Module 11 - Viral Pathogenesis Flashcards
What is viral pathogenesis?
The mechanisms where viruses cause disease in target hosts
What must viruses do to reproduce?
- Get into permissive host
- Acquire resources needed for replication
- Evade host defenses
- Spread to new hosts
What feature of viruses makes pathogenesis more complicated compared to bacteria?
They must replicate intracellularly
For viruses, what is infection?
Entry of a virus into a host cell
What is a productive infection?
New infectious viral particles are produced (viral replication occurs)
Which cell leads to productive infection?
A permissive cell
What is an abortive infection?
Few, if any, new viral particles are produced (viral replication does not occur)
Which cell leads to abortive infection?
A non-permissive cell
What are the different types of viral infections?
Acute, latent, and persistent
What is an acute infection?
An infection with a short duration
What are some characteristics of an acute infection?
Signs/symptoms observed, infection is cleared, usually results in immunity
What is an example of an acute infection?
Rhinovirus infection (common cold)
What is a latent infection?
A period of acute infection is followed by latency
What causes an infection to be latent?
The virus is still present, but replication is shut down
What does reactivation mean in a latent infection?
Reactivation can lead to the recurrence of acute infection signs and symptoms
What are some examples of latent infections?
Lambda phages and herpesviruses
How do lambda phages remain latent?
Via repression by the cI repressor
How do herpesviruses remain latent?
Through LATs
What does LAT stand for?
Latency associated transcripts
What do herpesviruses maintain during latency?
A circular episome
What does HHV-1 lead to?
Cold sores and genital sores
What does HHV-2 lead to?
Cold sores and genital sores
What does HHV stand for?
Herpesvirus
What does HHV-3 lead to?
Chicken pox rash and shingles
What does HHV-4 lead to?
Burkitt lymphoma, mononucleosis
What does HHV-8 lead to?
Kaposi sarcoma lesions
What is another name for persistent infections?
Chronic infections
What is a persistent infection?
New viral particles are continuously produced
What are some characteristics of a persistent infection?
The host does not clear the virus, but signs and symptoms may cease
How come the host may not clear the virus in a persistent infection?
Either targeted weakening of the immune system, or mutational changes in the virus and/or host target cells
What are some examples of persistent infections?
Hepatitis B and C
True or false: hepatitis B and C are always persistent
False: they are not always persistent, but they can be in some individuals
What are the basic types of viral transmission?
Horizontal, vertical, zootonic, and mechanical
What is horizontal transmission?
Transfer from individual to individual within the same species
What does horizontal transmission require?
A mode of exit and mode of entry
When someone says they “caught” a cold from someone, what type of transmission is this?
Horizontal transmission
What are some examples of horizontal transmission?
Respiratory, fecal/oral, and sexual
What are some examples of respiratory horizontal transmission?
Rhinoviruses, influenza
What are some examples of fecal/oral horizontal transmission?
Polioviruses, hepatitis A
What are some examples of sexual horizontal transmission?
HIV, human papillomaviruses
What is vertical transmission?
Transmission within the same species, from mother to fetus or newborn
What are some mechanisms of vertical transmission?
Via placenta/during birth, via breast milk, or via germ cells
What are some examples of vertical transmission via placenta/during birth?
Rubella, hepatitis B and C, HIV
What are some examples of vertical transmission via breast milk?
HIV
What are some examples of vertical transmission via germ cells?
Spermatocytes/oocytes infected with mouse mammary tumor virus (MMTV)
What does MMTV stand for?
Mouse mammary tumor virus
Which vertical transmission is intensely studied?
HIV vertical transmission
How come rates of HIV vertical transmission have dropped in the US?
Antiretroviral drug therapies and C-sections
What is zootonic transmission?
Transfer between individuals of different species (from animals to humans)
What are some examples of zootonic transmission?
Rabies, West Nile, and Ebola
What may zootonic transmission lead to?
More widespread horizontal transmission events
What is an example of zootonic transmission leading to more widespread horizontal transmission events?
HIV arising from SIV
What is mechanical transmission?
Facilitated transfer of virus from host between individuals in the same species
How can viruses travel in mechanical transmission?
Via vectors like mosquitoes, or contaminated medical equipment
What are some examples of mechanical transmission?
