-
most common type of hepatitis
second most common?
A
then B
-
Hepatitis found in pregnant women found in water and rare
Hepatitis E - abortion
-
Hepatitis mostly in aids patients
Hepatitis G
-
Hepatitis A,C,G,E genome?
+ssRNA
-
Hepatitis D genome
Hepatitis B genome
torque teno
sentinel virus
-ssRNA
DNA (partial ds)
ssDNA
ssDNA (circular)
-
Enveloped hepatitis
B,C,D,G
-
Hepatitis A symptoms - what are the other 3 symptoms?
– Fatigue
– Abdominal pain
– Nausea and vomiting
- – Dark urine
- – Jaundice (occurs in 70–80% of individuals older than 14 years of age, less likely to occur in children)
- – Loss of appetite
-
Hepatitis B
Endemic areas: Major model of spread is mother (carrier) to infant
what are the other 3 high risk groups for hepatitis B aside from these 2
– Individuals with multiple sexual partners
– Institutionalized patients
- – IV drug users
- – Hemodialysis patients
- – Healthcare workers
-
Average incubation period for hepatitis A, B, C, and and E
A- 30 days
B- 80 days
C- 6-7 weeks
E- 40 days
-
Hepatitis B ____ % of individuals have no signs or symptoms
30%
-
Chronic HBV infections occur in ____ of cases
5–10%
-
Death from chronic liver disease results in
______% of individuals
15–25%
-
_____% of U.S. population is infected with HCV
1.8%
-
Hepatitis C virus
Between _____ and ____ of infected persons
experience a chronic infection, resulting in
chronic liver disease
55% and 85%
-
– ____% of IV drug addicts test positive for HDV
39–90%
-
hepatitis E virus
_____ % mortality in general population
_____ % mortality in pregnant women
1–3%
15–25%
-
Torque Teno Virus
– Found in 1997 using _______
representational difference analysis
-
Lab Diagnosis of viral hepatitis infections based on:
– Symptoms and physical findings
– Elevated antibodies against a virus (serology testing,
ELISA)
and TWO more...
– Blood tests for elevated liver enzymes (AST and ALT)
– Detection of viral proteins or genomes (nucleic acid tests)—require specialized laboratories
-
– Alanine Aminotransferase
– Your body uses ALT to break down
food into energy. Normally, ALT
levels in the blood are low. If your
liver is damaged, it will release more
ALT into your blood and levels will
rise. (ALT used to be called serum
glutamic-pyruvic transaminase, or
SGPT).
- – Alanine Aminotransferase
- – Your body uses ALT to break down
- food into energy. Normally, ALT
- levels in the blood are low. If your
- liver is damaged, it will release more
- ALT into your blood and levels will
- rise. (ALT used to be called serum
- glutamic-pyruvic transaminase, or
- SGPT).
-
• Hepatitis A–E virus structure
– _____ shape and _____ symmetry
– ____ nm in diameter
– Enveloped (B, C, D) or nonenveloped (A or E)
– HAV is _____ and bile resistant
Spherical , icosahedral
28–50 nm
acid
-
HAV
• Very stable, naked ______
picornavirus
-
1963: Antibodies in the serum of a New York
hemophiliac reacted with an antigen present in the blood of an Australian aborigine infected with hepatitis
• Australia antigen was the _______
• Further experiments by _____ led to the
discovery of the _____ (complete infectious HBV)
hepatitis B surface antigen (HBsAg)
David Dane
Dane particle
-
• Three types of HBV particles present during
infection:
1. Spherical 17–25 nm particle: Most abundant HBV particle in carriers
2. Noninfectious filamentous particles: Up to ______ nm in length; less numerous
3. Infectious Dane particle: 42 nm diameter; contains _____, ______, and _____ associated with viral genome
200 nm
viral DNA polymerase (DT)
protein kinase C
heat shock 90 protein
-
HBV genome
– HBV is a hepadnavirus
- (blank 1)
– Full length strand is 3.2 kb
– Shorter stand is 1.7 kb in length
- (blank 2)
– Circular partially dsDNA
– Uses a replication strategy common to retroviruses
-
Hepatitis C virus
• Icosahedron-shaped, enveloped, +ssRNA flavivirus
• Little known about HCV ultrastructure
( blank)
• Similar to picornaviruses (poliovirus), except HCV
particles are enveloped
• Viral nucleic acid cloned in 1989
• Only flavivirus not transmitted by arthropod vectors
-
HVC genome
– _____ kb in length
– Contains______ and one long ORF that encodes polyprotein precursor
– Translated to host ribosomes by ______ translation
9.2
internal ribosome entry site (IRES)
cap-independent translation
-
Hepatitis E virus
• ______ transmission
• HEV structure
– _____ genome
– Clinically indistinguishable from HAV, but HEV particles much _____ stable
– Viruses 32–34 nm in diameter, (enveloped or non-enveloped?), and
icosahedral shaped
• HEV genome
– Approx 7.2 kb in length
– Short 5′ and 3′ noncoding regions
– 3′ end contains a poly(A) tail
– (how many?) ORFs
• Overall knowledge of HEV replication is poor
Fecal–oral
+ssRNA
less
nonenveloped
3
-
Many variants of HBV and HCV because _______
how many major genotypes of HEV ?
