Download Spring 2015-Chapter 10

Chapter 10
VIRUSES
Scientists Grow Human Muscle That Contracts Like The Real Thing In what's being hailed
as a medical first, researchers at Duke University announced this week that they had
bioengineered human skeletal muscle tissue capable of contracting like the real thing.
The scientists said the lab-grown tissue could become a powerful new tool for studying
diseases like muscular dystrophy. In addition, it could facilitate the development of
specialized drugs to treat these diseases--and eliminate the need to test the drugs on
humans, which can be risky.
“One of our goals is to use this method to provide personalized medicine to patients,” Dr.
Nenad Bursac, a professor of biomedical engineering at the university and one of the
researchers, said in a written statement. “We can take a biopsy from each patient, grow
many new muscles to use as test samples and experiment to see which drugs would work
best for each person.” Other scientists praised the research.
"This breakthrough allows one to rapidly screen a large number of drugs on normal and
diseased human muscle cells, facilitating development of therapies for neuromuscular
diseases," To create the lab-grown muscle, Bursac and his colleagues extracted muscle
"precursor" cells from human tissue and then multiplied the cells 1,000-fold in a dish full of
nutrients. Then they mixed the cells with a nourishing gel and placed them into a 3D mold,
which encouraged the cells to line up and fuse into muscle fibers.
The moment of truth came when researchers watched as they stimulated the fibers with
electrical impulses and a range of drugs, including cholesterol-lowering statins and the
performance-enhancing drug clenbuterol. Sure enough, the researchers said, the muscle
reacted to these stimuli just like native human tissue.
Next, the researchers hope to create artificial muscle tissue from stem cells taken from skin
or blood samples. That would eliminate the need to collect the cells via biopsy, which can be
tricky with patients suffering from certain diseases.
HIV cure 'likely lies in targeting dormant virus reserves‘ HIV inserts itself directly into the DNA
of our immune cells. AIDS develops when the virus hijacks cell machinery and replicates itself,
gradually weakening our immunity. Anti-HIV therapy interrupts the hijacking but does not
touch intact virus that remains dormant. Now, a new study shows how lurking pools of
dormant HIV may hold the secret to curing the disease. In the case of HIV, it inserts itself into
the DNA of a type of white blood cell called CD4 T lymphocytes. These cells are involved in
triggering immune responses. When HIV inserts itself into the DNA of CD4 T cells, one of two
things can happen. Either it becomes active and hijacks the cell to make copies of itself that
then invade and take over other cells (and this eventually kills the host cell); or it lies
dormant, the only sign of its presence being a tiny fragment of foreign DNA in the cell's
genome. As anti-HIV drugs only target the active infection - when the virus is taking over cell
machinery and making copies of itself - the dormant virus lies untouched and continues
lurking in the dormant pool, ready to wake up at any time.
First author Lillian Cohn, a graduate student in the Molecular Immunology Lab at the
Rockefeller University, says:
"If a patient stops taking antiretrovirals, the infection rebounds. It is truly amazing that the
virus can give rise to AIDS 20 years after the initial infection."Tests showed HIV in expanded
clones could not hijack cells and replicate Altogether, the team tested 75 viral sequences they
found in the expanded clones to see if they had the potential to go on to the hijacking stage
and produce more virus. None could, so they concluded it was highly unlikely that viable
dormant virus was lurking in cloned cells.
Meanwhile, in December 2014, Medical News Today learned of a study that found as HIV
evolves to become resistant to the host's natural immunity, this adaptation may also slow its
ability to cause AIDS.
What are Viruses?
• Obligate intracellular parasites
• Viral components
– Nucleic acids
– Capsid
– Envelope
Flu Attack How A Virus Invades Your Body
http://www.youtube.com/watch?v=Rpj0emEGShQ&feature=related
Components of Viruses
What are Viruses?
