Viral Pathogens: Classification, Biology And Disease Part II Flashcards
Describe how CD4+ cell count and HIV numbers change over the course of a ‘typical’ HIV infection
- more HIV in the primary infection = more T cell killing
- then HIV falls to the viral load set point
Explain why the T cell count is falling in the chronic phase of HIV
The virus is at the viral set point and is very slowly replicating - over time this will cause a loss of many CD4+ T cells as seen in the part called clinical latency (you do not need to have a lot of virus replication to have a very profound effect on the T cell count)
Why do viruses infect T cells?
They have CD4 on their cell surface membrane which allows the binding and invasion of viral particles
What is the viral load set point?
The minimum number of HIV particles that there can be in the body for the virus not to be detected by the immune system but it is still replicating so v small amount of virus replication
Explain why HIV replicates in immune cells (T cells)
To evade immune response - they hide here and kill them and inhibit their function
What does inhibition of immune cell function allow?
Other pathogens to replicate in virus infected hosts
What is meant by a permissive vs non-permissive T cell?
Most CD4 T cells are not able to allow for HIV replication (95%) = non-permissive. But HIV can get into the cell, just not replicate as it is seen by the innate immune system.
- Permissive = 5%
What is the HIV pathogenic cycle?
- Pyrophosis causes inflammation
- T cell recruitment
- HIV Tcell infection
- Infected + cell death by pyroptosis
What 2 general ways do we think that HIV kills CD4+ T cells?
- Replication in permissive cells can lead to the activation of apoptosis
- Infiltration of HIV in a non-permissive cell will lead to the cell detecting it by the innate immune system and the cell kills itself by pyroptosis
Describe what pyroptosis causes and how does this contribute to the pathogenicity of HIV?
Inflammation - so there is recruitment of immune cells including T cells to the site of infection → so these cells can be infected → … positive feedback
Describe the HIV independent pathogenic cycle
Inflammation (from the HIV-dependant pathogenic cycle) can cause T cell death so this is how HIV can indirectly cause death of T cells
How does HIV cause AIDS and then death?
T cell count drops very low = immunodeficiency = infection of the person with opportunistic infections of HIV associated pathogens
- opportunistic infections with some viruses can cause cancer also
Why is there inflammation caused by the HIV pathogenic cycle?
Migration of neutrophils and monocytes into the tissues
→ Cell death and release of pro-inflammatory cytokines and cellular contents
→ More inflammation
What are the HIV associated viruses?
- Herpes simplex virus
- Kaposi’s sarcoma herpesvirus
- This group is also the most common cause of death in aids.
- The others can infect and colonise but the viruses often are the cause of death
What are the HIV associated bacteria?
- Mycobacterium tuberculosis
- Salmonella
What are the HIV associated fungus?
- Candida
- Cryptococcosis neoformans
What are the HIV associated parasites?
- Cryptosporidium
- Toxoplasma gondii
What are the two routes of possible infection in AIDS?
- Primary infection
- Reactivation from latency
The 4 groups of HIV/AIDS associated pathogens are opportunistic. What does this mean?
They would not be able to infect the patient unless they are immunosuppressed
What is latency and how does it work?
- This is what we think of when we call a virus ‘dormant’
- It is where the primary infection is resolved but the infection moves to places where the immune system does not access and the virus remains here without replicating = latency
When does reactivation from latency occur?
Immunodeficiency
Describe the general mechanism of infection of HSV (herpes simplex virus)
- Virus infects an epithelial cell of the lip or eye then replicates
- HSV moves into dendrites of a neurone that is closely associated with the epithelial cell
- HSV can move up and down the axons in the PNS or CNS
- In latent infection it remains in the cell body of the neurone
Why does HSV pick this cell to invade specifically?
The immune system does not ‘see’ dendrites (dendritic cells) very well at all
What type of cancer does KSHV cause?
A sarcoma of the skin - is very rapid and aggressive
What type of cancer does human papilloma virus cause?
Skin
What type of cancer does Epstein-Barr virus cause?
Lymphoma
What type of cancer does hepatitis B virus cause?
Carcinoma
What type of cancer does hepatitis C virus cause?
Carcinoma
What type of cancer does human herpes virus 8 cause?
Lymphoma
What type of cancer does human t-lymphotrophic virus-1 cause?