One ______ of HAV, but at least 7 different
_______
– Viral polymerases lack proofreading ability
4
serotype
genotypes
-
Hepatitis A virus
– Management
• _________
• _________
– Prevention
• Handwashing and proper sanitary disposal of human feces
• __________
– Vaccines: Formalin-inactivated, cell
culture−produced, whole virus
No specific treatment
Supportive care
Passive immunity via immunoglobulin injection
-
6 licensed drugs: Interferon α-2b, lamivudine,
adefovir, dipivoxil, entecavir, telbivudine, and
tenofovir
Drugs to manage hepatitis B virus
- – Prevention
- • Antibodies effective if used shortly after
- exposure
- • Immunoglobulin used as an adjunct to vaccine
-
What type of vaccine is a hepatitis B vaccine?
Recombinant DNA vaccine in yeast
-
Hepatitis C
– Management
• _____% of infections progress to chronic liver disease
• Pegylated interferon α-2a or pegylated interferon α-2b and/or _______
• Close monitoring of ______ treatment
necessary due to adverse reactions
• _____% of patients cannot tolerate side effects, such as _______
85%
ribavirin
interferon/ribavirin
50%
anemia
-
Greek scholars coined the term herpes, which
means to ______ in reference to the
spreading of herpetic lesions
“creep or crawl”
-
Herpes simplex 1
______ of the eye (leading cause of
corneal blindness in the U.S.)
_______ (“mat herpes”
transmitted during wrestling)
_______ (seen in contact sports
like rugby) hands and wrists
Herpes keratitis
– Herpes gladitorium
– Herpes rubeiorum
-
Herpes simplex 1
Reactivation associated with the following:
(blank 0)
– Sexual contact
(blank 1)
– Temperature changes (hot or cold)
– Excessive UV light exposure
(blank 2)
– Pregnancy
(blank 3)
(blank 4)
– Excessive fatigue
- – Immune suppression by cytotoxic drugs
- – Physical and emotional stress
- – Menstruation
- – Lactation
- – Malnutrition
-
Only herpesvirus that spreads through airborne mode
of transmission (coughing or sneezing)
chicken pox
-
Other symptoms: chicken pox
– Fever
– Malaise
– Average of ______ lesions on the body during an attack
– Blisters dry and form scabs in 4–5 days
• Adult complications:
– (blank)
– Bacterial infection of the skin
– (blank)
• CDC recommends that children be vaccinated with
the _______ or Varivax vaccines at _____ months or
before their ______ birthday
300–400
Pneumonia
Encephalitis (swelling of the brain)
MMRV measles mumps rubella varicella
12–18 months
13th
-
Shingles or Herpes Zoster
• After a primary VZV
infection (chickenpox), the
virus remains latent in the
dorsal root ganglia
(neurons of the nerve roots)
• The virus is ___________
• Risk of reactivation
increases with age
• Onset of shingles is more
common and severe in
immunocompromised
patients
most commonly reactivated later in life after the age of 60
-
Symptoms of Shingles
- Severe pain
- headache
(blank)
- Itching
(blank)
– Rash follows a nerve on one side of the body
– In a healthy individual, disease lasts _____ days
– Postherpetic neuralgia occurs in 1/5 with zoster and is characterized by severe pain that can continue long after the rash clears up
– Disease lasts ______ weeks in an immunocompromised patient
- - numbness
- - Followed by a vesicular rash that forms in a 3- to 5- day period
-
CMV Transmission
• Via close, intimate contact with a person
who is excreting virus in:
– ______
– ______
– Other bodily fluids
• It can be transmitted:
– Sexually
_________
– Transplanted organs
________
- – Through breast milk
- – Blood transfusions
-
CMV is the Most Important Cause
of Congenital Infections
• 1–3% of women infected during pregnancy
in the U.S.
• Developing, unborn babies (neonates) are
at highest risk for developing
complications of CMV infection
– Hearing loss
_________
– Varying degrees of intellectual and
developmental disabilities
_________
- – Visual impairment
- – Motor problems
-
_____ causes 79% of infectious mononucleosis
_____ causes 21% of infectious mononucleosis
Epstein-Barr Virus (Often referred to as the “kissing disease”)
- Common infection throughout the world
- • Vast majority of EBV infections occur in young children
- and are asymptomatic
- • Individuals infected with EBV during their teens or 20s
- become symptomatic
- • May be associated with MS lesions (see Virus File 11-2)
- • In developing countries, EBV infection is associated with
- Burkitt’s lymphoma (type of B-cell cancer in kids)
- Incubation period ranges from 4–6 weeks
cytomegalovirus
-
Epstein-Barr Virus
• Symptoms:
– Sore throat
(blank 1)
(blank 2)
– Malaise
(blank 3)
– Enlarged liver (sometimes)
– Heart problems (rare)
(blank 4)
• Symptoms usually resolve within 1 or 2 months
- – Fever
- – Swollen lymph nodes
- – Enlarged spleen (sometimes)
- – CNS problems (rare)
-
Mild disease in childhood that
begins with sudden fever followed by a red rash
Sixth disease (human herpes virus 6 causes this)
-
Herpesvirus Life Cycle
• Virus structure and classes of herpesviruses
– Large (150–300 nm in diameter)
– Enveloped (obtained via a double envelopment
process)
(blank 1)
(blank 2)
– Transmitted by direct contact with mucosal surfaces
or secretions
– Cannot be transmitted by toilet seats (or other
inanimate objects) since herpesviruses dry out and
become damaged when exposed to air
– Pleomorphic particles
– Fragile and easily disrupted by heat, desiccation(extreme dryness), 70% alcohol, soap, and detergents
-
Herpesvirus Structure
• what genome?