• Obligate intracellular parasites
Enveloped icosahedral virus
• Viral components
– Nucleic acids
– Capsid
– Envelope
H and N of influenza, (such as, H5N1)
Fig. 10.1 The components of an animal virus (a herpesvirus)
Virus Classification
• 108 families so far
– Pathogens for all life forms
• Classification based upon
–
–
–
–
–
Nucleic acid type
Single strand vs. double strand chromosome
+ versus – single strand
Enveloped versus “naked“
RNA genomes occur only in viruses
Envelopes-enveloped viruses have a typical bilayer membrane outside of their capsids. The
proteins of the membrane are typically derived from viral genes information whereas, the lipid is
synthesized by the cellular machinery (i.e., there are no viral genes that code for the lipid moiety
of the viral envelope). Envelopes often have glycoprotein projections termed spikes that
are very important for attachment of the virus to a host cell receptor.
Enveloped viruses are relatively sensitive to environmental insults such as drying, pH, freezing
and thawing and many types of disinfectant , and are easily damaged whereas, non-enveloped
viruses or naked viruses are often quite resistant to these insults. Hence, enveloped viruses are
rarely spread via fomite (inanimate object)
Fortunately HIV is an enveloped virus-Fortunate because that assures that it cannot survive
very well outside the body.
http://www.youtube.com/watch?v=NKoZfHLQu5M
Herpes simplex virus envelopment and release
http://www.youtube.com/watch?v=bgj1YpevA6A&feature=related
Host range and specificity of viruses.-The host range of
a virus refers to the spectrum of hosts that a virus can infect. Most
viruses are limited to only one host and to only specific cells and/or
tissues of that host. –(e.g., Polio)- exceptions, e.g, rabiesvirus
Viral specificity is determined mainly by whether or not
a virus can attach to a cell. Attachment depends on the presence of
specific receptor sites on the surfaces of host cells and on specific
attachment structures on viral capsids (polio) or envelopes (H1N1;
HIV)-flu, immunodefeciency virus.
Specificity also depends on whether the host can supply the
appropriate enzymes and other proteins the virus needs to replicate
Additionally, virus specificity, refers to the specific kinds
of cells a virus can infect, e.g, papillomaviruses, which cause warts, can
only infect skin cells. Hepatoma virus, rabies virus, liver and nerve cells
respectively. In contrast, cytomegalovirus (CMV) can cross placenta
salivary glands, GI tract, liver, lungs and other organisms. CMV is an
important virus that attacks the fetus.
Classification of Viruses.
Currently the International Committee on Taxonomy of Viruses
(ICTV) requires that the English common name, rather than a Latinized
binomial term, be used to designate a viral species. For example, for
rabies virus and HIV would be: family:
rabies virus= Family: Rhabdoviridae; genus: Lyssavirus ;
species: rabies virus
HIV=Family: Retroviridae, genus: Lentivirus; species: human
immunodeficiency virus (HIV).
Scientists seek to weaponize new family of bacteria to fight malaria By genetically
modifying bacteria that they found to be uniquely associated with disease-carrying
mosquitoes, scientists hope to create a new weapon to prevent transmission of
malaria. The team isolated the bacterial strains from larvae of the mosquito Anopheles
arabiensis, one of the most important spreaders of malaria in sub-Saharan Africa and
surrounding areas. Thorsellia bacteria seem to be uniquely associated with diseasecarrying mosquitoes
When we discovered the first species of Thorsellia in a Kenyan malaria mosquito and
decided to name the unique bacterium after Thorsell, we did not know that it would
prove to be so common in mosquitoes."
Since first discovering Thorsellia bacteria in Kenyan malaria mosquitoes, the scientists
have also isolated strains from mosquitoes spreading malaria in Africa, Brazil, India
and Iran, and in mosquitoes spreading West Nile virus in the US.
It is unusual to find a new family of bacteria in this part of the family tree - it has only
happened once before in the last 50 years. "We are looking for bacteria that live in
the mosquito gut and which grow quickly when the mosquito has taken a blood
meal. The idea is to genetically modify these bacteria to produce substances that
stop malaria parasite development."
Scientists seek to weaponize new family of bacteria to fight malaria By genetically
modifying bacteria that they found to be uniquely associated with disease-carrying
mosquitoes, scientists hope to create a new weapon to prevent transmission of
malaria. The team isolated the bacterial strains from larvae of the mosquito Anopheles
arabiensis, one of the most important spreaders of malaria in sub-Saharan Africa and
surrounding areas. Thorsellia bacteria seem to be uniquely associated with diseasecarrying mosquitoes
When we discovered the first species of Thorsellia in a Kenyan malaria mosquito and
decided to name the unique bacterium after Thorsell, we did not know that it would
prove to be so common in mosquitoes."
