week 7 and 8 Flashcards
evasion of the immune system, general
large DNA viruses in particular have many strategies for immune evasion. these include HSV, chickenpox, cytomegalovirus (CMV)and epstein barr (EBV), also poxviruses. they employ two strategies to evade the immune system, for one by not being recognized and also by interfering with the function of particular immune mechanims.
general mechanisms that the viruses employ to evade the immune system
- latency
- antigenic variation in epitopes
- blocking priming of dendritic cell by t cell by mechanisms: blocking TLR signalling, DC maturation and interaction with naive t cells
- decreased production of MHC class 1
- cytokine receptor homolouges
etc.
persistant infections
the most common example is latency were the virus evades detections because the viral genome is repressed. there are almost no viral proteins for the cell or immune system to react to. other ways for a virus to remain persistant chronic infection caused by hep B or C. they remain chronic because they cause immune exhasion by production of decoy antigens. HPV also delays or avoids immune response because of non-cytopathic infection of inaccessible site.
neutralizing antibodies and evasion
when b cells encounter an antigen they become activated and differentiate to plasma cells. these plasma cells secrete a high quantity of this specific antibody. these antibodies will then move around freely in the blood and tissues and bind to the pathogen. they are our biggest defence against virus infection and the epitopes they bind usually has a function in entry of the host cell, which binding can inhibit. they can also induce aggregation and immune clearence. this is evaded by antigenic drift which is the genetic drift on viruses to change their epitopes by mistakes produced by rdrp. antigenic drift can either occur on a population (influenza) or single patient scale (HIV)
evasion of t cells
t cells have a unique receptor (TCR) that recognizes antigens that are presented on the surface of APC cells using MHC molecules. when a t cell binds antigen it undergoes clonal expansion. antigenic drift can result in changes of the anhor residues so the antigen can no longer bind well to the MHC or to the TCR. in HCV, mutations in the TCR ocntacts residues have been described.
inhibition of t cell priming by dendritic cells
dendritic cells are APCs that present antigens to t cells causing them to undergo clonal expansion and differentiation upton binding to t cell receptor. viruses can inhibit the maturation of dendritic cells. DC relies on PPR such as TLRs to recognize viral components and initate maturation. viruses can block the signal transduction of PRRs. HSV blocks signal transduciton in immature DC and vaccinia virus encodes a homolouge of TLR4 that does not cause response. vaccinia and HCV blocks cytokine induced maturation
evasion of CD8 t cell recognition, how iit works and what methods different viruses employ
some viral proteins in the cytoplasm will be degradeed by the proteosome. the peptides will then be transported back to the ER via TAP complex. will then be transported via golgi to plasma membrane where the epitope is shown to t cells. will activate killing of the cell. many steps where virus can intervene. for example,
- CMV protein US6 binds to luminal side of TAP transporter and prevents peptide translocation to ER.
- HSV protein ICP47 binds to cytosolic side of TAP transporter and prevents peptie translocation to ER.
- adenovirus E3 binds MHC peptide complex and retains it in the ER so it wont be inserted in the plasma membrane.
- HIV and RV decreases transcription of MHC class 1
- epstein barr in latent cells evades proteosome degradation so viral components cant be presented on MHC.
evasion of natural killer cell recognition
NK cell activity is controlled by a balance of stimulatory and inhibitory signals. NK cells detects the level of MHC molecules and i MHC is not presented the cell is killed. so viruses that evade t cells by inhibiting insertion of MHC molecules may become more suceptible to NK killing.
NKG2D is a ligand that is expressed on cell surface if the cell is stressed or infected which causes the cell killing by NK. CMV encodes a protein m152 which retains the NKG2D ligand in the ER. CMV also encode a MHC1- like molecule that is presented on cell surface and delivers a negative (inhibitory) signal to NK cell to evade killing.
interfering with cytokine function
- poxviruses encode homolouges of cytokine receptors that does not cause response in cells
- epstein barr encodes a IL-10 homolouge which is a cytokine that repress the t cell response and redirects it to other places.
