Killing Intracellular Pathogens Flashcards
Which of the reasons below correctly explain why many pathogens choose an intracellular lifestyle?
- To directly manipulate immune cells
- Can be transported around the host
- There is more oxygen inside cells
- To ensure they remain at the infection site
- Can take nutrients from inside the cell
- It’s warmer inside host cells
- Hide from the immune system
- To directly manipulate immune cells
- Can be transported around the host
- Can take nutrients from inside the cell
- Hide from the immune system
There are many reasons that pathogens choose to be intracellular. Viruses, in particular cannot produce copies of themselves without using the host translational machinery. Many bacteria and protozoa have adapted to living inside host cells and use this niche to get access to host nutrients, to avoid many immune system components (e.g. complement and antibody), to be transported around the host, and to directly modulate host immune cells.
Match the immune cell to its function.
CD4+ Helper T cells
CD8+ Cytotoxic T lymphocytes
NK cells
Macrophages
A. Organise the immune response
B. Kill infected cells by recognising antigen presented by MHC class 1
C. Kill infected cells that have downregulated MHC class 1
D. Kill intracellular pathogens within phagolysosomes
A. Organise the immune response
B. Kill infected cells by recognising antigen presented by MHC class 1
C. Kill infected cells that have downregulated MHC class 1
D. Kill intracellular pathogens within phagolysosomes
Multiple arms of the immune system are involved in killing of intracellular pathogens, and often all arms have to act correctly in order to result in immunity to a pathogen. CD4+ helper T cells organise the immune response, and are important for memory, CD8+ CTLs kill infected cells through recognition of foreign peptides presented on class I MHC of infected cells. Likewise, NK cells kill infected cells which have either downregulated class I MHC (due to e.g. viral evasion of the CD8+ CTL response) or have upregulated stress molecules on their surface due to an infection. Macrophages can kill intracellular pathogens by switching on killing mechanisms such as oxygen radical production, lowering the pH of phagolysosomes, and scavenging metal ions away from the pathogen, however to do so they usually have to be activated by IFN-γ from CD4+ T cells.
CD8+ CTLs and NK cells can both kill virally infected cells in different situations. Match the situation with the immune cell that is most likely to kill the infected cell.
- Cell infected with virus producing viral proteins, which are loaded onto class I MHC
- Infected cell with viral proteins on its surface, bound by specific antibodies
- Cell infected with latent HSV
- HCMV-infected cell with downregulated classical MHC class 1, but upregulated non-classical class I MHC and viral UL18 on surface
- Virus infected cell with downregulated MHC class 1, and expressing cell stress markers
- CD8+ CTL
- NK cell
- Neither
- CD8+ CTL
- NK
- Neither
- Neither
- NK
CD8+ CTLs and NK cells are both effective killers of infected cells, inducing apoptosis through FAS ligation or release of perforin and granzyme. CD8+ CTLs will kill cells which are presenting viral proteins on class I MHC on their surface, while NK cells will kill cells which are marked by antibodies bound to surface viral proteins (ADCC) or cells which have downregulated class I MHC and/or upregulated stress markers. In HCMV infection, where the virus both downregulates class I MHC and upregulates non-classical class I MHC and expresses a viral class I MHC homologue, neither cell is effective at killing infected cells. Likewise, in latent HSV infection no viral proteins are produced, and so the infection cannot be seen by CD8+ CTLs nor NK cells.
The cytokines TNF-α, IFNα/β (type 1 IFNs), IFN-γ, and IL-4 are important in combatting infections with pathogens. Select which cytokine is being described in each statement:
Causing Fever
Inducing an antiviral state
Activating macrophages
Produced by T cells to combat intracellular bacterial infections
Produced by virally infected cells and NK cells
- IL-4
- IFN-α/β
- TNF-α
- IFN-γ
- TNF-α
- IFN-α/β
- IFN-γ
- IFN-γ
- IFN-α/β
During an infection with an intracellular pathogen, IFN-γ produced by helper T cells is important to coordinate the immune response, resulting in macrophage activation. Type I IFNs (IFNα/β) are produced by virally-infected cells and by activated NK cells, acting on non-infected cells to induce an antiviral state, with increased class I MHC expression, and decreased total protein expression, resulting in decreased viral replication. TNF-α is produced by macrophages and other immune cells, and acts both locally (to increase inflammation), and systemically, upregulating acute-phase response proteins from the liver and acting on the hypothalamus in the brain to induce fever. Although IL-4 is extremely important in the response to extracellular parasites, it does not have an important role against intracellular pathogens.
Why do pathogens become intracellular?
What are some examples of intracellular pathogens, and the cells they infect?
Viruses, bacteria and protozoa, Many target immune cells
How do pattern recognition receptors (PRRs) detect intracellular pathogens? What are examples of intracellular PAMPs?
What are some macrophage killing mechanisms of intracellular pathogens?
list some examples
Describe upregulation of macrophage killing mechanisms
How do intracellular pathogens evade the immune system?
- Prevents lysosome fusion with phagosome ( eg Legionella, Salmonella, Leishmania and Mycobacteria)
- Break out of phagosome (E.g. Shigella and Listeria)
- Granulomas (e.g. in Mycobacterium tuberculosis (TB))
- Type III secretion systems (E.g. Salmonella, Yersinia, Shigella and E. coli)
Listeria uses host actin to move within and between cells
In TB Infection can’t be cleared and so is sequestered.
What are some functions of T3SS?
T3SS= type 3 secretion system
Type III secretion system functions:
- phagocytosis and apoptosis prevention/promotion
- phagosome rupture
- lysosome fusion or cell signalling inhibition
How do how CD8+ CTLs and NK cells kill infected cells?
How do NK cells recognize infected cells?
What are the mechanisms by which HMCV evades CTL/NK killing?
What is Antibody-Dependent Cell-mediated Cytotoxicity (ADCC)?
