#11-13 Viral pathogenesis Flashcards
- -
- gain entry to body
- multiply and spread
- target appropriate organ (where they will replicate lots to be given to a new host)
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- shed into environment OR - taken up by arthropod vector or needle OR - be passed congenitally
what are the 6 routes of virus entry for a virus
- Conjunctiva
- Respiratory tract
- Alimentary tract
- Urogenital tract
- Parenteral inoculation (mosquito, tick etc.)
- Skin
where do most viruses enter? why
Most viruses enter via the epithelial cells of the mucosa because the epidermis of the skin is covered by dying cells covered with keratin and provides a hostile environment for viruses
what is the most important site of virus entry
respiratory tract
how is respiratory tract infection acquired
Acquired by aerosol inhalation or mechanical transmission of infected nasal secretions
Droplet size will determine where the virus initially deposits - where will small / large particles deposit in a RT infection
more than 10µm will lodge in nose (big droplets), 5-10µm will lodge in the airways, less than 5µm will lodge in the alveoli (very small particles)
what are the barriers to RT infection?
mucus, cilia, alveolar macrophages, temperature gradient, secreted IgA. Cilia and mucous are the main barrier!
Name the RNA viruses that stay localised in the RT tract and what they cause
- Picornaviridae: Rhinovirus (causes common cold, very sensitive, needs a certain temperature for replication. Needs upper airway epithelial cells to replicate in that temp.)
- Coronavirus: (common cold, upper RT)
- Orthomyxovirus: Influenza (flu, upper RT)
Paramyxovirus: Parainfluenza and Respiratory syncytial virus (RSV)
name RNA viruses that spread systemically in RT infection
- Togaviridae: rubella (German measles)
Paramyxovirus: measles, mumps
name DNA viruses that stay localised in the RT
adenovirus
name DNA viruses that spread systemically in the RT
- Herpesvirus: varicella-zoster virus
Poxvirus: small pox
why is RSV virus significant in children
- common infection in kids
- Macrophages can become infected in lung of a child - provide a mechanism for the virus to become systemic
- Syncytia occurs where macrophages fuse together to form a multinucleated giant cell in the lung
where does mumps replicate?
what receptor does it use?
- primary viral replication in epithelial cells of URT
- receptor is sialic acid
- Can cause a systemic infection involving virtually all organs including the CNS
what is an indicator of mumps?
large swollen glands
where does measles replicate? explain the infection cycle
what receptors does it use/
- Primary viral replication in epithelial cells of URT
- It first infect local macrophages, lymphocytes and DC’s.
- It will then enter the draining Lymph node (this is where first round of viremia occurs. It will infect more immune cells to spread
- (infects immune cells, therefore can access everywhere)
- It will then enter circulation and amplify in lymphoid tissue
- Returns to epithelial cells in lung and mouth via secondary viremia
- The replicating in the skin causes the measles rash - this gives the virus the ability to replicate in the mouth again which will allow it to be transmitted to someone else via coughing. It is not transmitted by the rash!
- The receptors used are CD150, CD46 (all cells have CD46)
what is an indicator of measles
koplick spots in the mouth from accumulation of lymphocytes in the mouth from replication from virus
is measles transmitted by rash?
no its transmitted by coughing
what are barriers to infection of the alimentary route
- Sequestration in intestinal contents (constant movement of contents and allow contact with specific receptors)
- Mucus
- Stomach acidity - pH 2.8 roughly
- Intestinal alkalinity - below stomach
- Proteolytic enzymes secreted by the pancreas
- Lipolytic activity of bile - will eat envelopes
- IgA
Scavenging macrophages
how do viruses enter the alimentary route
Ingested viruses can either be swallowed or infect the oropharynx and then be carried elsewhere
If viruses do not have receptors for epithelial cells - they need to enter via a breach in the epithelial surface i.e. HIV, Hep B can infect via abrasions of the rectal route
what are some characteristics of a virus that can infect via the alimentary route
- acid and bile resistant
- do not have an envelope (except coronavirus SARS which can infect in ingested milk or food)
what are RNA viruses that infect via alimentary route and stay localised
- Coronaviridae: Coronavirus (SARS)
- Calicivirus: Norwalk virus
Reovirus: rotavirus
what are RNA viruses that infect via alimentary route and spread systemically
- Reoviridae
- Picornaviridae: enteroviruses, Hep. A virus
what are DNA viruses that infect the alimentary tract
Herpes simplex virus and EBV can infect the alimentary tract but do not pass through the gut (rectal route)
DNA virus that infects alimentary tract and spreads systemically
adenovirus EBV (doesnt pass through gut)
what is EBV and
how is EBV acquired
- infectious mononucleosis - glandular fever
- acquired by direct contact of infected saliva with oropharynx
how is HSV acquired
Acquired by direct contact of infected saliva with abrasions in the lip or mouth
or genitals
how does Rotavirus infect
how is it transmitted
- enters intestinal tract
- has a double layered capsid core
- infects and destroys M cells
- causes diarrhoea
- NSP4 protein increases secretion
- virus is transmitted via faeces
- infection stays local
how does Caliciviridae: Norovirus & Norwalk virus infect
- enters alimentary route
- naked
- causes gastroenteritis
- cannot be cultured
- common infection
what viruses will enter the alimentary route and cause systemic infection?
