Lecture 20 - Rotavirus Flashcards
What viral family does rotavirus belong to?
Reoviridae
What diseases does rotavirus commonly cause and in which individuals?
diarrheal disease in infants and young children
What type of genome does rotavirus have?
dsRNA
What are Reoviruses that infect humans and animals known as?
rotaviruses
What type of particle is the rotavirus virion?
Triple-Layered Particle - surrounds genome
What is the rotaviral protein NSP4?
enterotoxin – modulates intracellular Ca2+ levels
What cells are susceptible and permissive to rotavirus? (What cells does rotavirus infect?)
mature, non-dividing enterocytes of the villi in small intestine
What are 3 viral receptors on host cells that rotaviral protein VP4 attach to?
sialic acid | integrins | tight-junction proteins (SIT)
How are progeny virions released through the cell?
lysis
In what bodily product are rotaviruses shed?
in the stool
What is the mode of transmission of rotaviral infections?
fecal-oral route, close person-to-person contact
Who are the most susceptible to rotaviral infections and why?
infants and young kids because they are at the stage where they put things in their mouths, have close contact with others
Which cells in the body lyse first due to rotaviruses?
enterocytes
What does rotavirus pathogenesis induce?
secretory and osmotic diarrhea lasting a short time
What causes the osmotic diarrhea?
due to malabsorption (enterocyte death or damage)
What causes the secretory diarrhea?
due to NSP4 that activates of the enteric nervous system (ENS)
What happens when NSP4 activates the enteric nervous system?
tells the body to not absorb the fluids and dispel it more
What are the 3 ways why the secretory diarrhea occurs due to rotaviral infections?
damage of tight-junction between cells, the NSP4 enterotoxin, destruction of enterocytes via lysis
What causes damage to the tight junctions?
virus changes (increases) in the intracellular calcium levels = changes in the expression of tight junction proteins or ability to be on the cell surface to work= allows leakage and malabsorption
What does the NSP4 enterotoxin also induce other than ENS responses?
CFTR mediated diarrhea
How are rotaviral infections treated?
replacement of fluids (MOST EFFECTIVE TREATMENT)
Is there a vaccine available to prevent rotaviral infections?
yes - oral vaccine via drops; highly effective in eliminating the disease
What protein regulates the growth checkpoint?
Rb protein
What does the Rb protein do?
bound to E2F (transcription factor) and holds it until it receives a signal telling it that the cell is ready for DNA replication
What genes does E2F turn on when it is unbound from Rb?
the DNA replication genes to encode enzymes needed such as polymerases and ligases
In order to phosphorylate Rb, what is needed upstream to tell it that it needs to be phosphorylated?
the RAS signaling pathway
What does the RAS protein trigger?
a signaling pathway that will lead to the phosphorylation of Rb
What triggers RAS?
growth factors that attaches to it cell surface receptor (kinase) that activates RAS
What does the RAS signaling pathway also do other than phosphorylating Rb?
inactivates PKR by dephosphorylating it
What activates PKR? What does it do once activated?
dsRNA = phosphorylates it to activate it | shuts down protein synthesis
What occurs when PKR is inactivated?
protein translation moves forward
Where do oncogenic mutations occur in >30% of human cancers? Generally in what protein/gene?
RAS Signaling pathway | mostly RAS itself
What type of mutation does RAS have to cause cancer? What is the effect of this?
has a gain-of-function mutation | effect = it is always on despite if growth factors are present or not
What is the status of PKR in cancer cells? What is the effect of this?
always inactivated due to RAS mutation = makes these cells more susceptible to dsRNA viruses
What is the effect of infecting cancer cells with Reoviruses?
lyses cancer cells
How are scientists using Reoviruses as an oncolytic agent?
engineering the Reovirus where it can only infect cancer cells (from any part of the body)
If you treat a cancer patient with Reoviruses to target the cancer cells, what happens when the virus enters a non-tumor cell?
virus is immediately shut down because PKR is not inactivated by the RAS pathway
Why can Reoviruses potentially be used as a treatment for cancer cells?
due to their preference for RAS-activated cells and their cytolytic ability
Why do Reoviruses prefer RAS-activated cells even though they replicate their dsRNA genome in their double-layered capsid?
sometimes dsRNA leaks out into cytoplasm | since PKR is inactivated via RAS = no inhibition of protein translation = doesn’t matter if there was dsRNA present in the cytoplasm