- intracellular blocking of cytokine synthesis: pox encodes crmA protein which inhibits the cleavege of IL-1beta precursor
- intracellular interference with cytokine function: adenovirus encode proteins that interfere with pathway of TNF alpha mediated killing of the cell. tnf alpha is a proinflammatory cytokine and also induce antiviral effects when it binds to its receptor on infected cells and cause apoptosis.
modulation of apoptosis
many viruses needs to inhibit apoptosis to complete replication but some induce apoptosis in the late stages to release virions. the cell
modulation of autophagy
autophagy is a process where cells degrade organelles or proteins by forming a double membrane autophagosome containing the material and fusing with a lusosome to degrade. it has antiviral functions to degrade viral components or virions. some viruses encode proteins to block autophagy and some viruses utilize components of this machinery for their replication or non-lytic cellular release.
evasion of the complement system
the complemeent system is part of the bodies innate immune defence. it consists of a group of proteins found in blood or tissue that can promote inflammation by attracting other immune cells or directly kill pathogens. the complement pathways (classical, lectin and alternative) are normally carefully controlled by control proteins that can stop the complement cascade by binding to complement rpoteins. pox and herpes encode proteins that are homologes of control proteins to stop immune activation.
herpes general
“battleship” of viruses bc encodes many proteins. there are 8 types in humans, all establishing life long latency. shows periodic reactivation, normally following immunosuppression. has a linear dsDNA
herpes subtypes and site of latency
- alpha: HSV 1 and 2 and varicella zoster virus that cause chickenpox and shingles. is latent in neurons.
- beta: cytomegalovirus (CMV) and human herpesvirus 6 that seems to form latency in monocytes or secretory glands.
- gamma: epstein-barr and kaposi sarcoma virus. latent in lymphocytes
herpes genes
- early genes: made before DNA replication. involves encymes such as HSV thymidine kinase that is a drug target, regulatory genes that interfere with host gene expression.
- structural genes: made after replication
- limited gene expression during latency, produces some latency-associated transcripts (LATs). Epstein barr is latent in lymphocytes whihc divides and therefore the virus needs to replicate when latent compared to HSV that are latent in neurons which generally dont divide.
HSV primary infection
infects through breach in epithelial tissue which sometimes cause local replication in the tissue resulting in lesions or there is no apparent infection (seropositive). can result in CNS disease which is very rare. can happen either from primary or recurrent infection and is very dangerous. enters neuron at the axon terminal and travel to cell body by retrograde axonal flow to dorsal root ganglion. HSV-1 is generally oral and HSV-2 is generally genital.
varicella zoster virus
priamry infection results in chickenpox. first infects upper respiratory tracts and replicates in epithelial cells and then reach and replicates in regional lymph nodes. results in primary viremia, spread by DC and further replication ad amplification in liver and spleen. secondary viremia via t cells. then infects skin which results in rash. lays latent and reactivation results in chingles. shingles is associated with immune deficit ex in elderly. vaccine is live attenuated and is recommended for seronegative children after 1 year of age and also risk occupations. therapeutic interventions are antiviral chemotherapy by ex. aclylovir and passive immunization with zoster immunoglobulin.
epstein barr virus (EBV)
cause glandular fever (körtelfeber). acquired by direct contact of infected saliva with oropharynx. latent in b cells. initial infection in epithelial cells is lytical and spread to b cells generates a widespread immune response resulting in swelling of the lymoh nodes. has 2 ori for replication, one used during lytic and one during latent infection. makes latent proteins such as EBNA-1 which drives replication in dividing b cells. reactivation of EBV is associated with cancer and immune response to EBV is associated with onset of muultiple sclerosis (MS)
cytomegalovirus
infection in older childeren and adults leads to mild disease. immunosuppression leads to reactivation of virus, seen in for example aids. it is the main cause of death in bone marrow transplant patients and also the leading infectious cause of stillbirth. can be transmitted via placenta to fetus which often results in asymptomatic infection bur can also lead to mental disibilites, blindness and deafness.