Myxoma virus and yellow fever in mosquitoes, Ebola in contaminated medical equipment, plant viruses
What is viral exposure?
Simply coming into contact with a virus
When does an infectious disease occur?
During a productive infection
What do almost all viral infections activate?
The host immune system
What does the overall outcome of viral infection depend on?
The interplay between viral replication and immune response of the host
What type of infection is the majority of viral infections?
Acute infections
In acute infections, what does the severity of symptoms depend on?
The rate that the virus replicates, and the strength of the individual immune response
What are the best studied human viruses that exhibit latency?
Herpes viruses
What happens after acute infection of HSV-1?
It enters the nuclei of neurons
What happens after HSV-1 enters the nuclei of neurons?
It exists as an episome
What is an episome?
A non-integrated extra chromosomal closed circular DNA molecule that can be replicated in the nucleus
What genes are expressed in the HSV-1 episome?
LATs
What happens when HSV-1 is reactivated from latency?
The viral particles travel back down the neuron to the periphery to cause disease symptoms
How might a virus maintain a chronic infection?
By weakening the immune system, or suppressing apoptotic signals
True or false: Ebola virus can be transmitted in various ways
True: it has multiple mechanisms of transmission
Why do rhinoviruses cause sneezing and coughing?
They allow the virus to leave the infected individual and find a new host
How can Ebola virus be transmitted horizontally?
By direct contact with contaminated bodily fluids
Why might a virus only be transmitted zootonically and not horizontally?
The virus is dead in the human host, and thus cannot spread
How can rabies be transmitted to humans?
Through the saliva of an infected animal
How is Ebola transmitted zootonically to humans?
Either directly through bats, or indirectly from primates
What does SIV stand for?
Simian immunodeficient virus
What is HIV to SIV an example of?
A zootonic virus mutating to become more infectious to humans
How does the myxoma virus gets transmitted?
By rabbit to rabbit via mosquitos or fleas (mechanical transmission)
True or false: the myxoma virus replicates in the mosquitoes or fleas
False: they just act as passive vectors
True or false: yellow fever virus replicates in the insect vector
True: unlike myxoma virus, it can replicate in the insect vector
How can Ebola virus be transmitted mechanically?
Through medical devices contaminated with the blood of an infected individual
How do some viruses cause cytopathology?
By inhibiting host cell transcription and translation processes, or avoiding immune responses
How can viruses induce cellular damage?
Through necrosis, apoptosis, or inclusion body formation
Why might a virus induce necrosis or apoptosis?
It gives it access to more resources for translating its own proteins
How does poliovirus lead to necrosis?
It inhibits host cell mRNA translation
How does poliovirus inhibit host cell mRNA translation?
It cleaves an essential translation initiation factor (eIF-4G)
What happens when eIF-4G is cleaved by poliovirus?
Rapid inhibition of host cell translation, and initiates translation of viral mRNA
How does cleaved eIF-4G lead to translation of viral mRNA?
It is moved to internal ribosome entry segment of the viral mRNA to initiate translation
What does IRES stand for?
Internal ribosome entry site
What does an IRES do?
An RNA element that allows for translation in a cap-independent manner
What is needed for the initiation of the translation complex in eukaryotic cells?
A 5’ cap
How does bunyavirus lead to necrosis?
Through a cap snatching process
What happens when the cap is stolen from mRNA?
It is promptly degraded
Besides bunyaviruses, what other viruses cleave the 5’ cap off of mRNA?
Automyxo viruses
What do cap-snatching viruses do with the 5’ cap?
Use it to prime synthesis of viral mRNA
What is apoptosis?
Programmed cell death
What type of organisms undergo apoptosis?
Multicellular organisms
How does apoptosis work?
Biochemical processes lead to characteristic cell changes
What are some characteristic cell changes during apoptosis?
Blebbing, global mRNA decay, and chromosomal DNA fragmentation
When might induction of the apoptosis pathway be useful?
To prevent the production of more virus particles and limit the spread of virus within the host
Why might a virus want to inhibit apoptosis?
So it can multiply and produce more virions
How do herpesviruses and adenoviruses interact with the apoptosis pathway?