Picornaviridae enteroviruses viruses
- poliovirus
- Coxsackie A virus
- Coxsackie B virus
- echovirus
- other enteroviruses (68-71)
- rhinovirus
- hepatoviruses (Hep. A)
does norovirus have a vaccine
no - it cannot be cultured !
describe how Hep A and Picornaviridae enteroviruses infect and replicate
- Normally enter via aerosol - breathed in / or ingested
- Can replicate in the URT or intestine first
- Objective is to expand the amount of virus particles in the URT or intestine before the immune system can detect them
- These particles will enter the blood conduct the first round of viremia
- In first round it will transmit to the lymphoid tissue such as they payers patches or spleen where it gains access to the systemic circulation
- It will then be able to target other organs and tissues to make more virus and conduct secondary viremia
what organ does hep a target for secondary viremia
hepatocytes of liver
what organ does Picornaviridae enteroviruses target for secondary viremia?
brain and CNS
how does papillomavirus enter the body?
via minor trauma in the skin
what viruses enter via insect/animal bite?
- Dengue - fever, rash
- Ross river: fever, rash
- Rabies: animal bite, fever, neurological symptoms
- Bat lyssavirus virus: bat bite
what viruses enter via the transcutaneous route (bypassing the skin)
Hep. B, Hep. C, HIV
- they need to do this as they have an envelope and need to be in blood
what virus can enter the conjunctiva of the eye and cause conjunctivitis
adenovirus
describe the mechanisms of spread in the body
- local spread on epithelial surfaces OR - sub-epithelial invasion and lymphatic spread OR - spread in the bloodstream - viremia OR - neural spread
describe the two modes of viremia
Viruses are free in the plasma:
- Occurs in primary and secondary phases
- The infected vasculature endothelium releases lots of virus in a short amount of time (i.e. from liver or spleen). Occurs before Ab’s have been made (unless vaccinated)
- The virus is neutralised by the Ab response or removed by macrophages (usually lasts 1-2 weeks)
cell associated transmission:
- The virus will hitch a ride on immune cells like monocytes, or t-cells etc.
- It will be taken to the lymph nodes where it can replicate and stay in more immune cells
- Once virus is within a cell it can persist for months or years if the viral genome becomes latent to avoid CTL attack (i.e. HIV)
i. e. Measles and dengue spread via monocytes and HIV spreads by T-cells
explain the typical course of viremia
- infection of epithelial surface
- particles will translocate to a regional lymph node
- particles released into blood stream via primary viremia (occurs before the onset of Ab’s)
- virus reaches more organs like spleen and liver - will then shed again via secondary viremia
- virus can now access more organs
explain the course of viremia for poliovirus
- Virus ingested
- Replicates locally fast - Enters intestine and enters gut lymphoid tissue like Peyers patches, also invades M cells and replicates in monocytes
- Travels to regional lymph nodes where it replicates more
- Enters the blood via primary viremia. Then performs secondary viremia
- Virus crosses the endothelium of the blood brain barrier and replicates in anterior horn causes cell destruction and paralysis
- Poliovirus levels are high in the cells of the gut, and therefore high in faeces. This is how the virus is transmitted to other people
(pathogenesis from this virus is not beneficial to the virus as the host dies)
how is polio transmitted
via the faeces - virus is high in the faeces
why is tissue evasion from the blood good for virus
how do viruses invade tissues from the blood
- Is a highly successful strategy for transmission for a virus
- viruses will transit the blood and enter the tissues via capillaries
- The barrier to entering the tissues is the capillary endothelial cells
- In some tissues the endothelial cells of the capillary are not joined by tight junctions and virus can pass between them eg. mumps in choroid plexus of brain
- Some viruses will cross to tissues in monocytes and lymphocytes as part of normal cell trafficking
- Some viruses are transported across these cells by transcytosis
- Some viruses can replicate in endothelial cells and progeny virus is released into tissues passively
how does neural spread occur?
