herelle independently recognizes viruses
which infect bacteria, which he calls
bacteriophages (eaters of bacteria).
The discovery of bacteriophages provids an
invaluable opportunity to study virus
replication at a time prior to the development
of cell culture when the only way to study
viruses was by infecting whole organisms.
Wendell Stanley (1887-1955)
Wendell Stanley (1887-1955) crystallizes
tobacco mosaic virus (TMV) and shows that it
remains infectious (Nobel Prize, 1946).
Stanley's work is the first step towards
describing the molecular structure of any virus
and helps to further illuminate the nature of
viruses.
Max Theiler (1899-1972)
Max Theiler was the first to propagate yellow
fever virus in chick embryos and successfully
produced an attenuated vaccine - the 17D
strain. Theiler's vaccine was so safe and
effective that it is still in use today!
This work saved millions of lives and set the
model for the production of many subsequent
vaccines. For this work, Theiler was awarded
the Nobel Prize in 1951.
The Year 1939
Emory Ellis (1906-) and Max Delbrück (1906-1981)
Established the concept of the "one step virus
growth cycle" essential to the understanding of
virus replication.
This work laid the basis for the understanding of
virus replication - that virus particles do not "grow"
but are instead assembled from preformed
components.
The Year 1941
George Hirst demonstrated that influenza virus agglutinates
red blood cells. This was the first rapid, quantitative method
of measuring eukaryotic viruses. Now viruses could be
counted!
The Year 1945
Salvador Luria
(1912-1991)
Salvador Luria (1912-1991)
and Alfred Hershey (19081997) demonstrated that
bacteriophages mutate. (Nobel
Prize, 1969)
This work proves that similar
genetic mechanisms operate in
viruses as in cellular organisms
and lays the basis for the
understanding of antigenic
variation in viruses.
Alfred
Hershey
(1908-1997)
The Year 1949
John Enders (18971985)
Thomas Weller (1915–)
Frederick Robbins
(1916–)
John Enders, Thomas Weller (1915–) and Frederick Robbins
(1916–) were able to grow poliovirus in vitro using human
tissue culture. (Nobel Prize, 1954) This development led to the
isolation of many new viruses in tissue culture.
The Year 1950
André Lwoff (1902-1994) Louis Siminovitch and Niels Kjeldgaard
discovered lysogenic bacteriophages in Bacillus megaterium
irradiated with ultra-violet light and coined the term prophage.
(Nobel Prize, 1965).
Although the concept of lysogeny had been around since the 1920s,
this work clarified the existence of temperate and virulent
bacteriophages and led to subsequent studies concerning the control
of gene expression in prokaryotes, resulting ultimately in the operon
hypothesis of Jacob and Monod.
Also in 1950, the World Health Organization proposed a
programme to eradicate smallpox from the Americas. This was
acheived in 8 years.
The Year 1952
Renato Dulbecco (1914-) showed that animal
viruses can form plaques in a similar way to
bacteriophages. (Nobel Prize, 1975) Dulbecco's
work allowed rapid quantitation of animal viruses
using assays which had only previously been
possible with bacteriophages.
Alfred Hershey (1908-1997) and Martha Chase
demonstrated that DNA was the genetic material of
a bacteriophage. Although the initial evidence for
DNA as the molecular basis of genetic inheritance
was discovered using a bacteriophage, this principle
of course applies to all cellular organisms (though
not all viruses!).
The Year 1957
Heinz Fraenkel-Conrat (1910-1999) and R.C. Williams showed
that when mixtures of purified tobacco mosaic virus (TMV)
RNA and coat protein were incubated together, virus particles
formed spontaneously.
Alick Isaacs and Jean Lindemann discovered
interferon. Although the initial hopes for interferons
as broad spectrum antiviral agents equivalent to
antibiotics have faded, interferons were the first
cytokines to be studied in detail.
The Year 1963
Baruch Blumberg discovers hepatitis B virus (HBV). (Nobel
Prize, 1976) Blumberg went on to develop the first vaccine
against the HBV, considered by some to be the first vaccine
against cancer because of the strong association of hepatitis B
with liver cancer.