They produce proteins that mimic anti-apoptotic proteins to inhibit apoptosis
True or false: apoptosis induces inflammation
False: it is usually safer for surrounding cells
How does the immune system use apoptosis?
It can induce apoptosis to safely kill virally infected cells
Which viruses form syncytia?
HIV and measles virus
How do syncytia form?
Infected cells fuse with adjoining infected or uninfected cell
What is the result of a syncytia?
The formation of a multinucleated giant cell that ultimately dies
What do rabies virus, adenovirus, and reovirus do to cells?
They form nuclear of cytoplasmic inclusion bodies to kill cells
What are inclusion bodies?
Clumps of virus/proteins inside host cells
What do inclusion bodies do?
They lead to disruptions in cellular morphology and cellular function
What is the viral advantage of a syncytia?
They can avoid extracellular immune responses
What can cause the symptoms of a viral infection?
The virus itself, or the actions of the host immune response
How do rhinoviruses affect cells of the upper respiratory tract?
There is not much pathology
How do rhinoviruses lead to the clinical symptoms?
They lead to elevated levels of inflammatory cytokines IL-6 and IL-8
What does IL-6 and IL-8 lead to?
Vasodilation and a buildup of fluid in the respiratory tract
What is the sneezing and coughing of a rhinovirus infection a direct result of?
A buildup of fluid in the upper respiratory tract
What do invading microbes usually trigger?
The release of various cytokines
What do cytokines do?
Facilitate communication between cells of the immune system and initiate inflammatory response
What does the clinical outcome of HBV infection depend on?
The particular immune response
In most cases, what is the clinical outcome of HBV infection?
They are cleared by the immune response with no significant site of pathology
What does hepatitis result from?
Cytotoxic T-lymphocyte mediated destruction of infected hepatocytes
What are hepatocytes?
Liver cells
What does accumulation of HBV antigen - antibody complexes lead to?
It can cause kidney damage in kidneys
What can chronic HBV infection of the liver lead to?
Liver cancer
How might viruses cause disease indirectly?
Through auto-immunity
How do auto-immune diseases occur?
When the immune system incorrectly targets normal cellular components
How can auto-immune diseases be triggered by viral infections?
Through molecular mimicry
How does molecular mimicry lead to auto-immune diseases?
If viral antigens are structurally similar to host cell proteins, immune cells may target both the virus and the host cells
How is multiple sclerosis an auto-immune disease?
Myelin is similar to a viral antigen, so it is attacked by T cells
When was the tumor causing virus in chicken discovered?
1911
What is tumorigenesis?
The formation of a tumor
What is a tumor?
An abnormal growth of tissue
How can transformation make a cell cancer-like?
It can make the cell immortal or grow uncontrollably
What may cancer transformed cells exhibit?
Reduced growth factor requirements and chromosomal aberrations
What type of cancer does HPV 16 and 18 lead to?
Cervical, anal, penile
What are some notes on HPV 16 and 18?
Oncogenic HPV strains may cause up to 10% of all human cancers
What percentage of cervical cancers are caused by HPV 16 and 18?
70%
What virus family is HPV 16 and 18 a part of?
Papillomaviridae
What type of cancer does SV40 lead to?
Sarcomas in rodents
What are some notes on SV40?
It can transform some human cell lines
What virus family is SV40 part of?
Polyomaviridae
What type of cancer does Adenovirus lead to?
Transformation of cells in culture
What are some notes on Adenovirus?
Both E1A and E1B proteins are needed for transformation
What type of cancer does HHV-8 lead to?
Kaposi sarcoma
What are some notes on HHV-8?
It transforms endothelial cells, and it is a defining cancer of people with HIV/AIDS
What virus family is HHV-8 part of?
Herpesviridae
What type of cancer does HHV-4 lead to?
Burkitt lymphoma
What is another name for HHV-4?
Epstein-Barr virus
What are some notes on HHV-4?
It also causes infectious mononucleosis
What virus family is HHV-4 part of?
Herpesviridae
What type of cancer does HBV lead to?
Hepatocellular carcinoma
What are some notes on HBV?
An effective vaccine is available
What virus family is HBV part of?
Hepadnaviridae
What type of cancer does HCV lead to?
Hepatocellular carcinoma
What are some notes on HCV?