• ______ kb pairs in length
• More than ______ virally coded
proteins
• ________ capsid
surround the core
• Amorphous proteinaceous
tegument surrounds the
nucleocapsid (at least 8
proteins)
- Linear dsDNA
- 125–229
- 30
- Icosahedral
-
Classes of Viral Genes
• 3 classes: Immediate-early (α), early (β), and
late (γ)
• Viral mRNAs are transcribed by the host’s RNA
polymerase II inside the nucleus of the host cell
• Viral VP16 protein activates the expression of
the α genes
– α genes encode DNA binding proteins that play a role
in viral transcription of β genes
– β genes encode DNA replication and additional viral
transcription factors
– γ genes encode the late structural proteins that are
produced after viral genome replication has begun
– Synthesized γ proteins are transported to the nucleus,
where capsid assembly begins
- Classes of Viral Genes
- • 3 classes: Immediate-early (α), early (β), and
- late (γ)
- • Viral mRNAs are transcribed by the host’s RNA
- polymerase II inside the nucleus of the host cell
- • Viral VP16 protein activates the expression of
- the α genes
- – α genes encode DNA binding proteins that play a role
- in viral transcription of β genes
- – β genes encode DNA replication and additional viral
- transcription factors
- – γ genes encode the late structural proteins that are
- produced after viral genome replication has begun
- – Synthesized γ proteins are transported to the nucleus,
- where capsid assembly begins
-
genes expressed in latency that may prevent apoptosis in neurons
Latency-associated transcripts (LATS)
-
• Most commonly prescribed for HSV-1, HSV-2, VZV
• Guanosine analog (ACG)
• Converted 200x more efficiently to ACGmonophosphate
by herpesvirus thymidine kinase
(TK) than the cellular TK
• Acts as a chain terminator (prevents DNA
elongation)
• Relatively nontoxic
• Can be used for long-term prophylaxis
• Can be administered topically to the skin or eye,
intravenous or orally
Acyclovir
-
Diet and Herpesvirus Infection?
• Foods high in _____ increase outbreaks
• Foods rich in ______ reduce occurrence,
severity, and healing time
L-arginine
- L-lysine (beef, chicken, fish, lamb, milk,
- cheese, beans, brewer’s yeast, and most fruits
- and vegetables)
-
Chickenpox vaccine is a ______ Oka strain
live attenuated
-
Results of Department of Veteran Affairs
Shingles Prevention Study: Varivax vaccine
reduced shingles cases by _______
• 2006: New vaccine, _______, approved by the FDA to reduce the risk of shingles in
people 60 years of age or older
51.3%
Zostavax (Merck)
-
Developing a CMV vaccine is a top priority
for several reasons:
– CMV infection is a major disease of the
_______
– CMV infection is the leading cause of _______ and ______ damage in children
• A _______ vaccine containing CMV genes is being investigated in clinical
trial
immunocompromised
inner ear (cochlea) hearing loss
nervous system
recombinant canarypox
-
The Use of Genetically
Engineered HSV to Treat Brain Tumors
• 30% of brain tumors
are malignant gliomas
• Patients with malignant
gliomas are ideal
candidates for novel
molecular-based
therapies because:
________
– MRI studies are
available to monitor
the outcome
_______
– Metastases are rare
– Viruses provide a delivery technique that can target the tumor
-
According to the latest figures from the World Health Organization, about
40 million people worldwide are living with HIV/AIDS. In the U.S., about 1
million are living with the virus, and 1 in 7 of those infected don't know it.
- According to the latest figures from the World Health Organization, about
- 40 million people worldwide are living with HIV/AIDS. In the U.S., about 1
- million are living with the virus, and 1 in 7 of those infected don't know it.
