L15 - GL Smith - Viruses in multicellular hosts Flashcards
list some viruses which enter via the orpharynx
Herpes simplex virus (HSV), human cytomegalovirus (HCMV), Epstein- Barr virus (EBV)
list viruses entering using the respiratory tract
Influenza virus, measles virus, mumps virus, rubella virus, rhinovirus, varicella-zoster virus (chicken pox), adenovirus (respiratory types), SARS-CoV-2
list viruses entering using the alimentary canal
Poliovirus, hepatitis A virus (HAV), rotavirus, adenovirus (enteric types)
list viruses entering throguh the conjunctiva
HSV
list viruses entering through the skin
Human papillomavirus (HPV), HSV, rabies virus
list viruses enteirng through the genital tract
Human immunodeficiency virus (HIV), HSV, HPV (genital warts)
list viruses entering via the Blood: iatrogenic
Hepatitis B virus (HBV), HIV
list viruses entering via the Blood: biting insects
Yellow fever virus (YFV) dengue virus, blue tongue virus
physical defences viruses must evade?
- skin
- cilia
- mucous secretions
- pH of stomach
- proteases in small intenstine
To be successful a virus must:
(3)
– Enter by breaching these defences
– Replicate despite the immune system
– Be released to enable transmission to new hosts
give some ways the innate immune system can destroy viruses
- destroyed by complement in blood
- phagocytosis(macrohpages and neutrophils)
- presence in cell detected by PRR binding PAMPS
components of the innate immune system
Phagocytes
Complement
Interferon (IFN)
Apoptosis
Cytokines
Chemokines
Natural killer cell
Fever
how can cells sense viral infection
- DNA in cytoplasm
- unusual structures - (RNA with a 5’ triphosphate)
- sensed by PRRs as foreign
*
what happens when PRRs bind foreign molecules in the cell
activate signalling cascades
activate transcription factors (eg nuclear factor kappa B (NF-κB) or the interferon response factors (IRFs).)
promote transcription of a wide range of genes that activate innate immunity. These include: interferons, chemokines (that recruit leukocytes to the site of infection) and cytokines that promote the inflammatory response (such as IL-1β and TNF).
what are interferons
Interferons (IFNs) are secreted glycoproteins that bind to specific receptors on cells to induce activation of an anti-viral state. Subsequently, if a virus enters an IFN-treated cell it will be unable to replicate.
There are _ types of IFN.
There are 3 types of IFN.
describe tpye 1 interferons
Released by infected cells and bind to type I IFN receptors on adjacent cells to induce an antiviral state. Up-regulate class I MHC.
alpha and beta
describe type 2 interferons
Released by activated T cells and macrophages, bind to the type II IFN receptor. Promotes inflammation and Th1 (cellular) immunity.
INFgamma
describe type 3 interferons
Bind to the type III IFN receptor. Important in epithelial cells.
are INFs important against viruses?
yep
which out INFs or their receptors - is the course of disease worse?
yep - theyre needed
the fact that very many viruses, probably all mammalian viruses, have at least one way of
avoiding or disabling IFNs, or the functions of IFN-induced proteins
T
After a virus infects a cell, it’s presence is detected by PRRs either within the cytosol or in endosomes by _______. These PRRs then activate ____ and -_____ that move to the nucleus and activate transcription of the IFN_ gene.
After a virus infects a cell, it’s presence is detected by PRRs either within the cytosol or in endosomes by Toll-like receptors (TLRs). These PRRs then activate IRF3 and NF-κB that move to the nucleus and activate transcription of the IFNβ gene.
binding of IFNβto the type I IFN- receptor (IFN-R) on cells causes what to happen?
- induces the JAK-STAT signalling pathway
- activation of a transcription factor complex interferon stimulated gene factor 3 (ISGF-3)
- binds to the interferon stimulated response element (ISRE) that is present in scores of interferon stimulated genes (ISGs).
- ISG proteins prime cell - make it resistant to furture infection
give some ISG examples:
Examples of ISGs are protein kinase R (PKR), 2’-5’ oligoadenylate synthetase (OAS) and the Mx protein.
In the case of PKR and OAs, the proteins require activation by what and inhibit what?
In the case of PKR and OAs, the proteins require activation by dsRNA (produced during infection by both DNA and RNA viruses) and, once activated, these proteins induce the inhibition of protein synthesis (host and viral).
give some ways viruses interfere with the interferon response
- stopping activation of the PRR-induced signalling cascades, so IFNβ is not produced
- releasing soluble proteins to bind IFNs and stop IFNs binding to the IFN-Rs on cells
- inhibiting the JAK-STAT signalling cascade to block induction of ISGs
- targetting the ISG proteins directly to block their action (e.g. 2’5’-oligo adenylate synthetase, and protein kinase R)
Some viruses (such as the poxviruses) exploit all these strategies. The IFN system and the virus strategies for interfering with interferon illustrate nicely virus-host evolution.
how do some viruses block apoptosis
blocking the action of caspases (needed for induction of apoptosis), or targetting Bcl-2 family pro-apoptotic proteins, which function at the mitochondrion to induce apoptosis.