- Can spread via peripheral nerves i.e. Herpes, rabies, varicella
- The uncoated nucleocapsid is carried passively along axons or dendrites
- Multiplication in the body of the nerve and released progeny can cross the synaptic junction - eventual entry into the CNS
- Viruses are protected from attack by CTL as the nerve cells do not have MHC class I molecules
Other viruses can enter the CNS directly via the bloodstream
explain the infection and neural spread process of rabies virus
- Bite
- There is local replication in the muscle tissue (1-60 days!) - hence we can vaccinate after bite
- As its replicating it can access peripheral motor neurons
- The virus will move up the synapses via axonal transport
- Will reach the CNS and brain - changes behaviour of victim
- Enters the salivary glands
- It reprograms the behaviour of the animal, it will be transmitted to the new host when new host is bitten
explain neural spread process of Varciella Zoster virus VZV
what does it cause?
- Causes chickenpox in initial phase
- Access human via conjunctiva, or upper RT
- Replication in regional lymph nodes
- Primary viremia in blood
- Replication further in liver and spleen
- Secondary viremia
- Infection of skin and vesicular rash appears
- At this point it can gain access to the sensory nerves. It will become a latent infection in the dorsal root ganglia
- It can reactivate when the CTL response wanes as Shingles!
congenital infection - what occurs with a cytocidal vs. non-cytocidal infection
- Can cause death and abortion via cytocidal viruses (i.e. smallpox)
Developmental abnormalities can result by non-cytocidal viruses i.e. Rubella, CMV
or can affect baby at birth
congential HCMV infection - how does this affect baby
- Most common cause of congenital infection
- Most common cause of mental disability after down syndrome
- Causes microencephaly
- Infection of mum
- Spreads to the foetus
- 40% chance of babies having defects
Hep. B is shed in the faeces from the liver - is it infectious?
no - as it doesnt have an envelope. it is transmitted via blood and bodily fluids
how is poliovirus shed
- via faces
how is HPV spread
via top layers of skin
mechanical contact
how are Hep. B, Hep. C, HTLV and HIV spread
blood
how are flaviviurses (dengue and yellow fever) transmitted
insect bite into blood
cannot transmit man to man as virus levels in blood are too low
how can CMV be transmitted
transferred through blood, urine, saliva, tears, breast milk, semen and other cervical secretions
CMV infection is inapparent - how is this bad for pregnant women
- Infection of CMV is usually inapparent. It will cause damage to the developing foetus leading to abnormalities
Causes microencephaly
what determines if a cell is susceptible to a virus
receptor will determine if a virus can enter the cell or not
however not all viruses will/can access cells with the receptor - other determinants of tropism factor in
what determines tropism
-receptor available
-permissive (has the right products to allow gene replication of virus)
-accessibility (virus has to be able to access the cell)
also need to consider local factors such as temperature, pH and ability of virus to survive bile and proteases etc.
where is rhinovirus restricted to? why
restricted to the URT
needs cool temperature
what are the factors affecting cell accessibility for a virus
- Ability to replicate in macrophages and lymphocytes or travel free in blood - if they can they can gain access to many tissues
- Polarized release (apical versus basolateral) - its hard to gain access to deeper tissues if only released from apical side of cell. if it is released via basolateral surface it can gain access to deeper tissues
what restricts influenza to the respiatory tract?
- Influenza HA is made as a single polypeptide chain which must be cleaved next to the fusion peptide for the virus to be infectious by tryptase clara
which is only secreted in the respiratory tract
(Some highly pathogenic influenza can use furin - which is ubiquitous in the body which can cause systemic infection)
what are the genome transcription requirements for papillomavirus. where does it replicate
the skin is the only tissue that can support the complex cascade of transcription factors to support the replication cycle of the virus
- The virus commences genome replication in the germinal cells in the base layer of the skin - it has access to all the proteins and enzymes it needs
- These base cells produce proteins that block transcription of late structural genes
- As the cell moves outwards the transcription factors in the cell change
- Now the virus can produce capsid and infectious virus particles
- When the dead keratinocytes reach the surface of the skin they are loaded up with infectious virus particles
- Virus can then be transferred from the wart
what is pathogenicity
- is a organisms inherent genetic capacity to cause disease (i.e. genes)
- i.e. highly pathogenic influenza strains are cleaved by furin - this is a result of their genetics.
They are distinguished genetically from the seasonal strains of flu
what is virulence
- Is a measure of the degree of disease that a pathogen causes.
- Quantitative trait that can be measured. Representing the degree of pathology seen in a given pathogen-host interaction
- can correlate with pathogen’s capacity to multiply in the host, e.g. virus titre when symptoms appear or the rate of viral multiplication
- Can be affected by host and environmental factors: e.g. route of infection, age and immune status of host
what are virulence factors?