Since first discovering Thorsellia bacteria in Kenyan malaria mosquitoes, the scientists
have also isolated strains from mosquitoes spreading malaria in Africa, Brazil, India
and Iran, and in mosquitoes spreading West Nile virus in the US.
It is unusual to find a new family of bacteria in this part of the family tree - it has only
happened once before in the last 50 years. "We are looking for bacteria that live in
the mosquito gut and which grow quickly when the mosquito has taken a blood
meal. The idea is to genetically modify these bacteria to produce substances that
stop malaria parasite development."
Emerging Viruses
Emerging Viruses- viruses that were previously endemic (low levels of infection in
localized areas) or had “crossed species barriers”.
1. Polio virus- stable + stranded RNA virus-endemic with isolated cases.
Growth of cities, crowding, pressure on the sanitary systems became a major health
problem until vaccines were discovered. The outbreaks in the US were largely due to
the superb sanitation system we developed.
2. HIV- likely came from crossover of SIV (simian immunodeficiency virus).
3. Hanta virus. Emerging problem in the southwest USA.
?----rodents---increased rodent population---feces--infection of humans
4. SARS (severe acute respiratory syndrome)- Coronavirus-that can cause
severe upper respiratory disease and has a mortality rate of about 10%
5. Bird flu. H5N1- currently a major potential health problem
6. West Nile virus- It mainly infects birds, but is known to infect humans,
horses, dogs, cats, bats, chipmunks, skunks, squirrels, and domestic rabbits. The
main route of human infection is through the bite of an infected mosquito.
7. Might add Ebolavirus
Based on recent history it is quite likely that the next emerging disease will be a
virus.
Let us examine the strategy of replication of
RNA viruses
Strategy of positive
stranded RNA virus
replication- both retrovirus
and non-retrovirus
Fig. 10.13 Replication of RNA viruses
What is the strategy of a negative single stranded virus?
negative
How a negative stranded virus (rhabdovirus) replicates
Viral Replication
General characteristics of replication
1. Adsorption
2. Penetration
3. Synthesis
4. Maturation
5. Release
Replication of bacteriophages
d’Herelle and Twort given credit for identifying and naming
bacteriophage (eaters of bacteria)
Properties of bacteriophages
1. Either double-stranded or single-stranded RNA or DNA
2. Can be relatively simple or complex in structure
3. Can be used in antibacterial therapy because they are quite
specific and can work against antibiotic resistant bacteria. Phage
resistance can readily be overcome by selection. Russians routinely use
phage therapy with very good results.
Bacteriophage Therapy – from Biotech Journal
Bacteriophage therapy has many advantages over antibiotics. Bacteriophages are highly specific, where as
antibiotics kill all bacteria without specificity, beneficial bacteria (e.g. in the intestinal tract) that perform
crucial functions for the human body are also affected by antibiotics and harmful pathogens can then grow
more easily. Secondary infections like the Pseudomonas species or Clostridium dificile develop in this way
and cause severe diarrhea and colon infections. Bacteriophages can specifically target the harmful bacterium,
eliminate it, and leave the beneficial bacteria intact. Bacteriophages cannot cause disease to humans,
animals, or plants; they can only cause harm to bacteria. Furthermore, for almost all known bacterial species
there exists one or more bacteriophages specific to that species. The bacteriophage therapy is currently being
used to treat post-burn bacterial infections, which are a major problem for those recovering from the trauma
of third-degree burns. Within 24 hours, burn patients can start suffering from opportunistic bacterial attacks.
As an alternative to treating post-burn bacterial infections by antibiotics, bacteriophages have been in use in
certain parts of the world, such as at Tbilisi in Georgia and in Poland, and this approach has now been more
widely recognized. Results have shown that bacteriophage therapy has an 80% success rate against
Enterococcus infections and up to 90% against Staphylococcus aureus, Pseudomonas aeruginosa,
Escherichia coli and Klebsiella pneumoniae. Pseudomonas aeruginosa is the most common post-burn
infection, and it is known to be notoriously resistant to a variety of antibiotics. For the most effective
treatment of post-burn infections, a cocktail of bacteriophages is sprayed at the site of burns, this will
reduce the chance of the bacteria developing resistance against the different bacteriophages.
