Lecture 8 - The immune response to viral infection Flashcards
What type of viruses generally cause greatest mortality?
Zoonotic viruses (those that have ‘jumped’ species)
Viruses are ‘obligate intracellular pathogens’ what does this mean?
They are dependant on host proteins for replication
What are viral genomes enclosed with?
Capsids (coat proteins)
What are Cytopathic (lytic) viruses?
Viruses that lyse host cells by inducing apoptosis or autophagy, e.g. poliovirus or influenza
How does the cytopathic herpes virus infect cells?
It can infect cells without producing infectious virions until immunity wanes or until reactivated by various physiological signals - known as latent viruses
What are non-cytopathic viruses?
Viruses that replicate without destruction of cells e.g. Hepatitis B
How do intestinal viruses such as poliovirus enter the host body?
Enter via antigen sampling M cells
How do respiratory viruses such as influenza and rhinovirus enter the host body?
They establish infection in the epithelial cells of the airways
Name 2 viruses that require insect vectors for infection
dengue virus ans west nile virus
How do bloodbourne viruses such as HIV and Hep B enter the host body?
Invade through mucosa or epithelia following physical trauma (such as epithelial hair, injections or blood transfusion
What is tissue tropism?
Cells and tissues of a host that support growth of a particular virus or bacterium.
Viruses invade either via widely expressed surface molecules or using receptors with more restricted tissue expression patterns
What is major innate immunity mediated via?
Type 1 interferons, compliment and NK cells
What is major adaptive immunity mediated via?
Antibody and cytotoxic t lymphocytes
What are type 1 interferons?
A group of proteins that host cell enzymes that affect transcription and translation of viral genes
What is the initial appearance of a virus rapidly followed by in response?
Massive expansion of virus specific CD8 T cells.
CD4 T cell expansion and contraction also occurs but at a lower magnitude
What is produced relatively early after acute infection with a cytolytic virus, and what is their role/ mechanism?
Neutralising ABs
The AB binds the virus, allowing recognition by macrophages
Binding to the complement receptor on the macrophage allows activation of the classical complement pathway via the C1q/r/s complex.
Direct activation of the macrophages can also occur by binding of the ABs Fc receptor
Neutralising ABs are able to block binding of receptors that the virus uses to enter the host cell
Define epidemic
Classification of a disease that appears as new cases in a given human population, during a given period, at
a rate that substantially exceeds what is ‘expected’, based on recent evidence
Define pandemic
An epidemic that spreads through human populations across a large region e.g. a continent, or even worldwide.
(When a virus moves across continents it becomes a pandemic not an epidemic)
What virus causes AIDS?
Human immunodeficiency virus (HIV)
What type of cell does HIV target?
It infects and destroys CD4+ T lymphocytes
What is pneuocystic pneumonia (PCP)?
A form of pneumonia caused by yeast like fungus pneumocystis jirovecii
How do patients develop pneuocystic pneumonia (PCP)?
Pneumocystis fungi is commonly found in the lungs of healthy individuals but, being a source of opportunistic infection, it can cause lung infection in immune compromised patients.
It is therefore commonly seen in patients with HIV/ AIDS and those undergoing chemotherapy or on medications that affect the immune system
Where did HIV-1 originate from?
Human immunodeficiency virus 1 originated from a retrovirus (SIVcpz) that infects non human primates in west central africa. It was introduced to humans through bushmeat and then mutated to produce HIV
What are the key surface proteins possessed by HIV that allow it to dock to T cells in order to cause infection?
GP120
GP41
HLA-DR class I and II
What are HLA-DRs?
Human Leukocyte Antigen - antigen D Related proteins, which are ligands for TCRXs
How does HIV enter via the epithelia?
- HIV-1 can cross mucosal surfaces through M cells prevalent in tonsils and rectal epithelia
(It can also gain access via epithelia damaged by ulcerative infections or trauma/ injections) - Epithelia cells in the small intestine express CCR5, a chemokine receptor to which HIV-1 binds via GP120
- This allows the virus to be trancytosed
The vaginal epithelia lack M cells. How does HIV gain access to the body via this route?
HIV gains access via interdigitating processes on langerhans cells.
Once across the mucosal epithelial barriers, how is HIV transported to lymph nodes?
- C type lectin receptors (CLRs) on DCs bind GP120
- This interaction initiates DC migration to regional lymph nodes
- Once in lymph nodes, virus is re-exposed at the surface and displayed to T cells
* Regardless of the route of infection, the predominant site of virus replication early in disease is in the small intestine - this reflects the large number of activated T cells that express CCR5 in that organ
What does GP12 on HIV bind?
CD4 and chemokine receptors CCR5 or CXCR4 on host surfaces
What is the mechanism of HIV infection? (9 steps)
- HIV infects cells via cd4 and CCR5/CXC4 (coreceptors)
- HIV binds CD4 via GP120
- Interactions with coreceptor allows entry of nucleocapsid containing viral genome into cell
- Viral reverse transcriptase makes viral rna genome of HIV into double stranded DNA
- Integration of viral DNA into host chromosome.
In this state, virus remains latent - Then when host cell becomes activated, viral transcription is initiated
- Viral proteins and genome linked RNA transcripts of the virus are produced
- Viral proteins assemble at cell membrane, along with copies of the RNA genome, and can bud off to form new viral particle
- This can then mature to form a new infectious virus particle
How soon after infection with HIV do DC translocate it from the mucosa?
