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Viral Pathogenesis
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Early association of viral diseases with
unique or distinctive signs/symptoms
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Poliomyelitis (paralysis)
Rabies (illness following bite by rabid dog)
Smallpox (characteristic fever/rash)
Early theories of “contagion”
Viral epidemics
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Clues point to a single transmissible agent
Evolution (“natural history”) of the infectious
process observed
Measles
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Measles infection was distinguished from
smallpox as early as the 9th century by an Arab
physician by the name of Abu Becr (or Rhazes of
Baghdad).
However, there is no record of repeated
epidemics identified as measles until the 11th and
12th centuries. Measles was first mentioned as a
childhood disease in 1224.
The Danish physician Peter Panum is generally
given credit for illuminating the basic principles
of measles infection and epidemiology during his
trip to the Faroe Islands in 1846 during a measles
epidemic.
Measles Epidemic
(P. L. Panum. (1847). Observations made during the epidemic of
measles on the faroe Islands in the year 1846. Bibliothek for Laeger,
Copenhagen, 3R, I: 270-344.
1846, Faroe Islands (North Atlantic)
 Population 7,900
 “Patient Zero”: from Copenhagen
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Arrived March 28,
developed measles early April
By October:
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6,000 cases of measles
170 deaths
Inferences from Clinical Observations
of the Measles Epidemic
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Transmission by direct person to person contact
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Consistent signs & symptoms
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Patient was contagious at onset of disease symptoms
Febrile rash associated with viral shedding
Differential mortality
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n
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Distinct agent involved for each transmissible disease
Interval btw exposure & disease ~ 2 weeks
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measles was caused by a specific agent
purely contagious, not miasmic-borne; isolation is best Rx
Variable host responses
to single infectious agent
Immunity
Disease does not appear
n
twice in the same person
 Long lived (65 years)
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Establishment of the Germ theory
(18th, 19th century)
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1850, Semmelweiss
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1857, Pasteur
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different fermentations associated with different microbial
agents
each infection caused by a specific agent
1867, Lister
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“child-bed fever” (streptococcal infections) in OB-GYN
ward spread by physicians due to failure to wash hands
between examining patients
Carbolic acid (antiseptic) can reduce post-operative
infections
1865, anthrax bacillus cultured
1877, anthrax experimentally transmitted
1881-1884, Koch postulates formulated
Henle-Koch Postulates
(1884)
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The incriminating agent can be cultured
from lesions of the disease
The agent can be grown in pure culture
The agent reproduces the disease when
introduced into an appropriate host
The agent can be recultured from the
disease host
Road to Virology
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“Contagium vivium fluidum”
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Beijerinck, 1898
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QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
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Proved that the mosiac disease of tobacco plants (now
known to be caused by TMV) can be transmitted by
extracts of infected leaves--"contagious living fluid”
Extracts were still infectious even after filtration through
procelain filters (which can sterilely remove all known
bacteria at the time)
No bacteria can be cultured from this fluid by known
bacterialogical techniques
Road to Virology
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“such a minute living being”
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Loeffler and Frosch, 1898, characterized transmissible
agent of foot-and-mouth disease
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Obtained infectious fluid from alcohol-sterilized vesicles
(free from contaminating skin bacteria)
Proved that causal agent was in filtered lymph of infected
animals, but was “unculturable” and microscopically
invisible
Serial dilutions indicate that causal agent was active in
greater than one part in 1017--must be replicating agent
Suggested that causal agents of smallpox, measles,
cowpox might also belong to the same class of
“minute living beings”
Road to Virology
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Yellow fever (first demonstration of a
transmissible viral disease in humans, 1900)
 Mosquito transmission
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Infected
Beddings
Mosquito
Screens
“Volunteer soldiers”
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Developed
Yellow Fever
Road to Virology
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Yellow fever (first demonstration of a
transmissible viral disease)
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Serum transmission
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“Volunteer soldiers”
Injected with serum from patients with acute yellow fever
Serum was filtered through bacteria-excluding filters
IRB Approval ??!! Not!!!