Bacteriophage solutions or aerosols can also be used to treat the surfaces and instruments in operating
rooms as well as the skin of the surgical patient (prior to surgery).
The above use not withstanding problems exist with the use of phage:
1. resistance
2. immunological response
Fig. 10.8 Escherichia coli attacked by bacteriophage
capsid with nucleic acid inside
Tail sheath
ATP-mediated
contraction
Fig. 10.10 Bacteriophages
Start
http://www.youtube.com/watch?v=OxvqhneAX40
&feature=related
Fig. 10.11 Replication of a virulent bacteriophage
Bacteria exchange food via nanotubes A new study shows that some bacteria can form
nanotubes between single cells that allow the cells to exchange essential nutrients or
metabolites with each other. Now, writing in the journal Nature Communications, a team of
scientists from several German research centers - including the Max Planck Institute for
Chemical Ecology in Jena - reveals that bacteria exchange nutrients directly with each other
through nanotubes strung between single cells. Their study investigates two species of bacteria:
the gut microbe Escherichia coli, and the soil bacterium Acinetobacter baylyi. The scientists
found that when cultured together, the bacteria were able to cross-feed each other - supplying
to the other the amino acids that the other could not produce for itself. Then, they grew the
two species of bacteria very close together but separated them with a filter so amino acids
could not pass between them via the culture medium and there was no direct contact
between the cells of the two species. In the second experiment, the bacteria died. The team
concludes it showed that direct contact between cells is necessary for nutrient exchange and for
both strains to thrive. When they looked at the culture containing the two species mixed
together under an electron microscope, the researchers saw tiny filamentous nanotubes
connecting individual cells. These were enabling the cells to exchange metabolites with each
other. When the missing amino acid was introduced to the culture, the bacteria did not form
nanotubes, suggesting that they only do so when they are "hungry" for the required nutrient,
explains Kost.
FOLLOWING SLIDE SHOWS THE NANOTUBES IN E. COLI
Replication of a virulent DNA bacteriophage
1. Adsorption- specific proteins in the phage tail
fibers bind to specific receptor sites on the host cells. The fibers bend and
allow the pins to touch the cell surface.
2. Penetration- The enzyme lysozyme (characterized
by Sir Alexander Fleming), weakens the bacterial cell wall. And allows the
viral DNA to be “injected” into the cytoplasms (either directly or into the
periplasmic space and then into the cytoplasm).
3. Synthesis- once the phage DNA enters the cell the
phage genes take control of the host cell’s metabolic machinery. Phage
DNA is transcribed to mRNA, using the host cell’s machinery. The mRNA
translated on host ribosomes, then directs the synthesis of capsid proteins and
viral enzymes such as DNA polymerase that replicates the phage DNA.
4. Maturation - the parts of the phage are put together
in a certain order but essentially it is a rapid process of assembly
5. Release- the enzyme lysozyme, which is coded for
by a phage gene, breaks down the cell wall allowing viruses to escape. In the
process
The time from adsorption to release is called the burst time; it
varies from 20 to 40 minutes depending on the phage. The
number of new virions released from each bacterial host
represents the viral yield, or burst size.
Phage growth and the estimation of phage numbers
The eclipse period represents the time after penetration through the biosynthesis of mature phages. The latent period
represents the time after penetration through the release of mature phages. The number of viruses per infected cell is the viral
yield or burst size.
Fig. 10.12 Growth curve for a bacteriophage
The number of bacteriophages in a sample is
assayed by spreading the sample out over a lawn
of solid bacterial growth. When the phages
replicate and destroy the bacterial cells, they leave
a clear spot, called a plaque, in the lawn. The
number of plaques corresponds roughly to the
number of phages that were initially present in the
sample.
Fig. 10.13 Plaque assay
http://www.youtube.com/watch?v=_J9-xKitsd0&NR=1
lysogeny is very important for toxin production since in many instances the phage carries the toxin gene
Fig. 10.15 Replication of a temperate bacteriophage
Replication of a temperate (lysogenic) bacteriophage
Insertion of a lambda phage into a bacterium alters the
genetic characteristics of the bacterium.
Two genes present in the prophage produce proteins
that repress virus replication.