hepatatis general
hepatitis is a disease of the liver and the symptoms are mostly caused by inflammation. in the liver we have the hepatocytes and other cell types. the liver produces bile and filters the blood which passes through the hepatic artery and portal vein.
acute disease persists for weeks to months and results in flu-like symptoms, accumulation of bilirubin leading to dark urine and yellow eyes and damage to the liver.
chronic disease persists from years to life time and damages the liver, can lead to cancer, liver failure
hepatitis viruses replicates in hepatocytes, they are not cytolytic meaning the virus itself doesnt damage the liver but rather the immune system does. severity of disease depends on age. young people has less immune response and therefore less severe acute disease but are more likely to develop chronic infection.
viral hepatocytis is one disease but is caused by many different viruses: A, B, C, D, E. they are from different virus families and protection against one does not mean protection against another virus (no cross-protection)
hepatitis a and e
leads to acute infection
transmitted by faecal-oral route by transmission into bile and feces, contaminated water
diagnosis by blood test using ELISA. looks for igM and igG antibody to viral proteins, elevation nin igG confirms acute infection. PCR can tell us if a person is infected but does not say if the infection is actue.
hepatitis A is more prevalent in low developed countries such as africa, asia and south america. also higher amongs indigenous
hepatitis A
picornaviridae, related to polio and rhinovirus
non-enveloped +ssRNA virus
small particle resistant to stomach acid and enzymes.
codes for a single polyprotein
the virion assembly is completed in multivesicular bodies within hepatocytes and are exocytosed. does not need to kill cell to be relased (non cytolytic) but ar cytopathic because immune response can kill the hepatocyte.
ingested via water or food and replicates first in intestinal epithelial cells. is then transmitted to the blood causing viremia and finds its way to the liver where it replicates to high levels. is then released into bile which is why feces contains virus.
symptoms lasts for 2-3 weeks and are jaundice, vomiting, pale feces, dark urine
in beginning of infection, high levels of ALT= liver enzymes are seen (?), also high levels of virus in feces. after a while, igM antibodies goes up and total anti-HAV too.
prevention and treatment: sanitation, immune globulin contains antibodies against hep A which can be administered preventative for travellers and also post exposure to protect from onset of disease.
vaccine: inactivated whole virus, highly effective but expensive to produce since it requires diploid cells.
hepatitis E
hepevirus family
non-enveloped but more fragile
+ssRNA
distributed in africa and asia. most outbreaks comes from contaminated drinking water and not spread from person to person.
dangerous for pregnant women, overall not that deadly
has no specific antiviral therapies
prevention with sanitation, immunoglobulin is not effective
vaccine virus like particle
hep B
viral partivle with envelope and small, medium and large glycoproteins
incomplete particles without genome= HBsAg particles
dsDNA genome that creates pregenomic RNA that undergoes reverse transcription to make dsDNA inside core particle
virion release i non-cytosolic, virion assembly is completed in multivesicular bodies (MVBs) and released by exocytosis
life cycle of HBV (same as HDV and HCV) is infection by blood, semen or secretions that penetrates the mucosal epithelia, does not replicate there but enters the blood to reach the liver where it replicates. is then secreted back into the blood where it can infect other people.
older people are more likely to have severe acute inflammation but less likely to develop chronic
recovery: total anti-HBc increases until virus is cleared
chronic infection: even though there is increase in antibodies, the virus is not cleared and high levels of HBsAg is still detected
can lead to immune mediated liver damage, liver failure and is the most common cause of liver cancer.
cirrhosis is chronoic scarring in the liver which increases risk of cancer
HBV can integrate genome in host cells, causing mutations which can lead to cancer.
since the immune sysem is weakened, cancer cells are less likely to be detected and destroyed
vaccine from yeast, subviral particles purified and inactivated