-
• HIV is present in (name 6)
- blood
- saliva
- tears
- vaginal fluid
- semen
- breast milk
-
Most common ways HIV can be transmitted:
(blank)
– Sharing of contaminated needles (IV drug users)
(blank)
– Accidental needlestick injuries
(blank)
– Sharing HIV-contaminated tattoo needles, razors,
acupuncture needles, ear-piercing implements
- – Anal and vaginal intercourse
- – Blood transfusions (using infected blood or blood products)
- – Congenital AIDS
(premastication and organ transplants are RARE to contract HIV)
-
Prevention of HIV Infection
• Abstinence from sex
• Use of barrier methods (e.g., condoms)
during sexual activity
• Microbicides (e.g., intravaginal 1%
tenofovir gel before and after
intercourse)(blank)
• Pre-exposure prophylaxis (PREP)
• Postexposure prophylaxis (PEP): 4-week
program
#1 women
-
Reasons that HIV patients who are not receiving
treatment are left behind:
(blank)
– Inequalities in access to treatment and services
– Gender-based inequalities
(blank)
– Human-rights violations, stigma, and discrimination
– Criminalization and exclusion
-
Put in order of most people with HIV
India
South Africa
Nigeria
-
HIV infection rate is ____ times higher among
prison inmates than for the general population
• Activities in prisons that pose a risk for HIV
transmission:
(Blank)
– Intravenous drug use
(blank)
– Sharing of toothbrushes and shaving equipment
(blank)
5−7
- – Homosexual activity
- – Tattooing and body piercing
- – Incidents of violence
-
What disease leads to these issues?
Wasting syndrome is also common (a loss of more
than 10% of body weight due to fever or diarrhea for
more than 30 days)
non-Hodgkin’s lymphoma
CD4+ TH lymphocyte cell count
below 200 cells/μL of blood and/or one or more
opportunistic infections
AIDS
-
HIV Virion Structure
HIV genome?
100 nm icosahedron-shaped sphere surrounded by an envelope
• Envelope contains glycoproteins ______ and ________
spikes
• Matrix proteins located ______ the envelope
_______ and ______bound to viral genome
• ______ also found within nucleocapsid HIV
+ssRNA
below
- Reverse transcriptase (RT; p64)
- integrase (p34)
- Protease (p10)
-
Coreceptor on T lymphocytes:
Coreceptor on macrophages:
CXCR4 (fusion)
CCR5
-
HIV-1 _____ and _____ regulate gene
expression
tat - early regulatory protein
rev - early regulatory protein
-
HIV-1 Assembly
• HIV-1 virion components (e.g., the viral
RNA, ____, ____, and _____ proteins) are
assembled at budding sites located at the
cellular plasma membrane
gag - structural protein
pol - structural protein
env - structural protein
-
HIV enters cell by binding to CD4 receptor and a co-receptor either CCR5-macrophage or CXCR4-t-cell and fuses and enters cell and brings its reverse transcriptase with it. It then transcribes a DNA strand, degrades the RNA, and synthesizes a second DNA strand. The double strand then enters nucleus through nuclear pore and integrates into the host cell DNA genome and transcribes viral RNA, then in cytoplasm translates viral proteins go to host cell membrane and assemble then bud and release from cell through lyses.
HIV enters cell by binding to CD4 receptor and a co-receptor either CCR5-macrophage or CXCR4-t-cell and fuses and enters cell and brings its reverse transcriptase with it. It then transcribes a DNA strand, degrades the RNA, and synthesizes a second DNA strand. The double strand then enters nucleus through nuclear pore and integrates into the host cell DNA genome and transcribes viral RNA, then in cytoplasm translates viral proteins go to host cell membrane and assemble then bud and release from cell through lyses.
-
The rare CCR5Δ32 allele led to increased
survival during smallpox outbreaks in 14th century Europe
-
Measure HIV-1 RNA copies per ml of plasma
• ______ copies per ml of plasma = clinical AIDS
CD4+ T lymphocyte counts
– Less than 200 per µl plasma
100,000
-
HIV Antiviral Therapy
• Zidovudine (AZT), a _______, RT
inhibitor first approved HIV-1 treatment
thymine analog
-
Use of at least 3 compounds to jointly block HIV replication by
inhibiting the viral protease and/or reverse
transcriptase of HIV
Antiretroviral therapy (ART):
-
Put these in order of greatest to least amount of rabies animal reservoirs in the U.S.
Fox
skunk
raccoon
bat
-
Human Rabies
• WHO estimates over 10 million people
receive postexposure prophylaxis (PEP)
annually
• More than ____ rabies-related deaths
each year, or ____ each day
• Significant public health problem in _____
55,000
150
China
-
characterized by extreme
behavioral changes, including overt aggression and attack behavior.
– Furious rabies (encephalitic)
-
characterized by weakness and loss of coordination, followed
by paralysis.
Paralytic rabies (or dumb)
-
Rabies symptoms
Symptoms During Prodromal Period
• Headache
(blank)
• Fever
(blank)
• Nausea
• Vomiting
• Anorexia
• Malaise
-
Secondary Symptoms of Furious Rabies
• Hydrophobia
(blank)
• Agitation
(blank)
(blank)
• Hypersalivation
• Bizarre behavior
• Biting
(blank)
• Jerky and violent contractions of the diaphragm
• Difficulty swallowing
• Anxiety
• Hallucinations
-
Secondary Symptoms of
Paralytic Rabies
• In humans:
blank
blank
blank
– Weakness and ascending paralysis
- – Lack of hydrophobia
- – Lack of hyperactivity
- – Lack of seizures
-
Symptoms of Rabies in Wild Animals
• Furious rabies: Excitation and aggressiveness, biting of objects, other animals, humans, or oneself
• Dumb rabies:
blank
– Drooling and salivation (often choke to death)
blank
blank
– Irritation around bite side (with frequent licking or biting)
• Wildlife seem to lose fear of people, and nocturnal creatures may be out during daylight
– Startled response to sudden noise or light
– Reclusive behavior
– Anorexia
-
Rabies vaccine injection:
– Dose: ______ shots injected
intramuscularly into the forearm or shoulder
on days 0, 7, 21, or 28
– Usually takes 7–14 days to induce immunity
– Immunity lasts approximately ______
3 × 1-mL
2 years
-
What Should You Do if You Are Bitten by an Animal?