Leukaemia/lymphoma
What type of cancer does merkel cell polyomavirus cause?
Carcinoma
HIV-1 specifically infects a small group of immune cells such as helper T cells, monocytes, and macrophages. We say that is a tropism; what determines that tropism?
The specific binding of GP120 to CD4 on the T cell
(Consolidation session) How do blebs link with endotoxin? Do they contain endotoxin?
Blebs = protrusions of the cell membrane
I think that blebs can cause release of endotoxin as endotoxin is in the wall of the bacteria?????
(Consolidation session) To clarify, is it mainly alpha and beta toxins which help initiate the production of biofilms?
- During the initial bacterial cell attachment phase, alpha-toxins are involved in establishing cell-to-cell contacts, enabling the formation of secondary biofilm structures.
- In the later stages of the biofilm, extracellular matrices develop, surrounding the cells within the biofilm.
- Made from extracellular DNA (eDNA), beta-toxin covalently cross-links with itself, adding to this extracellular biofilm matrix and contributing to the formation of complex biofilm secondary structuring.
(Consolidation session) Could you please explain again how type 1 E.coli stable heat toxin leads to diarrhoea: is it because there is less water found intracellularly?
- The Guanylate cyclase-C (GC-C on the slides) is a membrane receptor that controls chlorine, bicarbonate ions out from and sodium ions into gut cells concomitantly regulating the movement of water molecules across.
- STa over activates GC-C leading to an increase in cGMP which in turns activates cGMP-dependent protein kinase II (PKGII), which co-localises with the CFTR (cystic fibrosis transmembrane receptor) and phosphorylates it thus promoting the electrogenic release of mostly excess Cl− which then induces the transport of excess water molecules producing diarrhoea.
(Consolidation session) Could you please explain again how type 1 E.coli stable heat toxin leads to diarrhoea: is it because there is less water found intracellularly?
- The Guanylate cyclase-C (GC-C on the slides) is a membrane receptor that controls chlorine, bicarbonate ions out from and sodium ions into gut cells concomitantly regulating the movement of water molecules across.
- STa over activates GC-C leading to an increase in cGMP which in turns activates cGMP-dependent protein kinase II (PKGII), which co-localises with the CFTR (cystic fibrosis transmembrane receptor) and phosphorylates it thus promoting the electrogenic release of mostly excess Cl− which then induces the transport of excess water molecules producing diarrhoea.
(Consolidation session) To confirm, is the way to cause damage to the host cell membrane: inserting channels which lead to enzymatic damage?
- No.
- There is a little confusion here.
- Membrane damaging toxins like PVL, LukAV and LukGH bind to host cell surface receptors (like ADAM10) and polymerise into membrane channels disrupting the membrane and ultimately killing the cell; that is receptor-dependent.
- Other toxins like phenol-soluble modulins have enzymatic activity and just directly destroy the host cell membrane (receptor independent).
(Consolidation session) Are all cells involved in the innate immune response, tissue-resident and migrate easily to their site of action?
- Generally, those innate cells are two different types of cells.
- First tissue-resident cells, like macrophages and some lymphocytes (NK cells and gamma-delta T cells) live and within and are highly adapted to the tissue in which they reside.
- They recognise pathogens and damage and start or mediate immediate immune responses.
- These responses tend to trigger the release of chemokines that will attract other migratory cells like neutrophils, T cells and monocytes to the site of infection/damage.
(Consolidation session) How is it that a vaccine has been produced against serotype B and C (MenB etc), if endotoxins cannot be converted to toxoids?
- You are correct when saying that vaccines cannot be made by just having inactivated endotoxins as they are difficult to inactivate, poorly immunogenic, diverse, and sometimes similar to self-molecules (the latter not a good idea if we want to use them as vaccines)
- But the meningitis vaccines against serotype B and C are made with recombinant proteins from Neisseria (made transgenically to produce the proteins and then purifying them).
- Those Neisseria antigens include, for the MenB vaccines: adhesin A (NadA), Neisserial Heparin
- Binding Antigen (NHBA), and factor H binding protein (fHbp) as well as lipidated fHBP variants.
- All those antigens are relatively conserved in Neisseria, so they make very good targets for a vaccine immune response when compared with the endotoxin.