60-85% of people infected with HCV develop a chronic infection
What virus family is HCV a part of?
Falviviridae
What type of cancer does Rous sarcoma virus lead to?
Sarcoma in chickens
What are some notes on Rous sarcoma virus?
Led to the identification of proto-oncogenes
What virus family is Rous sarcoma virus a part of?
Retroviridae
What is an oncogene?
Genetic material capable of inducing a transforming event in host cells
What have almost all mammalian DNA virus been shown to cause?
Transformation of cells in culture or tumor formation in animals
What types of genes do mammalian DNA viruses usually contain?
Oncogenes
What is similar between mammalian DNA viruses?
The mechanisms by which they transform cells
What do strains of papillomaviruses lead to?
Genital warts and cervical cancer
What do papillomaviruses typically infect?
Certain mucosal surfaces and keratinocytes
What are keratinocytes?
Cells that form the outer layer of skin
How come keratinocytes are quiescent cells?
They do not actively divide
What is the consequence of keratinocytes being quiescent?
They have very few nucleotides and enzymes needed for DNA replication
How do viruses overcome the lack of resources in quiescent cells?
They stimulate the cell to enter S phase of the cell cycle
What happens when a cell enters S phase?
It prepares the resources needed for DNA synthesis
What happens to epithelium infected with papillomavirus?
The cells proliferate rather than differentiate
What is the structure of papillomavirus?
Non-enveloped icosahedral dsDNA (8 kb) virus
What proteins are used by papillomavirus to transform the cell?
E6 and E7
What vaccines for papillomaviruses exist?
Those for the most common E6/E7 carrying strains
What does Rb stand for?
Retinoblastoma
What do Rb and p53 do?
They act as tumor suppressors to stop the cell cycle
What does Rb do?
It binds to E2f transcription factors to prevent entry into S phase
What happens when Rb is phosphorylated?
It cannot bind to E2f, so E2f can stimulate the transcription of genes needed for entry into S phase
When is p53 activated?
In the event of DNA damage or cell stress, it is phosphorylated
What happens when p53 is phosphorylated?
It acts as an active transcription factor for p21
What does p21 do?
It prevents the cell from entering into S phase
What does accumulated phosphorylated p53 lead to?
It induces apoptosis
How does E6 interfere with cell cycle control?
In the presence of E6AP, it targets p53 for destruction
What happens when p53 is degraded in proteosomes?
p21 is not transcribed, so the cell is free to enter S phase
How does E7 interfere with cell cycle control?
It binds to Rb and prevents Rb from binding to E2f
What happens when there is no Rb-E2f complex?
The cell is free to enter S phase
True or false: cells infected with papillomavirus die
True: the virus triggers apoptosis
What happens if the papillomavirus genome is inserted into the host genome, without the production of viral particles?
The host cells are not killed, but they are transformed
What happens if E6 and E7 genes are inserted into the host genome?
They continue to inactivate p53 and Rb, leading to more division of the cells
How does papillomavirus lead to cancer?
The continuously dividing cells acquire mutations over time, and thus become cancer
True or false: very few RNA viruses seem to cause cancer
True: many DNA viruses, but not many RNA viruses, seem to cause cancer
What type of RNA viruses usually cause cancer?
Retroviruses
What is the only non-retrovirus RNA virus associated with cancer?
Hepatitis C
How does hepatitis C lead to cancer?
Via constant attempts to replace damaged liver cells in chronic hepatitis C, altering the genetic material (not through direct transformation)
What have several retroviruses been associated with?
Tumorigenesis
How do retroviruses cause cancer?
They can insert their cDNA into the genome to alter proto-oncogenes
What are the two ways in which a proto-oncogene can become an oncogene?
- The pro-viral DNA may integrate near a proto-oncogene and alter its expression
- The retrovirus may acquire a cellular oncogene and transform another cell
What do cis-acting retroviruses do?
They integrate cDNA into the genome to convert a proto-oncogene into an oncogene
How come a retrovirus is called “cis-acting”?
It only affects the portion of DNA near it
What is the best studied cis-acting retrovirus?
MMTV
What does MMTV stand for?
Mouse mammary tumor virus
What does MMTV do to infected animals?