• Provide the following information to a physician:
– Animal involved
blank
– Vaccination status of the animal (if known)
blank
blank
– Whether the bite was provoked or unprovoked
– Geographic location of the incident
– Whether the animal can be safely captured for rabies testing
-
Rabies bite animal
If the animal shows signs of rabies and can be captured, it will be euthanized and the head shipped to a qualified laboratory for testing
If the animal shows signs of rabies and can be captured, it will be euthanized and the head shipped to a qualified laboratory for testing
-
Postexposure Vaccination rabies:
• 3 categories of vaccine:
– Nerve tissue vaccines
(blank)
– Cell culture vaccines
• Early vaccines made of nerve tissues
– Produced serious side effects such as ______, Guillain-Barré−like syndrome, CNS disease, ________
– ______ vaccine: 1 in 200 recipients experience serious neurological side effects, up to ______ mortality
– Nerve tissue vaccines are still being used in ______, South America, and ______
– Avian embryo vaccines
paralysis
meningoencephalitis
Semple
14%
Asia
Africa
-
The Rabies Virus Replication Cycle
• Classification:
– Order: _______
– Family: Rhabdoviridae
– Genus: ______
• Structure and properties
– Unique ______ appearance
– 75 nm diameter by 180 nm in length
– Surface of the particle is covered with
glycoprotein spikes
– _____ protein inside of particle
– ______ core
• Genomic RNA tightly encased by N, P, and L proteins
Mononegavirales
Lyssavirus
bullet-shaped
Matrix (M)
Ribonucleoprotein
-
RABIES
• Genome consists of 11,932 nucleotides
• What genome?
• 5 genes and a remnant gene or
pseudogene (Ψ)
-ssRNA
-
Rabies life cycle:
After amplification in muscle cell its released into synaptic cleft to bind to nicotinic acetylcholine receptors
1. Rabies virus attachment
2. Entry into neuron
3. ______
4. ______
5. Transcription (L (RNA-dependent RNA polymerase) begins to
transcribe the viral genome
– A separate +ssRNA transcript is generated for each
viral gene
– Each viral transcript is capped and polyadenylated by
the viral L protein)
6. Translation (N, P, M, and L mRNAs are translated by free
ribosomes
– G mRNAs are translated on membrane-bound
ribosomes of the ER)
7. _______
8. Replication
9. _______
10. Release
3. axonal retrograde transport
4. uncoating - – M protein dissociates from the RNP during uncoating
7. Processing of G via ER and golgi (glycosylated)
9. assembly
-
A new or recently
identified virus to humans
Emerging virus
-
A virus under control
from a public health perspective but is
making a comeback or reappearance, and
increasing in incidence and geographical
range of exposed human populations
Reemerging virus
-
Higher population densities favor the spread of
viral diseases:
– Crowding
blank
– Contamination of drinking water
blank
Human demographics drive viral disease
emergence more than virus evolution or ecological factors (_____, race/ethnicity, ______, occupation, etc.)
– Sanitation
– Healthcare facilities
sex/gender
mobility/travel
-
Increase in gastrointestinal illness caused by
norovirus 10-fold between 2001 and 2004 on cruises
– blank
– blank
– Hard to determine the ______ in the virus that trigger more severe outbreaks
Noroviruses cannot be cultured in the lab
No animal model for noroviruses
genetic changes
-
Close proximity of wildlife to humans may
contribute to viruses crossing the species barrier
blank
– Free range farming in Asia
blank
– Bushmeat in Africa
– Monkeypox, U.S. exotic pet trading (prairie dogs)
– “Wild taste”—Chinese delicacy from wild animals
-
Viral Hemorrhagic Septicemia (VHS) Virus
• Serious pathogen of fresh and saltwater fish
• Emerging disease in the Great Lakes region of the U.S. and Canada
• Infected fish show signs of:
– Bulging eyes
blank
blank
– Inactive or overactive behavior
– Bloated abdomens
– Hemorrhaging in the eyes, gills, skin, and the base of the fins
-
Porcine Reproductive and
Respiratory Syndrome (PRRS)
Also called _______
• Economically significant disease: Pork shortage
• The virus attacks ______, crippling the
animals’ immune system (allows viruses and
other pathogens to do damage; e.g., severe
pneumonia)
• ______ strain is particularly virulent
• Virologists are concerned that this virus may
cross the species barrier from pigs to humans
“Blue-ear pig disease”
macrophages
China
-
Metagenomic survey results: ______ found in 25 of 30 Colony Collapse Disorder hives and only 1 healthy hive
2010: Researchers detected a virus and fungus co-infection to cause CCD
blank and blank
Israeli acute paralysis virus (IAPV)
- – Invertebrate iridescent virus-6 (IIV-6)
- – Nosema ceranae
-
Medical Practices and Susceptibility
to Infection
• Health-related infections:
– Unsafe medical practices (e.g., reusing
syringes and overuse of antimicrobials)
blank
– Poor hospital practices
blank
blank
- – Xenotransplantation
- – Immunosuppression
- – Blood transfusions
-
Use of immunosuppressive drugs used
during organ or bone marrow transplants
– Kidney dialysis
blank
– Chemotherapy
– Chronic corticosteroid treatment
-
Viral Infections in
Immunocompromised Individuals
blank