The Year 1970
Howard Temin (1934-1994) and David Baltimore
independently discovered reverse transcriptase in retroviruses.
(Nobel Prize, 1975).
The discovery of reverse transcription established a pathway for
genetic information flow from RNA to DNA, refuting the socall "central dogma" of molecular biology.
Year 1973
Peter Doherty and Rolf Zinkernagl demonstrate the basis of
antigenic recognition by the cellular immune system. (Nobel
Prize, 1996) The demonstration that lymphocytes recognize
both virus antigens and major histocompatibility antigens in
order to kill virus-infected cells established the specificity of
the cellular immune system.
1978 Smallpox Eradication Program
 Only 10 years after the eradication
program began in 1977, the last
smallpox case occurred in Somali.
 No natural cases have occurred in
the past 25 years.
 Lab outbreak of Smallpox occurred
in Britain in 1978.
 Smallpox was declared eradicated
throughout world in 1980.
 Only remaining viral stocks are
stored at CDC in Atlanta GA & in
Novosibirsk, Russia. There are
proposals for their destruction.
 Major worry is bioterrorism.
Ali Marlin Last Natural Smallpox Case - October, 1997.
Year 1983
Luc Montaigner and Robert Gallo announced the discovery of
human immunodeficiency virus (HIV), the causative agent of
AIDS.
In only two years since the start of the AIDS epidemic the
agent responsible has been identified.
Year 2001
The complete nucleotide sequence of the human genome is
published.
About 11% of the human genome is composed of retroviruslike retrotransposons: "transposable elements in which
transposition involves a process of reverse transcription with
an RNA intermediate similar to that of a retrovirus".
Viruses
 Small size
 Filtrable agents
 Obligate intracellular parasites:
Can not make energy or proteins
independently of a host cell
Viral genome
 RNA or DNA
 Never both !!!!!!
 A naked capsid or +envelope
 Do not replicate by division=binary fusion
 Viral components are produced in the host
cell and assembled.
Consequences of viral properties
 Viruses are not living
 Viruses must be infectious to endure in
nature.
 Viruses must be able to use host cell
processes to produce their components
(viral messenger RNA, protein and identical
copies of the genome)
Consequences of viral properties
 Viruses must encode any required processes
not provided by the cell.
 Viral components must self-assemble.
Knowledge of
 the structural (size and morphology)
 Genetic (type and structure of nucleic acid)
Provides insight how the virus replicates,
spreads and causes disease.
Viruses
 Very small
 Nanometers (nm)
 Clinically important viruses
range from 18nm (parvoviruses)
to 300 nm (poxviruses)
Range from small and simple
(parvoviruses and
picornaviruses) to
Large and complex viruses
(pox viruses and herpesviruses)
Naming of viruses
 Structure: size, morphology and nucleic acid
(picornavirus (small RNA) togavirus (cloak)
 Members of its family : papovavirus
(papilloma, polyoma, vacuolating viruses)
 The disease they cause:smallpox(poxviruses)
Naming of viruses
 Tissue or organ tropism: adenovirus,
enterovirus, reovirus(respiratory,enteric,
orphan)
 Place of isolation: Norwalk, Coxsackie and
many toga,arena and bunyaviruses are
named after African places where they were
first isolated.