The prophage also contains another gene that provides
“immunity to infection by another phage. This process called
lysogenic conversion, prevents the adsorption or biosynthesis of
phages of the types whose DNA is already carried by the lysogen
and
Lysogenic conversion can be of medical significance
because the toxic effects of some bacterial infections are caused
by the prophages they contain, e.g., Corynebacterium
diphtheriae and Clostridium botulinum which contain prophage
that code for their respective toxins.
Replication of Animal Viruses
DNA Animal Viruses
Stages of animal virus infection with a DNA virus
Adsorption
penetration
Synthesis
Maturation
Release
• Chromosome
replication in host cell
nucleus
• Cytoplasmic
ribosomes for viral
mRNA translation
• Viral proteins must
return to nucleus for
maturation phase
• Early vs. late
transcription
How do viruses avoid
digestion by lysosomes?
•
Use RNAdependent
RNA
polymerase
•
Cytoplasmic
chromosomal
replication and
protein
synthesis
•
+ strands
always needed
for mRNA
Synthesis. In
picronavirus the (+)
strand acts as
mRNA.
HIV budding from T-4 lymphocyte
Fig. 10.17a Replication of RNA viruses-Polio
•
Use RNAdependent
DNA
polymerase
(Reverse
transcriptase)
•
+ strand
chromosome
acts as
template for ds
DNA provirus
•
Later
transcription
of provirus
allows for
virus
production
Synthesis. In the
retroviruses, such as HIV,
the two copies of (P) sense
RNA do not act as mRNA
but rather they are
transcribed into ssDNA
with the help of reverse
transcriptase.
HIV budding from T-4
lymphocyte
Fig. 10.17b Replication of RNA viruses-HIV
Adsorption
Figure 10.16 Viral recognition of an
animal host cell
a) Rhinoviruses have “canyons,: or
depressions in the capsid that attach to specific membrane
proteins on the host cell membrane
b) HIV has specific envelope spikes (viral
glycoproteins) that attach to a membrane protein receptor
on the surface of specific host immune defense cells.
http://student.ccbcmd.edu/courses/bio141/lecguide/unit3/viruses/adsorp_ev_fl.html
Rhinovirus (non-envelope)
type attachment
HIV (envelope) type attachment
Fig. 10.18 Viral recognition of an animal host cell
From a practical standpoint 100
different cold viruses suggests 100
different serotypes which in turn
suggest 100 different capsid
proteins.
Structure of the
human rhinovirus capsid is seen in this image released to Reuters on February 12, 2009.
Researchers who mapped the DNA of more than 100 different cold viruses have discovered one
explanation for why they can inflict misery so quickly, and believe they may find ways to design drugs to fight them. A
key finding is that rhinoviruses can swap genetic material. That means two cold strains infecting the same
person may recombine to form a new strain with new properties, complicating the quest for a medicine or
vaccine that would remain effective. The U.S. cost of hospitalizations, doctors visits, loss of work
productivity, skipped school days and over-the- counter "remedies" is estimated at $60 billion.
New HIV drug growing problem of resistance to older HIV drugs.
FDA approved A new type of HIV drug, designed for people who are resistant to other
treatments, has been approved by the US authorities.
Roche, the makers of Fuzeon are confident it will also win European approval within weeks.
Fuzeon is the first of a new class of drugs known as fusion inhibitors.
It is designed to combat the growing problem of resistance to older HIV drugs. Unlike
existing drugs that work inside the cell, Fuzeon blocks HIV from entering healthy human
immune cells. "It highlights that whilst there is still no cure for HIV, medical and scientific
research is still offering longer and healthier lives for those fortunate enough to have access
to them.
Maturation- The cellular site of maturation (or
assembly) of viruses depends on the virus type.
Human adenovirus nucleocapsids are assembled in
the cell nucleus,
Whereas viruses such as HIV are assembled at the
inner surface of the host’s cell plasma membrane as are
many of the enveloped RNA viruses.
Other enveloped viruses bud through host nuclear
(herpes simplex) endoplasmic reticulum, golgi or plasma
membrane.
envelope
nucleocapsid
http://www.youtube.com/watch?v=bgj1YpevA6A
Budding
Release- The budding of new virions through a membrane may or may not kill the host cell.