Within 30 minutes of infection
When does the wave of viral proliferation in lymph nodes peak after infection with HIV?
4-7 days
when does viremia peak within a HIV infection and at what point are all lymphoid tissues infected?
Viremia peaks at 14 days and all lymphoid tissues are infected by 3 weeks
What are the stages of progression of an untreated HIV infection?
Infection typically results in flu-like illness from days to weeks after exposure - associated with a drop of CD4 T cells in the blood
The CD8 T cell response develops and is responsible for a prolonged period of stable viremia. This is known as the viral set point.
Patients remain asymptotic until CD4 count oops further, allowing the development of opportunistic infections
Death after around 2 years
What is a ‘viral set point’?
A prolonged period of stable viremia
Give some examples of the types of secondary infections you can expect from HIV
Toxoplasmosis Cryptococcal meningitis Cytomegalovirus Candidiasis (thrush) - oral and vaginal Tuberculosis Histoplasmosis Herpes simplex shingles Genital herpes
Which strains of influenza are major causes of human disease, and which of these are responsible for pandemic outbreaks?
Influenza A and B, only A is responsible for pandemic outbreaks.
Influenza A viruses are avian viruses that adapt to humans
How does the influenza virus spread?
Spread by aerosol droplets and establishes cytolytic infections in the epithelial cells of the upper and lower respiratory tract
What are the properties of the influenza A virus?
Spherical or rod shaped enveloped virus covered wit 2 spike like glycoproteins
Trimeric hemagglutinin (HA) Tetrameric neuraminidase (NA)
What does hemagglutinin (HA) on a virus mediate?
Binding to cell surfaces and internalisation
What does neuraminidase (NA) on a virus mediate?
Cleaves silica acid and promotes viral release from cells (allows virus to get back out of cell)
What are the _ steps in the process that allows viruses to enter and infects host cells? (HA, NA, binding and budding)
- Haemglutanin binds to sialic acid aka neuraminic acid (carbohydrate found within receptos on the epithelial cells) via HA receptor
- Once this happens its endocytosed
- RNA replication and production of viral proteins
- The viral particles are packaged back into the coat protein and then budds of and goes and finds another cell to bind to the neirominic acid and infect
Which receptors does avian influenza preferentially bind to?
alpha-2,3 silica acid linkage to galactose on intestinal cells
Which receptors does human influenza preferentially bind to?
alpha-2,6 linkage expressed on respiratory epithelial cells
Why are pigs important in human infection with influenza virus?
They express both alpha-2,3 and alpha-2,6 linkage on their epithelia.
Therefore influenza can enter the human population where there are humans, pigs and birds living in close proximity - exchange of viral genomes within the pigs, and give rise to variants expressing novel surface proteins, which can infect humans. This leads to epidemics.
What process leads to antigenic drift?
Point mutations in HA or NA, so that in previously immunised individuals, HA and NA are no longer recognised by neutralising ABs produced in response to earlier infections. This is how epidemics occur.
What process leads to antigenic shift?
When avian influenza viruses and human influenza viruses infect pigs and re-assortment of the two genomes leads to the expression of avian HA or NA in a virus otherwise adapted to infect humans. This is how pandemics occur
How is seasonal flu acquired through antigenic drift?
- Pathogens such as the influenza virus have receptors that enable them to bind to host surfaces
- ABs to these viral receptors prevent the virus from binding to and infecting cells – these are neutralising Abs
- However some viruses will have mutations that alter the receptor that prevent them binding the neutralising Abs whilst leaving the virus able to bind to and infect host cells
- The pattern of antigens expressed by virus can change over time because of these mutations
- This process of accumulation of small changes is called antigenic drift and contributes to our susceptibility to influenza infections year after year (seasonal flu)
What is the role of neutralising ABs produced against HA of a virus?
Block binding of receptor within epithelia of the lungs, which prevents the virus binding and entering the cell
What is the role of neutralising ABs produced against NA of a virus?
Prevents tethering of the virus as it comes out of the epithelial cell meaning they can’t leave to enter new cells for infection
How can large scale pandemics occur through antigenic shift?
- Pathogens such as the influenza virus, have receptors that enable them to bind to host cell receptors. ABs to vial receptors prevent binding to and infecting cells – these are neutrslising ABs (neutralise ability of virus to infect the cell)
- In some cases viruses arise that can escape the effects of neutralising ABs. This can happen when 2 strains of influenza virus are able to infect the host cell – the progene viruses can contain sediments of genome from either of the two strains of virus.
- Neutralising ABs are unable to recognise receptor from second strain, and will be unable to prevent the virus from binding to and infecting host cells, allowing antigenic shift to occur.
- Much of immunity against original virus is ineffective. This usually leads to large scale pandemics.
Which H and N subtypes are usually expressed by viruses capable of infecting humans?
H1, H2 or H3 and N1, N2 or possibly N8.
Which combination of H and N proteins caused the Spanish flu pandemic?
H1N1
Which combination of H and N proteins caused the Asian flu pandemic?
H2N2
Which combination of H and N proteins caused the hong kong flu pandemic?
H3N2
Why were many deaths from the Spanish flu seen in healthy young adults?
Extremely high infection rates and the
extreme severity of symptoms, suspected to be caused by hypocytokinemia (cytokine storm).
It most effected young adults as they had the strongest immune systems so had the largest overproduction of inflammatory mediators.