- are proteins encoded by the virus (or non-coding regions of genes) that influence replication, and modify host defences, allow efficient spread within the host, or are toxic to the host.
- We need to identify and counteract these
Measurable
how can relative virulence between two viruses be measured?
measuring factors such as:
- Mean time to death
- Mean time to appearance of symptoms
- Degree of fever, weight loss, clinical pathology score
- Loss of immune cells e.g. CD4+ T cells in HIV
- All relative measures of viral virulence
what are 4 virus induced changes to cells?
transformation: create tumor
lytic infection; cause cell lysis
chronic infection: slow release of virus without causing cell death
latent infection: no damage to cell but virus can later emerge as a lytic infection
what are the mechanisms of disease production?
- Viral induced damage to tissues and organs:
- Death can result from viral replication
- Can result in loss of function of that cell - Consequences of the immune response:
- Immune system causes damage and disease
- Immunopathology
- Immunosuppression
- Autoimmunity
how do cytocidal viruses cause direct damage to tissues
- Rotavirus: Tissue specific cell killing of enterocytes
polio: death of neurons causing paralysis
how do non enveloped viruses exit the cell
lyse the cell
how does polio shut down cell protein synthesis
Poliovirus encodes protease 2A that cleaves cellular eIF4G so cellular mRNA cannot be translated - leads to cell death
how does poxivirus shut down cellular nucleic acid synthesis
poxvirus makes a DNase that eliminates the capacity for the host cell to make cellular DNA
how does a non-cytocidal virus cause damage to a cell
3 ways
- Cells may lose their ability to perform particular functions
E.g. LCMV causes a non-lytic persistent infection of the cells in the pituitary gland that produce growth hormones. The infected cells produce less growth hormone mRNA. Animals are stunted because they do not have normal levels of growth hormone
- E.g. rhinoviruses cause cilia stasis in respiratory epithelium (cilia cant move mucous out of the airway) - Infected cell will become targeted by the immune system, attacked and killed
- Transformation - Some viruses encode oncogenes - in the virus infected cell they are associated with tumour production
immunopathology cause damage to tissues?
Antibody-mediated
pathology:
- Antibody-dependent enhancement of infection
- by FcR mediated uptake of virus-Ab complexes into macrophages and monocytes
- E.g. Dengue haemorrhagic fever/shock syndrome - if you get infected with a second strain of dengue the Ab’s will bind however they will not neutralise the virus. Haemarroging of the skin occurs
- Antigen-antibody complexes
- When they are deposited in the kidney can cause glomerulonephritis and in the blood vessel and vasculitis
- e.g. Hep B in chronic carriers
T cell-mediated pathology:
- CD4 T cell-mediated responses
- Is responsible for some viral rashes e.g. measles type IV (delayed-type) hypersensitivity in which T cells mediate an immune response to the virus involving inflammation
- in the endothelial cells of the small blood vessels in the skin Koplick spots are when these foci of inflammation in the mucosa form ulcers
- Induce cytokines that recruit eosinophils responsible for bronchiolitis in infants with respiratory syncytial virus (RSV) infection
CD8 T cell-mediated responses:
- Contributes to liver damage in Hep B virus infection
- Causes lysis of hepatocytes, recruitment of monocytes and neutrophils
- Yellow skin and eyes are a sign of liver damage
- Old RBCs are destroyed by macrophages in spleen
- Heme from the haemoglobin is converted to bilirubin (yellow)
- Bilirubin in tissues and none in faeces
how does autoimmunity cause damage to tissues
- when viruses perform Molecular mimicry
- e.g. Myelin basic protein is resembled by some proteins that that influenza produces
- e.g. coxsackie B4 virus can mimic heart muscle antigens (causing myocarditis)
- Polyclonal B cell activation: can be done by EBV
what are genetic factors that determine the host outcome to an infection
- Inherited defects e.g. Absence of Ig class etc. - detrimental
- Polymorphisms in genes controlling immune responses such as MHC - can be beneficial!
- Interferon inducible genes
- Receptor genes e.g. CCR5 if mutated can provide resistance from HIV infection
what are non-genetic factors that determine the host outcome to an infection
- Age: newborns and elderly more susceptible to severe disease. Young suffer less from immunopathology
- Malnutrition: decreases resistance
- Hormones, pregnancy: males and pregnant women are more susceptible to virus. It’s the androgens in males
- Dual infections: may result in more severe disease
what are possible outcomes of viral infection
- Fatal: rare i.e. Ebola
- Full recovery: virus completely cleared by the hosts immune system i.e. influenzas
- Recovery but permanent damage: virus is cleared but left with symptoms i.e. Poliomyelitis, cancer
- Persistent infection: virus not cleared and can resurface to cause disease