It causes tumors of the breast tissue
True or false: the MMTV genome contains an oncogene
False: it does not contain an oncogene, but it can lead to tumor formation
How does MMTV lead to tumorigenesis?
It integrated near Wnt1 to increase its expression
What does increased Wnt1 lead to?
Increased proliferation and tumor formation of the cell
Where is the cis-acting enhancer element found in MMTV?
In the pro-viral long-terminal repeat (LTR) transcriptional regulatory region
What do trans-acting retroviruses do?
They transform a cell with an oncogene from a different cell
How does a retrovirus obtain an oncogene?
It integrates near a cellular proto-oncogene, where it can be copied into the RNA genome
How come trans-acting retroviruses are not a major cause of cancer?
They are fairly rare
What are some examples of trans-acting retroviruses?
Avian leukosis virus, Rous sarcoma virus, and Avian myelocytoma virus
What is the structure of Avian leukosis virus?
LTRs with three genes
What is the structure of Rous sarcoma virus?
It has the Rous proto-oncogene src in addition to the normal retrovirus genome
What is the structure of Avian myelocytoma virus?
It has the proto-oncogene myc but missing the entire pol and other two genes
What genes are in a normal retrovirus genome?
gag, pol, and env
How can a proto-oncogene become an oncogene?
By being overexpressed or altered in some way
How are proto-oncogenes usually altered to become oncogenes?
They become truncated
What is an example of a proto-oncogene becoming truncated to become an oncogene?
EGFR
What does EGFR do?
It is a transmembrane protein that binds to EGF to stimulate growth
What does EGF stand for?
Epidermal growth factor
What gene encodes for EGFR?
ERBB
What happens when normal EGFR binds to EGF?
It becomes phosphorylated to continue the pathway
What does the mutant EGFR do?
It is truncated, so it can become phosphorylated without EGF present
What has study of cis and trans acting retroviruses led to?
The understanding of many cell cycle control genes
What are three ways in which viral genomes can change?
Mutations, recombinations, and assortments
How can mutations, recombinations, and assortments lead to virulence?
They can change the structure of proteins to make them more pathogenic
How come a 1 in a billion chance is not improbable for a virus over time?
They have a high replication rate
What type of genome is needed for evolution?
A mutating genome
What type of genome is desired in the short term?
A stable genome
How come the mutation rate in viruses is very high?
The mechanisms to reduce the mutation rate are not present
What does DNA polymerase have that RNA polymerase does not?
Proofreading ability
How come new RNA viruses will be geneticallly heterogeneous?
RNA polymerase lacks proofreading ability, so there are more mutations during replication
What does a high mutation rate imply?
The viruses are evolving at a fast rate
What is the mutation rate of influenza virus?
10^-5
What is antigenic drift?
The change in the protein structures of the surface proteins HA and NA on influenza virus due to mutations
How come mutations in HA and NA are significant?
They are the primary targets of the immune system, so if they change, the immune system will not recognize the influenza virus
What is the consequence of mutations in HA and NA?
A new influenza vaccine needs to be given every year
How come a person with HIV can have multiple viral alleles?
HIV has a high mutation rate inside the host
What switch can occur due to HIV mutations?
A switch from monocytes and macrophages to CD4+ T cells for recognition
How con HIV can switch host range?
Due to mutations in the gp120 protein
What receptors can gp120 bind to (before and after mutations)?
CCR5 on monocytes and macrophages, and CXCR4 on CD4+ T cells
When does viral recombination occur?
When a cell is infected by two different strains of a virus simultaneously
What is the result of viral recombination?
Progeny viruses that have part of each genome
What does RNA synthesis in coronaviruses appear to be?
Discontinuous
What is the consequence of RNA synthesis in coronaviruses being discontinous?
An RNA polymerase can jump from one RNA strand to another to produce recombinant RNA genomes
What is viral reassortment?
Combining of gene segments from two or more parental viruses
What types of viruses undergo viral reassortment?
Segmented viruses, such as influenza
What does each segment in a segmented genome encode for?
One or two polypeptides
How is viral reassortment similar to viral recombination?
It requires coinfection with two different strains of a virus
How is viral reassortment different to viral recombination?
Genome molecules do not undergo recombination to form a hybrid molecule
What does each progeny virus receive in viral reassortment?
One copy of each segment from either parental virus