• Varicella zoster
(causes chickenpox
and shingles)
• Herpes simplex
virus
blank
• Human herpesvirus
type 6
• Human herpesvirus
type 7
blank
blank
- • Human cytomegalovirus
- • Epstein-Barr virus
- • Adenoviruses
- • Hepatitis viruses
-
About ______% of human
cancers are associated
with viruses
20%
-
• Cancer has afflicted
humans throughout
history
blank
– Hippocrates observed
carcinomas
blank
– Reims, France, first
cancer hospital
– Fossilized bone tumors mummies in Egypt
– Chimney sweeps and scrotal cancer
-
Early Cancer Research on
Rous Sarcoma Virus (RSV)
• 1908: _____ and _____
demonstrated that _______ could
produce tumors in chickens
• 1911: ______ demonstrated a
bacteria-free _____ caused sarcomas in
chickens
– The agent was Rous sarcoma virus, a
retrovirus
Wilhelm Ellerman and Olaf Bang
Peyton Rous
“filterable agents”
filtrate
-
______ and ______
• Discovered that the
src gene of Rous Sarcoma Virus is
found in the normal
DNA of chickens
• Their work
demonstrated that
oncogenes are
cellular genes that
were hijacked by
viruses from cells
who?
Michael J. Bishop and Harold E. Varmus
-
• At least 6 viruses are thought to contribute to
10% of cancers
• They are:
– Hepatitis B virus (HBV)
– Hepatitis C virus (HCV)
blank
blank
– Kaposi’s sarcoma–associated herpesvirus (human herpesvirus 8)
blank
- – Human papillomavirus (HPV)
- – Human T-lymphotropic virus types 1 and 2 (HTLV-1 and HTLV-2)
- – Epstein-Barr virus (EBV)
-
A gene that has the potential to
convert a normal cell to a cancerous or
transformed cell
Oncogene
-
A viral gene responsible for the oncogenicity of the virus
– Retroviruses may carry altered cellular genes that are tumor promoters
Viral oncogene
-
Cellular genes that promote
the normal growth and division of cells
Proto-oncogene
-
Genes that suppress or inhibit the conversion of a normal cell into a cancer cell
– These genes cause cancer when they are turned off
Tumor suppressor genes
-
The change in the morphological, biochemical, or growth properties of a cell
Cell transformation
-
A term for diseases in which abnormal
cells divide without control
Cancer
-
When a cell or clump of cells separates from a tumor and spreads to another location
Metastasis
-
Characteristics of Cancer Cells (in vitro)
• Genetic changes: Polyploidy (Polyploid cells and organisms are those containing more than two paired (homologous) sets of chromosomes. triploid, tetraploid), high levels of telomerases
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• Metabolic changes: Grow rapidly
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• Anchorage independent: Loss of adhesion
• Require less serum in medium to grow
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• Changes in membrane structure and function
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- • Immortalization
- • Lack of contact inhibition: Cells pile up
- • Loss of cell cycle control
- • Tumor-associated carbohydrate antigens
-
Characteristics of
Cancer Cells (in vivo)
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• Loss of tumor suppressor gene function
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• Increased or unregulated level of growth factors
• Cells divide uncontrollably
• Increased levels of enzymes involved in nucleic acid synthesis and lytic enzymes
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- • Increase in oncogene mRNA expression
- • Changes in DNA methylation patterns
- • Immune evasion
- • Reactivation of telomerases
-
Cancer is a Multistep Process
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• Cells circumvent the need for growth
signals
• Cells escape immunosurveillance
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• Tumor suppressor genes lose function
• Cells (tumors) command their own blood supply
• Cells may metastasize
• Cells bypass apoptosis
-
____ gene encodes matrix and core proteins of the retrovirus that function to protect the viral ssRNA genome from damage
gag
-
_____ gene encodes a multifunctional protein that has
reverse transcriptase, RNase H, helicase, and
integrase activities
pol
-
_____ gene codes for a protein that is embedded
within a lipid bilayer that surrounds the nucleoprotein
core particle of the retrovirus
env
-
_____ gene codes a protein that induces cellular
transformation (not essential in viral replication)
v-onc
-
Human Endogenous Retroviruses
(HERVs)
• _____% of the human genome consists of
HERVs
• Most sequences are defective and
incapable of producing functional protein
• Possible cofactor in _____, autoimmunity,
and ______
8%
cancer
schizophrenia
-
DNA tumor viruses differ from RNA tumor
viruses in that the _______
v-oncs of DNA tumor viruses are essential viral genes used in replication
-
• DNA tumor viruses target the ____ and p53
tumor suppressor gene products of the host
Retinoblastoma protein
-
Burkitt’s Lymphoma
• _____ gene moves near the immunoglobulin
heavy chain or light chain gene
– Abnormal expression of the _____ gene and increased tumorigenicity of the cells
c-myc
-
Papillomavirus Structure
and Genome
• Small (52–55 nm in
diameter)
• Nonenveloped
• Icosahedralshaped
genome?
