viral pathogenesis

Question 1

virus entry via the respiratory tract

Answer 1

entry via the respiratory tract happens either via inhalation of droplets with viruses or infected nasal secretions. the size of the droplet determines how deep into the respiratory tract it can reach. small droplets can reach further down. to protect from infection in the resporatory tract, and defences for viruses to overcome, there is mucus, cilia, macrophages, temperature gradient with a higher temperature further down (some viruses have preferred temperature to replicate) and IgA. the virus will attatch to receptors on epithelial cells and the infection can spread systemically or remain local.
ex mumps virus: primary viral replication in epithelial cells of URT but then spreads to a systemic infection involving all organs. receptor is sialic acid
ex measels: primary infection in UTR, infects immune cells that drains in lymph nodes and amplifies there and is spread in circulation. then returns to lung and mouth.

Question 2

entry via the alimentary tract

Answer 2

these viruses are normally resistat to acid and bile and has no envelope. if viruses doesnt have receptors for epithelial cells they need to enter into systemic via a breach in epithelial surface, for example HIV and hepB via breach in rectal route. this is a very hostile environment for viruses due to the constant movement, macrophages, mucus, acidity and proteolytic enzymes (which some viruses can exploit). systemic infection can be achived by enteroviruses and hepatitis A. local infection can include symptoms like diarrohea and be caused by rotavirus, corona etc.

Question 3

entry via the placenta

Answer 3

viruses crossing from mother to fetus. dependent on multiple variables such as virus type and fetal age. can enter via multiple ways: breaks in the syncytial cell layer, targeting other cell types or direct antibody mediated transcytosis. ex of viruses are zika, rubella, herpes etc.

Question 4

Local vs systemic spread

Answer 4

many viruses multiplies in epithelial cells but fail to gain access to the deeper tissues. to spread systemically the virus targets budding to the basolateral side of epithelial cell. this can ex be via the viral glycoproteins directing where they bud off.

Question 5

Spread of infection within the body

Answer 5

for the virus to spread systemically it needs to gain entry to the blood via epithelial cells. to reach the tissue from the blood they need to pass the capillary endothelial cells and this can be done in different ways:
-some viruses replicate in the endothelial cells and are then released into the tissue
-transcytosis
-in some tissues the endothelial cells are not joined by tight junctions and then the virus can pass between cells
-enter via immune cells that normally passes through endothelial lining.
-neuronal spread: enters via peripheral nerves and travel via retrograde transport to reach nerve body where they replicate and can cross the synaptic junction to gain access to CNS. ex rabies.

Question 6

Viremia

Answer 6

viremia is the presence of infectious virus in the blood. the viruses can either be in free form or carried within cells. active viremia is produced by replication and release of newly synthesised particles into the blood. passive viremia if the viral particles are introduced into the blood without replication at the site of entry.
when infected, we first get passive viremia when the virus gains access to the blood. then we have our primary viremia and the viruses reaches tissues where they replicate and are then released again into the blood after being amplified to very large numbers and causing secondary viremia. when the virus is in the blood its easier for our immune defense to recognize but when they are in the tissues its dependent on cell mediated immunity.

Question 7

Transmission of spread

Answer 7

• respiratory tract: either by aerosols generated by sneezing or coughing ot secretions from the nose. large droplets reach shorter. viruses that cause acute respiratory disease are spread at high rate for for a short time. some spread before they show signs of symptoms
  -oropharynx and gastrointestinal tract: feces. can get there via epithelial cells in intestinal tract or from the liver via bile duct.
  -skin: HPV presents as warts that are spread by mechanical contact. virus filled vesicles that become aerosolized and transmitted via the respiratory route.
  -blood: usually by viruses that produce persistent viremia ex HIV, HBV. can be via a insect vector, does not require as high levels in blood to infect insect and can then be spread to man
  -can also be from urine, milk, oral and genital secretions.

Question 8

rabies

Answer 8

replicates at the site of infection until enough virus particles come in contact with sensory or motor nerve cells, enter axons that are not myalated and move by retrograde transport to cell body. do this until it reaches spinal cord. the transport is slow

Question 9

determinants of tropism

Answer 9

the key determinant of tropism is receptor avalibility. some viruses use receptors that are ubiquitous (found on all cells) for example influenza that uses sialic acid found on most cells but its tropism is for respiratory tract. also need to consider permissivity (if the cell has all the right intracellular gene products to replicate viral genome), accessibility (can the virus reach the cell) and if there are any local factors that permit or prevent infection. the local factors include temperature (some viruses needs a specific temperature for replication), pH (is the virus stable in that pH?) and ability to survive destruction of lipids by bile and proteases (in the stomach). accessibility of the virus is increased if its able to replicate in immune cells or travel free in the blood. of they have a polarized release from epithelial cell it also increases their ability to reach deeper tissues.

Question 10

determinants of tropism- influenza proteases

Answer 10

influenza hemagglutinin (surface protein) need to be cleaved by the protease tryptase which is only secreted by club cells in the respiratory tract to be infectous. this determines the tropism of influenza. some highly virulent avian influenza strains can be cleaved by furins that are ubiquitinously expressed in golgi which means they can spread to other cells in the body as well.

