L3 - VIRUS-CELL & CORONA Flashcards
Viruses only infect a subset of cells in host organism’s bodies (cells that express the viral receptor). Those cells can either be:
- Permissive: allow for viral infection and production of viral progenies (cause productive infection)
* Lead to cytopathic effects (observable effects that cause changes in the host cell ex. cell lysis)
* Permissive infection can be:
o An acute infection (usually by RNA viruses) – which either results in cell death due to production and release of viral progenies or cell survival by clearing of viruses
o A persistent infection (usually by large dsDNA viruses) – cell survives from infection but still contains the virus. Persistent infection can be:
Latent: the cell survives with the virus is still inside the cell but is not producing viral proteins or viral progenies. The virus just remains in the host for a long period of time and cannot be rid of (ex. herpes)
Chronic: the cell survives with the virus inside the cell producing viral progenies at low level over a long period of time - Non-permissive: only allows for viral infection but do not produce viral progenies
* Lead to abortive or restrictive infection (host cell produces proteins to defend against the viral infection vigorously)
- Some cells can switch between permissive and non-permissive states
Cancer from viral infection:
Both permissive and non-permissive cells can lead to cancer by causing cell transformation.
* Viral infection of permissive cells can lead to oncogenesis – virus cause turn on of oncogene, turn off of tumor suppressor gene, or the virus itself can contain a viral oncogene.
* Abortive & restrictive infection of non-permissive cells can also cause cell transformation, giving rise to cancer.
* Ex. SV40 causing abortive infection & cancer in mice, human papilloma virus
Viral effects on host cells:
- Morphological effects
- Effects on cell biochemistry and physiology
- genetics
- Morphological effects
- Changes to morphology of the cell (how the cell looks like under light microscope)
- Occurs due to accumulation of viral particles being produced, forming inclusion bodies
- Inclusion bodies are formed in different parts of the cell depending on where the virus associates, causing morphological changes to those organelles/parts of the cell.
o Includes: cytoplasm, nucleus, microtubules – some virus uses the microtubule network to move around so inclusion bodies form bends and change the microtubule network - Envelope virus can cause syncytia formation (giant multinucleated cells)
o Host cell infected by envelope virus will produce and traffic viral envelope proteins to surface of the cell
o These envelope proteins mediate fusion events between virus and host cells, but also between infected and uninfected cells
o this cause multinucleated syncytial cell – a process co-opted by humans for placenta formation (placenta cells are multinucleated - syncytins). Without co-option with envelope virus, placental mammals cannot occur.
- Effects on cell biochemistry and physiology
- During a virus life cycle, it will induce production of different proteins in waves
- function of those proteins is to interact and take over the host cell to prepare it for viral progeny production
- The waves of proteins produced are to cause stages of:
1. activation of cellular protein kinases & transcription factors
2. activation of cellular oncogenes, cell cycle arrest
3. inhibition of DNA synthesis - Ex. Cytomegalovirus (large dsDNA virus)
- Genetic effects
- Usually caused by DNA viruses because they replicate in the nucleus (closely associated with DNA replication)
- Can be due to:
o Virus stops cell from entering S phase – viruses encode for genes that cause cell cycle arrest by knocking down retinoblastoma or p53
The virus wants the cell to prepare for replication to replicate the viral genome, but not the host cell’s own genome
If the cell is paused at a stage for long = can cause damage to DNA
o A lot of viral replications happening inside nucleus can cause chromosomal damage, such as exchanged chromatids and mutations
o Abortive infection – cause a lot of chromosomal damage so cells are transformed (ex. SV40 in mouse cells)
Host cellular defenses against viral infection
Cells can be induced to defend against viral infection OR innately contain non-induced defenses such as constant low-level production of antiviral defense proteins
Induced defenses:
- Infected cells release interferons in response to viral infection
- Interferons will travel and bind to uninfected cells to warn them that viruses are present in the host and prime them by turning on antiviral defense mechanisms
- Uninfected cells are then induced to produce antiviral defense proteins that target many different stages of the viral life cycle
1. Transcription inhibitors
2. Translation inhibitors
3. Protein processing inhibitors
4. Virus maturation inhibitors
induced antiviral defense proteins
Cells do no produce inhibitors that target only 1 stage of the viral lifecycle because targeting of different stages can allow the virus to become less likely to develop resistance
* Ex. combination therapy used to combat HIV infection – utilize integrase, polymerase, protease inhibitors, all at the same time
These induced antiviral defense proteins are not always produced because they require a lot of energy and can slow down the efficiency of the host cellular mechanism
Examples of antiviral defense proteins:
Translation inhibitory protein (TIP)
TRIM5 protein
Tetherin
Translation inhibitory protein (TIP)
usually for defense against RNA viruses
* Interferon binding to uninfected cell triggers pathway that sends a signal to host cell chromosome to express TIP
* Once translated, TIP binds to ribosome & modifies the ribosome to be more particular about the RNA it is able to translate – the TIP modified ribosome will check more closely for the correct caps and structure of RNA
* Usually, viral RNA does not have the correct cap and is not the exact same as the host mRNA
* Therefore, TIP modified ribosome will not be able to translate the viral RNA and the ribosome efficiency will also slow down, translating mRNA more slowly (reason why it’s not always turned on in the host cell)
Interferon release and binding ensures that other uninfected cells in the host organism is primed with modified ribosome to defend against viral infection
However, Influenza uses TIP against the host cell
* Influenza RNA does not have a cap. Upon infection, it steals the cap of the host mRNA.
* Therefore, TIP modified ribosome will both be able to translate the viral RNA while also rejecting host RNA as foreign
TRIM5 protein
– in cytoplasm
* acts against uncoating of viruses by binding to capsid protein so viral DNA can’t be released into cytoplasm
Tetherin
– for defense against enveloped viruses (ex. HIV, Ebola, SARS-COV-2)
* Acts as a pair
* Has transmembrane region at 1 end and a GPI anchor at another end, thus can cross-link 2 membranes together (host cell membrane and viral cell membrane)
* So can prevents viral escape
* Viruses can also have a counter defense against host defense mechanism by encoding for proteins that degrade host cell antiviral defense proteins
Ex: viral counter defense against Tetherin
* HIV1 encodes for VPU gene that degrades Tetherin
Or viral machinery that prevents cell from undergoing apoptosis
Non-induced defenses:
- Antiviral defense proteins constantly expressed at low levels in cells
Ex: APOBEC3G gene which defends against retroviruses
* APOBEC3G gets packaged with the virus as the viral particle assembles and leaves the host cell
* As the virus infects another cell, it also releases APOBEC3G into the cell
* APOBEC3G will deaminate the viral genome during reverse transcription, causing C to U mutation in the minus strand which results in G to A mutation in the proviral DNA
* This will cause degradation of the hypermutated viral genome or result in hypermutation in the viral progeny which might cause it to not be virulent anymore
Viral counter defense:
acquisition of the viral infectivity factor (vif) gene which shunts the APOBEC3G into a degradation pathway