• Circular dsDNA genome (~8000 bp in length)
-
HPV
What keratinocyte differentiation stage layer?
virion assmbly
late capsid proteins L1 and L2
vegetative DNA amplification
- high levels of early and differentiated proteins , notably E4
- koliocytosis of productive keratinocytes
upper spinous layers
-
HPV
What keratinocyte differentiation stage layer?
differentiation-dependent E6 and 57 proteins
early proteins E1 E2 E4 E5
LOWER spinous layers
-
HPV
What keratinocyte differentiation stage layer?
possible alternative site of infection
immediate early proteins E1 E2 and E5
transit amplifying cells
-
HPV
What keratinocyte differentiation stage layer?
establishment replication
immediate early proteins E1 E2 E5
Primary infection
basal stem and reserve cells
-
Adenovirus Structure
• 80 nm in diameter
• Icosahedral-shaped
• Knobbed penton
fibers
genome?
• Can infect a wide
variety of cell types
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• dsDNA (36–38 kb in length)
– Chosen as a gene therapy vector
-
Simian Virus 40 (SV-40)
• Isolated from ______ by B.H. Sweet and
M.R. Hilleman during safety testing of the
______ vaccine in 1960
• Did not cause cytopathogenic effect
• Frequent contaminant of rhesus monkey
kidney cell culture cells
• SV-40 is a ______
primary African green monkey kidney cells
poliovirus
polyomavirus
-
Simian Virus 40 characteristics
• Small (45 nm in diameter)
• Nonenveloped
• Icosahedral-shaped
• Three capsid proteins (VP1, VP2, VP3)
genome?
– 2 sets of genes (expressed early and late)
– Origin of replications (ORIs)
– Promoters
– Enhancer sequences
• Large and small T-antigens and 17kT antigen
• dsDNA genome (5.2 kb in length)
-
Cancer Therapy:
The Last 150 Years
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• Radiation therapy
• Chemotherapy
– Mustard gas
– Aminopterin (folic
acid antagonist)
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• Surgery
• Immunotherapy
-
Believed that oncolytic viruses cause tumor cells
to die in 4 main ways:
– Infecting and replicating in cancer cells
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– Inducing lysis of cancer cell and expulsion of virus particles
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– Complicated mechanism such as stimulating the host’s immune system
– Induction of apoptosis
-
Challenges of Virotherapy
• Immunity
• Delivery
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• Biomarkers to track progress
-
Infectious proteins that cause a group of
diseases of the brain and nervous system called
transmissible spongiform encephalopathies
(TSEs)
Prions
-
Small, pathogenic RNAs that cause
virus-like diseases in plants
Viroids
-
______ cause a noninflammatory process that results in the vacuolation, or spongiosis, in the gray matter of the brain
transmissible spongiform encephalopathies
-
Kuru -cannibal
3 Stages of Symptoms
• _____ stage: Unsteady gait, voice, hands, and eyes; tremors and shivering; slurred speech; loss of coordination in lower extremities
• _____ stage: Patients could no longer walk
without support; increased severity of tremors and coordination problems; jerky movements; outbursts of laughter, depression, mental slowing
• _____ stage: Patients could not sit without
support; increased tremors and speech slurring; incontinence; difficulty swallowing; deep ulcerations
Ambulant
Sedentary
Terminal
-
• Practice of eating dead relatives
Endocannibalism
-
Tissues, infectious waste, and instruments
used in the processing of prion contaminated samples are decontaminated in:
– 1 N NaOH or undiluted fresh household bleach followed by autoclaving at 132°C for 4.5 hours
-
The normal cellular form proteinaceous infectious particle is the normal form abundant in neurons but post-translational misfolding occurs to get it to be a Proteinacous infectious particle resistant to protease digestion and this forms into clumps that damage nerve cells of brain
Protein only hypothesis for infectious prions
-
Hypothetical Model: PrPC
Involvement in Secretory Pathway
1. Proteinacous infectious particle cellular form is synthesized on rough ER
2. __________
3. PrPc cycled from the membrane into endocytic vesicles
4. PrPc is either degraded or moves back to cell surface to bind to copper
5. ________
PrPc moves to plasma membrane via golgi secretory pathway to bind to copper
Folding of PrPc to convert it to PrPres accumulation of fibrils
-
– Signal transduction
– Cellular differentiation
– Cell adhesion
– Copper transport
– Resistance to the accumulation of destructive free radicals that can
result in neuronal death
PrPC possible functions
-
The Three Ways That
TSEs Can Arise
• Infection
– Diet, variant Creutzfeldt-Jakob disease (CJD), endocannibalism
– Iatrogenic means (e.g., surgery)
– Growth hormone injections
– Corneal transplants
• Inherited
– Genetic CJD
– Gerstmann-Straussler-Scheinker disease (GSS)
– Fatal familial insomnia (FFI)
• Sporadic forms
– CJD
- The Three Ways That
- TSEs Can Arise
- • Infection