Interferon types summary
how does the vaccinia virus interfer with the interferon virus?
B18 binds type I IFN in solution and on cell surface
describe chemokines
- small chemo-attractant cytokines that recruit leukocytes
- The recruited leukocytes then produce more IFNs or cytokines to activate T cells and macrophages to fight the infection.
how do chemokines attract leukocytes
- Create a concentration gradient on the vascular endothelium
- Bind to chemokine receptors on the leukocyte surface
- Induce leukocyte activation and adherence to vascular endothelium
how do viruses interfer with cytokines?
Virus interference with CKs (herpes and poxviruses)
- Express CK receptors to soak up CKs
- Express virus CKs to recruit cells beneficial to virus
- Express secreted CK-binding proteins – block CK binding to receptors, or binding to endothelial cell wall
what are cytokines
Cytokines that promote the inflammatory response, such as IL-1, IL-12, IL-18, tumour necrosis fact (TNF) and IFN-γ
why are cytokiines important
Cytokines that promote the inflammatory response, such as IL-1, IL-12, IL-18, tumour necrosis fact (TNF) and IFN-γ, are particularly important during the response to virus infection because they drive the development of cellular immunity, such as CD8+ cytotoxic T lymphocytes (CTL) that recognise and remove virus-infected cells.
CTL are particularly important for recovery from systemic virus infections.
are CTLs important for recovery from viral infections?
yep
how does Epstein-Barr virus evade cytokine responses?
xpress a viral cytokine (vIL-10) that drives the immune system towards a Th2, rather than Th1 response.
how ar eNK cells important in dealing with viral infections
important early on in infection
kill viral infected cells
NK cells vs CD8+ CTL - what are the killing differences
lots of similarities
For CD8+ CTL, the target cell is identified by the presence of specific virus peptides associated with class I MHC molecules on the cell surface, and this is antigen-dependent.
In contrast, NK cells recognise the absence of class I MHC and this may be antigen independent.
NK cells can also develop pathogen-specific memory?
yep
how are antibodies important in the viral repsonse?
bind to and neutralise virus particles, either alone or in combination with complement
help to diminish spread
are antibodies effective at removing infected cells?
no
______ is important in preventing infection by viruses that enter by the respiratory system
Mucosal IgA is important in preventing infection by viruses that enter by the respiratory system
can CTLs combat free viral particel?
no
what are CTLs good for?
recognising and destroying virally infected cells
which viruses are CTLs important for?
viruses that remain largely cell- associated (e.g. HCMV and measles virus) and for those that cause systemic infections.
The herpesviruses have many strategies to block the presentation of peptides on class I MHC molecules. E.g.
(4)
- Block generation of peptides by the proteasome
- Block transport of peptides into endoplasmic reticulum (HSV and adenovirus)
- Destroy class I MHC molecules by inducing their transport back into the cytosol for proteolytic degradation (HCMV)
- Retain class I MHC molecules intracellularly and so preventing their transport to the cell surface (adenovirus, VZV and HCMV)
lab
does polio virus often lead to paralysis?
unusual for poliovirus to escape the gut and enter the central nervous system (CNS).
But when this happens, the motor neurones of the spinal chord are destroyed and paralysis will ensue.
This has no benefit for the virus, for the route of exit to find new hosts is via the gut.
give factors which affect the outcome for disease?
viral dose
route of entry
age and sex
wehy deos route of entry affect the outcome of disease?
The same dose of virus given by different routes can give different outcomes.
One example of this was the use of variola virus (the poxvirus that causes smallpox) to prevent severe disease if given by dermal infection (variolation), rather than by inhaling the virus naturally (respiratory infection)
give some exmaples of how age and sex influences the outcome of viral infections
SARS-CoV-2 infection of males is _____ serious than in females.
SARS-CoV-2 infection of males is more serious than in females.
howd oes age affect HBV infection?
Hepatitis B virus (HBV) infection of a neonate, from an HBV-infected mother, gives a high chance of a chronic infection, whereas infection later in life is more likely to be acute.
which is more severe - chronic or acute HBV
The chronic infection is more serious and has a strong chance of developing into liver cancer (hepatocellular carcinoma, HCC).
how does sex matter in HBV infected individuals
In this example, sex matters too, and
for males it is worse than females.
So if a male is born to an HBV-infected mother, becomes infected and no action is taken, he has a 90% chance of developing chronic HBV infection, and a 50% chance of dying from liver cancer due to this chronic infection.
how does physiological state affect the outcome for viral infection?
fat
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