Many viruses kill host cells (such as, polioviruses, rabies, measles, chickenpox, HIV)
Other viruses do not (most retroviruses, except HIV, do not kill the infected cells,
adenoviruses do not kill the host cell).
Death Toll From C. Difficile Is Raised The deadly bacterial
infection Clostridium difficile is estimated to have
afflicted almost half a million Americans and caused
29,000 deaths in 2011, according to a study by the
Centers for Disease Control and Prevention published
Wednesday in The New England Journal of Medicine. The
estimate is drawn from laboratory testing and reporting
in 10 states and is larger than previous figures based on
narrower data sources. C. difficile causes severe diarrhea
and colon damage and is linked to overuse of antibiotics.
The study estimated that 24 percent of cases occurred in
hospitals and 40 percent began in nursing homes or
community health care settings.
CDC innvestigates deadly bacteria’s link to doctors’ offices The Centers for Disease
Control is raising a red flag that a potentially deadly bacteria may be lurking in your
doctor's office. The bacteria, C. difficile, is typically found in hospitals, but a study out
Wednesday reports a substantial number of people contracted the bug who hadn't
been in a hospital, but had recently visited the doctor or dentist. The bacteria can
cause deadly diarrhea, according to the CDC, with infections on the rise. The new
report shows nearly half a million Americans infected in various locations in one year,
with 15,000 deaths directly attributed to C. diff. In a 2013 study, researchers found C.
diff present in six out of seven outpatient clinics tested in Ohio, including on
patients' chairs and examining tables. The CDC is so concerned that they're starting a
new study to try to assess nationally whether people are getting C. diff in doctors'
offices. In the meantime, patients should wash their hands after visiting the doctor's
office -- with soap and water, because alcohol-based gels don't get rid of C.diff. The
CDC study, published Wednesday in The New England Journal of Medicine, said
150,000 people who had not been in the hospital came down with C. diff in 2011. Of
those, 82% had visited a doctor's or dentist's office in the 12 weeks before their
diagnosis. The CDC is hoping its new study will help determine cause and effect,
because it's possible the patients had C. diff to begin with and went to the doctor to
get help. It's also possible that antibiotics prescribed during the doctor's visit, and not
microbes at the doctor's office, caused the infection.
Latent Viral Infections
i) cold sores or fever blisters due to herpes simplex
virus
ii) chicken pox/zoster
Lysogenic phage was an early model for latency
Viruses and Teratogenesis
Teratogenesis is the induction of defects during embryonic
development.
A teratogen is a drug or other agent that induces such defects.
Certain viruses are known to act as teratogens and can be transmitted
across the placenta and infect the fetus. The earlier in pregnancy the embryo is
infected, the more extensive the damage is likely to be.
Three human virusescytomegalovirus (CMV),
herpes simplex virus (HSV) types 1 and 2 and
rubella- account for a large number of teratogenic effects.
CMV infections are found in about 1% of live births(approximatly 4
million babies are born in the US each year); of those, about 1 in 10 eventually
die from the CMV infection with most defects being neurological in nature.
HSV infections are usually acquired at or shortly after birth.
Rubella virus infections in the mother during the first 4 months of
pregnancy are most likely to result in fetal defects referred to as rubella
syndrome and include: deafness, damage to there sense organs, heart and other
circulatory defects, and mental retardation.
Viruslike Agents: Viroids.
1. Each viroids consists of a single circular RNA molecule of low
molecular weight
2. Viroids exist inside cells as particles of RNA without capsids or
envelopes
3. Viroid RNA does not produce proteins
4. RNA is always copied in the cell nucleus
5. Viroid particles are not apparent in infected tissues without the use
of special techniques to identify nucleotide sequences.
Viroids are plant pathogens that consist of a short stretch (a few hundred nucleobases) of highly
complementary, circular, single-stranded RNA without the protein coat that is typical for viruses.
Viroids are usually transmitted by seed or pollen. Infected plants can show distorted growth. The
first viroid to be identified was the Potato spindle tuber viroid (PSTVd). Some 33 species have
been identified.