- – Diet, variant Creutzfeldt-Jakob disease (CJD), endocannibalism
- – Iatrogenic means (e.g., surgery)
- – Growth hormone injections
- – Corneal transplants
- • Inherited
- – Genetic CJD
- – Gerstmann-Straussler-Scheinker disease (GSS)
- – Fatal familial insomnia (FFI)
- • Sporadic forms
- – CJD
-
Iatrogenic transmission of CJD
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– Contaminated neurosurgical instruments
– Human growth hormone from CJD-infected donors
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• Blood-borne transmission (suspected)
– Variant CJD agent can be detected in lymphoid tissues
– Transmission of BSE to sheep by blood transfusion from asymptomatic, infected sheep to healthy sheep
- – Corneal grafts from infected donor
- – Contaminated deep EEG electrodes implanted into brain
- – Patients who received dura mater grafts
-
Creutzfeldt-Jakob disease
_____% of variant CJD patients die before age 30
– Average age at death is ____ years
• Patients suffering from classic CJD die at an average of ____ years of age
50%
28
68
-
Creutzfeldt-Jakob disease (CJD),
Initial symptoms
progessions
final symptoms
- Initial symptoms:
- – Anxiety
- – Memory loss
- – Mood changes
- – Depression
- – Withdrawal
- Progression of CJD
- • Neurological signs
- – Twitching
- – Spasms (jerky movements)
- – Posture and gait abnormalities (motor difficulties)
- • Final symptoms
- – Loss of speech
- – Stupor
- – Coma
- – Death 14 months after symptoms appear
-
Diagnosis of Variant CJD
• Prion-positive immunostaining of biopsy material
– Tonsils, spleen, and lymph nodes
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• MRI
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• Gold standard: Postmortem examination of brain tissues
– Western blot analysis
– Immunocytochemistry of PrPres accumulation in brain
tissues
• EEG (slow or negative brainwave activity)
• CSF testing for elevated levels of proteins
-
Brain Changes of transmissible spongiform encephalapathies
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• Neuronal loss: Apoptosis
• Astrocytosis: Spread of astrocytes to damaged tissues in the brain
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• Spongiform changes: Vacuoles (clear zones) similar to a sponge
• Amyloid plaques: Formation of PrPres threadlike aggregates
-
Chronic Wasting Disease (CWD)
• Prion disease of deer, elk, and moose
• Symptoms include:
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– Excessive drooling and thirst
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– Aspiration pneumonia
• 15% in free-ranging deer and >90% in captive deer herds
• Transmission directly or indirectly (through feed or water sources)
• Plants can act as carriers of prions and play a role in horizontal transmission of prion diseases
– Emaciation- state of being abnormally thin or weak
– Frequent urination
-
Viroids: Small RNA molecules that infect
plants in the same manner as conventional
viruses
blank genome?
– Internal base-pairing
blank
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– +ssRNA, covalently closed circular pathogenic molecules
– Depend upon the plant host enzymes for their replication and other functions
– Do not code for any proteins
-
Two Families of Viroids
• Avsunviroidae:
– Branched, “quasi” rodlike structure
– Accumulate and replicate in chloroplasts
– Lack a C region
• Pospiviroidae:
– True, rodlike secondary structure
– Nuclear localization
• Viroids contain 5 structural or functional domains:
– Central (C): Critical for replication and processing
– Pathogenicity (P): Symptoms of viroid-infected plants
– Variable (V): Highest variability in sequence
– Two terminal domains (T1 and T2): Role in viral movement
- Two Families of Viroids
- • Avsunviroidae:
- – Branched, “quasi” rodlike structure
- – Accumulate and replicate in chloroplasts
- – Lack a C region
- • Pospiviroidae:
- – True, rodlike secondary structure
- – Nuclear localization
- • Viroids contain 5 structural or functional domains:
- – Central (C): Critical for replication and processing
- – Pathogenicity (P): Symptoms of viroid-infected plants
- – Variable (V): Highest variability in sequence
- – Two terminal domains (T1 and T2): Role in viral movement
-
Viroids Do not replicate in the cytoplasm like
conventional plant RNA viruses
they replicate in the _____ or _____ of the plant
nucleus or chloroplast
-
• The cell’s _____-dependent RNA
polymerase ____ synthesizes viroid RNA
DNA
3
-
Localization of Viroid ssRNAs
• Viroid ssRNAs of positive polarity localize to
the _____ and _____ of host cells
• Viroid –ssRNA are localized only to the
_______
nucleolus
nucleoplasm
nucleoplasm
-
First viroid
characterized in 1971
Potato Spindle Tuber Viroid
-
Viroid Pathogenesis
• Viroids activate a plant ______
dsRNA-activated protein kinase (PKR)
-
The only DNA retro virus
DNA -> RNA -> DNA
Hepatitis B
-
only + sense RNA virus whose genome is replicated by the host
HIV
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