Means of classification
 Biochemical characteristics: structure and
mode of replication: current means
 Host cell (host range): animal (human,
mouse, bird), plant, bacteria
 Means of transmission: arboviruses by
insects
 Disease: ensephalites, hepatitis viruses
Viruses
 DNA viruses: 6 families
Poxviridae
 Herpesviridae
 Adenoviridae
 Hepadnaviridae
 Papovaviridae
 Parvoviridae
RNA viruses
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Paramyxoviridae
Orthomyxoviridae
Coronaviridae
Arenaviridae
Rhabdoviridae
Picornaviridae
Filoviridae
Togaviridae
Bunyaviridae
Flaviviridae
Retroviridae
Caliciviridae
Reoviridae
Delta
Naked viruses
 DNA or RNA +structural proteins=
Nucleocapsid
Enveloped viruses
Nucleocapsid+envelope
Virus capsid
 Helical (rod)
 İcosahedral (spherical)
DNA genome
 Double stranded
 Single stranded
 Linear
 Circular
DNA viruses
 Enveloped:
 Pox
 Herpes
 Hepadna
 Naked:
 Papova
 Adeno
 Parvo (ss)
DNA viruses
 Enveloped:
 Pox (ds-linear)
 Herpes (ds,linear)
 Hepadna(ds, circular, contains a single stranded
region!!!!!)
 Naked:
 Papova (ds, circular)
 Adeno (ds, linear)
 Parvo (ss,linear)
RNA viruses
 Mostly single stranded
 Reoviruses ds
 Segmented: orthomyxoviruses, reoviruses,
arenaviruses
Naked viruses
 Stable to environmental conditions.
 Temperature, acid, proteases, detergents,
drying
Naked viruses
 Can be spread easily(on fomites, from hand
to hand)
 Can dry out but retain infectivity
 Many of them are transmitted by fecal-oral
route
 Resistant to acid and bile of the enteric tract
Enveloped viruses
 Environmentally labile
 Must stay wet
 Spreades in large droplets, secretions,
respiratory droplets, organ transplants and
blood transfusion
Steps in viral replication (I)
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Recognition of the target cell
Attachment
Penetration
Uncoating
Macromolecular synthesis
Assembly of virus
Buddding of enveloped viruses
Release of virus
Steps in viral replication (II)
 Macromolecular synthesis:
-early mRNA and nonstructural protein
synthesis
-replication of the genome
-latemRNA and structural protein
synthesis
-posttranslational modification of protein
Viral attachment proteins
(VAP)
 Rhinovirus
VP1-VP2-VP3
complex
 Adenovirus
 Rotavirus
 Rabies
 Influenza A
 HIV
Fiber protein
VP7
G protein
Hemaglutinin
gp120
Viral attachment proteins
(VAP)
 Epstein-Barr virus
gp350 and
gp220
 Measles
HA
Viral receptors
 Epstein-Barr virus:
Target cell: B cell (C3d complement receptor)
 HIV:
Target cell: Helper T cell(CD4 molecule and
chemokine coreceptor)
 Rhinovirus:
Target cell: Epitelial cell (ICAM-1)
Viral receptors
 Rabies virus:
Target cell: Neuron(Acatylcoline receptor)
 Influenza A virus:
Target cell: Epitelial cells(sialic acid)
 B19 parvovirus:
Target cell: Erythroid precursors ( Erythrocyte
P antigen-globoside)
Host range
 Viruses may only bind to receptors only on
spesific cell types on certain species
Human, mouse
 Susceptible target cell defines the tissue
tropism
neurotropic, lymphotropic
Penetration
 Viropexis (receptor-mediated endocytosis):
naked viruses
 Fusion
enveloped viruses
Release
 Budding (enveloped)
 Lysis (naked)
Positive-strand RNA viral genomes
 Picornaviruses
 Caliciviruses
 Coronaviruses
 Flaviviruses
 Togaviruses
Positive-strand RNA viral genomes
 They act as mRNA
 Bind to ribosomes
 Direct protein synthesis
 Naked RNA is sufficient to initiate infection
Positive-strand RNA viral genomes
 The virus encoded RNA dependent RNA
polymerase is synthesized
 A negative-strand RNA template is
synthesized
 The template then used to generate more
mRNA’s and replicate the genome
The negative-strand RNA viruses
 Rhabdoviruses
 Orthomyxoviruses
 Paramyxoviruses
 Filoviruses
 Bunyaviruses
The negative-strand RNA viruses
 Not infectious by itself
 A polymerase is present in the virion
 A full length positive strand RNA is formed to
act as a template to generate more copies of
the genome