Viral Pathogenesis:
the early years 1900-1950
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No cell culture system, no titration method
1908, poliovirus passaged to monkeys by intracerebral
innoculation of spinal cord homegenate from acutely fatal
human case
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1910-1913
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Neuro-adapatation
Peyton Rous, tumors in chickens can be passed by cell-free,
bacteria-free (filtered) extracts
Chickens can be immunized against tumor transplantation and
“filterable” tumor producing agent
1949, cell culture methods developed for viral passaging
Viral Pathogenesis:
the classical era 1950-1975
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Three technological
advances
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Culture of primary and
continuous cell lines
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Detection of viral
replication by cytopathic
effects
Titration of viruses by the
plaque method
Cell Lines
HFB
NIH
3T3
HeLa
0 hr.
5 hr.
Cytopathic
Effects
Poliovirus
(rounding and
detachment)
8 hr.
24 hr. post-infection
Murine Leukemia Virus
(Syncytium formation)
--multinucleated “giant” cell
formation
Titration of viruses by the plaque method
--serial dilution of infectious innoculum onto
monolayer of cells,
--overlay with semi-solid medium
(e.g. agarose) to limit viral spreading to only
neighboring cells
Viral Pathogenesis:
the classical era 1950-1975
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Three technological advances
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Culture of primary and continuous cell lines
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Detection of viral replication by cytopathic effects
Titration of viruses by the plaque method
Immunofluorescence
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Identification of viral antigens in infected cells or
tissues
Viral Pathogenesis:
the classical era 1950-1975
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Three technological advances
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Culture of primary and continuous cell lines
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Immunofluorescence
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Detection of viral replication by cytopathic effects
Titration of viruses by the plaque method
Identification of viral antigens in infected cells or tissues
Measurement of immune responses to viruses
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Measurement of Antiviral antibodies
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neutralization
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End-point dilution assays
complement fixation
Hemagglutination
Immunoprecipitation/immunoblotting
Hemagglutination
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Viral Pathogenesis:
the modern era 1975-present
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Molecular Biology
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Cloning of Viral Genomes
Reverse Genetics
Viral Pathogenesis in the
21st Century
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Emerging Viruses
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Ebola
HTLV-1/HTLV-2
HIV-1, HIV-2
Hepatitis C Virus
Borna Disease Virus
Guantanto Virus
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Venezualan Haemorrhagic Fever
Hanta Virus (Sin Nombre)
Sabia Virus
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1977
1980,1982
1983,1986
1989
1990
1991
1993
1994
Brazilian Haemorrhagic Fever
Nipah Virus
(Smallpox?!)
1999
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Diversity of Viruses
How did viruses evolve? Why?
Transposable elements;
consequence of rapid gene evolution?
Themes of Viral Pathogenesis
“Nothing in biology makes sense except in the light of
evolution” ---Theodore Dobzhansky
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Pathogenic consequences of most viral
infections are due to the particular ways viruses
have evolved to solve three major problems:
 Reproduction: RNA vs DNA viruses
 Spread: Limits of pathogenicity
 Evasion: viral-host co-evolution
Pathology can be caused by host’s response to
the viral infection (“collateral damage”) rather
than to the direct virus infection itself
Mutualistic adaptation; co-evolution of viral
virulence and host resistance; achieve “balance”
with natural host
Biological control of wild rabbits:
co-evolution of viral virulence and host
resistance
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1859, 12 European rabbits were introduced into
an Australia farm; by 1928 more than a billion
rabbits (>500/sq.mile) were ruining agriculture
1950, rabbit myxoma virus (>99% mortality rate)
was introduced; by 1953, >95% of rabbit
population was eliminated, by 1955, rabbit
population began to increase.
Reasons:
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Virulence of rabbit myxoma virus decreased;
surviving rabbits developed increased resistance;
changes in vector activity (mosquitoes) decreased efficiency
of transmission
Viral Pathogenesis in the
21st Century
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Molecular Understanding Required
for
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Vaccine development
Virocides
Immunotherapy
Biodefense/National Security