Prions- cause slow but progressive dementing illness in
humans[
Creutzfeldt-Jakob disease (human form of mad cow
disease)
Kuru (Blumberg and Gajdusek-Nobel Prize)
scrapie in sheep
bovine spongiform encepholophaty (BSE) also
known as Mad Cow disease
Stanley Prusiner proposed that the infectious agent
of prion diseases is a small proteinaceous infectious particle which
he termed a prion. In 1997 he received a Nobel Prize for his efforts.
The U.S. healthcare system: worst in the developed world
Prions have the following characteristics:
1. Resistant to inactivation by heating to
90C which will inactivate essentially all known viruses
2. Infection not sensitive to irradiation
3. Not destroyed by enzymes that digest
DNA or RNA
4. Sensitive to protein denaturing agents
Helix and b-sheet
Helical structure
harmless form
harmful form
Antibodies can recognize the difference between harmless and harmful form as well
as between random CJD prion and mad cow prion.
Figure 10.24 Protein structure model of the two forms of the prion protein (PRP
Viruses and Cancer
Cancer is an uncontrolled, invasive growth of abnormal cells. Local
accumulation of cells is known as a tumor and a neoplasm can be benign
(wart-papillomavirus) or malignant when the cells invade and interfere
with the functioning of surrounding normal tissues. Malignant tumors and
their cells can metastasize, or spread, to other tissues in the body. F. Peyton
Rous discovered that a virus could cause sarcomas (connective tissue cancers)
cancer in animals. The virus was name the Rous Sarcoma virus (RSV).
Human cancer viruses
Epstein-Barr virus (EBV) also called human herpesvirus 4
(HHV-4), is best known as the cause of infectious mononucleosis but is also
a predisposing factor for Burkitts lymphoma a malignant tumor that
causes swelling and eventual destruction of the jaw.
Several human papillomaviruses have been shown to have a strong
correlation with some human cancers (genital warts in particular). A
vaccine against papillomavirus (Gardasil) is currently in use.
Genital Herpes simplex virus has also been positively correlated with
cervical cancer- although this result is somewhat controversial.
How Cancer Viruses Cause Cancer
In the case of DNA tumor viruses, which can exist as
proviruses, the major cytopathic effect CPE is the uncontrollable
division of the infected cells know as neoplastic transformation.
Example: SV40 virus T antigen. SV40 is believed to suppress the
transcriptional properties of the tumor-suppressing p53 in humans through the
SV40 Large T antigen and SV40 small T antigen.
p53 is responsible for initiating regulated cell death (“apoptosis"), or cell cycle
arrest when a cell is damaged. A mutated p53 gene may contribute to
uncontrolled cellular proliferation, leading to a tumor.
Many of the RNA tumor viruses, which are almost all
retroviruses, contain shortened versions of cellular growth genes.
The ability of these RNA tumor viruses to replicate is dependent
upon cellular proliferation. Hence, tumor production.
This slide shows the way a
normal cell sends a growth
signal. The arrows point to
genes shown to be carried by
some tumor viruses. They are
termed "protooncogenes".
The viral"oncogenes"
(oncogne=cancer causing) are
shortened versions of the
protooncogenes and they lack
"on/off" (typically associated
with phosphorylation/
dephosphorylation control
and therefore cannot be
turned off.
I do not expect you to learn this
slide only understand the point that
viral oncogenes are often
unregulated normal cellular
proliferation genes (i.e.,
protooncogenes).
Human cancer is thought to often be mediated by a
double mutation (in a single cell)- 1, a growth promoting
gene like src and 2, a cell cycle regulatory gene like p53.
This particular tumor is
caused by a papillomavirus
(DNA tumor virus).
Integration of the provirus
causes synthesis of viral
replication proteins that
promote host cell divisions,
leading to cancer.
In the 1980s, this winner of the Nobel Prize for Medicine, Harald zur Hausen, and his co-workers discovered that
specific types of human papillomaviruses (HPV) cause cervical cancer. Shortly after, scientists were able to elucidate
how these pathogens cause cell transformation and promote cancer. The main culprits, as is known today, are the two
viral oncogenes, E6 and E7, which switch off two key cancer brakes in infected mucosal cells. Oncogene E6 prevents
cells from undergoing programmed cell death, or apoptosis, while E7 blocks a protective mechanism of cells which
normally inhibits replication of the genetic material and, thus, slows down cell growth-cell cycle inhibitor.
Fig. 10.22 Malignant tumor formation