Question 11

determinants of tropism- sars cov2 proteases

Answer 11

for sars to gain entry into the cell, the spike protein must be cleaved into 2 parts: s1 and s2. the s1 part contains the receptor binding domain which interacts with ace2 and the s2 part is responsible for fusion with the host cell membrane. transmembrane serine protease 2 in the cell membrane cleaves between s1 and s2. in some cases, the virus can also be endocytosed and then an endosomal protease such as cathepsin L can cleave the spike protein instead. ACE2 receptor and TMPRSS2 (the protease) is only expressed together in the respiratory tract, gut, illeum, colon and liver which determines covid tropism.

Question 12

determinants of tropism- genome transcription requirements, papillomavirus

Answer 12

papillomavirus needs a complex cascade of transcription factors in order to be able to replicate. these are only found in skin cells. genome replication starts in the germinal cells in the basal layer of the skin but these cells produce proteins that block the transcritption of late structural genes and therefore, the capsid proteins can only be made once the germinal cells have differentiated and moved out to the outer part of the skin.

Question 13

what mechanisms determine disease progression?

Answer 13

• viral induced damage to tissues and organs: cell death as a direct result of viral replication/ loss of function in cel due to replication or other features of viral infection
• consequences of the immune response_ immunopathology/ suppression or autoimmunity

Question 14

cytocidal virus and mechanisms

Answer 14

a virus that is capable of killing the host cell. most non-enveloped viruses relay on cell lysing to be released but the replication cycle of some enveloped viruses can also leads to cell death. example of viruses: rotavirus kills enterocytes resulting in diarrea and paralytic poliovirus infection kills neurons in the spinal cord which can result in irreversible paralysis.
except for cell lysis, virus can also kill cell by shutting down protein synthesis. they may code for specific proteins for this purpose. for example, adenovirus protein inhibits transport of mRNA to the cytoplasm and poliovirus protease 2A cleaves eIF-4G so cellular mRNA cannot be translated. they can also shut down synthesis of nucleic acid, either as a consequence of protein synthesis shutdown or by more specific mechanisms.
- accumulated viral proteins can be cytotoxic
- formation of synctia: viral proteins inserted in cell membrane cause cell fusion
- proteins inserted into plasma membrane can chanhge permiability and lead to cell lysis
- initiation of apoptosis, virus escapes in apoptotic bodies

Question 15

mechanisms of cell damage that doesnt cause cell death

Answer 15

• cells may lose their ability to perform particular functions: HIV infection of immune cells affecting the immune system, LCMV causes persistent infection of growth hormone producing cells causing a decline in growth hormone
• transformation: some viruses encode oncogenes associated with tumor production

Question 16

consequences of the immune response in disease progression

Answer 16

• cd4 t cell mediated responses: they are responsible for some viral rashes, ex measels- the t cells produce an inflammation in the indothelial cells of the small blood vessels in the skin. they can also indice cytokines that recruits eosinophils responsible for bronchiolitis in infant with respiratory syncytial virus

Question 17

viruses that causes immunosuppression

Answer 17

-HIV replicates in cd4 t cells which kills them. also replicates in monocytes and inhibits their function
- norovirus replicates in macrophages and dendritic cells affecting their function during immune communication
- measles

Question 18

virulence

Answer 18

virulence is the capacity of a virus to cause disease in a host. can be quantified as mean time to death, measurement of fever, weight loss etc. to identify viral virulence genes, scientists can compare similar viruses or mutants that only differ in their degree of virulence. virulence genes can be placed in one of four categories:
- gene products that alter the ability of the virus to replicate
- gene products that modify the hosts defence mechanisms
- genes that enable the virus to spread in the host
- toxic viral proteins

Question 19

gene products that modify the hosts defense mechanisms

Answer 19

virla proteins that mess with the hosts immune system. the proteins can be virokines (homologes of cytokines but dont activate the receptor) or viroceptors (homologes of the receptors that bind cytokines but dont cause response). often found in the genome of large dna viruses.

Question 20

genes thar enable the virus to spread in the host

Answer 20

mutation of some viral genes disrupt the spread from site of entry to organ where disease occurs. for example reovirus in mice: type 1 spreads to cns via blood while type 3 spreads via neural routes. the route of spread is determines by the outer capsid protein σ1

Question 21

toxic viral proteins

Answer 21

gene products that directly causes cell injury. alterations in these genes reduces viral virulence. evidence of their intrinsic activity is usually obtained by adding purified proteins to cultured cells and see what happens to the cells or putting gene in vector. an example of toxic viral protein is NSP4 produced by rotavirus that causes increased intracellular calcium which triggers a signaling pathway in the intestinal mucosa. acts as an enterotoxin to cause diarrea

Question 21

genome recombination by rdrp

Answer 21

if two different viral strains have infected the same cell, the rdrp can switch templates in the middle of transcription, producing a chimeric viral genome. this generally occurs when subgenomic rnas are produced. a proof of this is virus sydney 2012 which is a combination of new orleans and lordsdale

Question 21

NSP1 covid

Answer 21

the non structural protein 1 in cov2 binds to the 40s ribosomal unit to inhibit translation of cellular mrnas. this also suppresses the production of antiviral proteins such as interferons, so it serves as a mean of immune evasion.

Question 22

filovirus infection and proteins to evade immune system

Answer 22

such as ebola and marburg. a hypothesis for their pathogenesis is that they induce cytokine storm by macrophages or monocytes. ebola produce an additional glycoprotein by transcriptional editing which is secreted and serves as a decoy for the immune system. VP35 prevents activation of IRF3 and thereby restricts the transcription and production of interferons. VP24 prevents nuclear translocation of the TF STAT1 to stop the production of interferon stimulated genes. both VP proteins also have additional functions in the virus life cycle.