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8 commonly used viral portals of entry and exit

1 - oropharynx - HSV, HCMV, EBV
2 - respiratory tract - influenza, measles, mumps, rubella, rhinovirus,VZV, some adenoviruses
3 - alimentary canal - poliovirus, hep A (HAV), rotavirus, some adenoviruses
4 - conjunctiva - HSV
5 - skin - HPV, HSV, rabies
6 - genital tract - HIV, HSV, HPV
7 - blood, iatrogenic - HBV, HIV
8 - blood, biting insects - yellow fever virus, dengue virus, bluetounge virus


physical barriers to infection

skin, cilia, mucous secretions, proteases, low pH. viruses are well adapted to their route of entry, eg poliovirus is v. resistant to low pH of the stomach and proteases.


7 componants of innate immunity vs viruses

1 - phagocytes - phagocytose free particles or infected cells and debris. some viruses can grow in macrophages
2 - complement
3 - interferon (IFN) - promote adaptive immunity and put cells into antiviral state
4 - apoptosis of infected cells
5 - cytokines - promote inflammation and Th1 response
6 - chemokines - recruit leukocytes
7 - NK cells - lyse infected cells in antigen dependent manner
8 - fever - restrict replication of some.


how is a viral infection sensed, cellular cascade

PRRs bind PAMPs, activate TFs such as NF-kB or interferon response factors (IRFs). these promote transcription inc - IFNbeta, chemokines, inflammatory cytokines (IL-1beta, TNF)


interferon classes and general functions

species specific soluble glycoproteins.
1 - type 1 - IFNalpha and beta - released by infected cells, binds type 1 IFNR on adjacent cells - induce antiviral state and up-regulate class 1 MHC
2 - type 2 - IFNgamma - released by activated T cells and macrophages, binds IFNgammaR, promotes inflammation and Th1 response
3 - type 3 - IFNlambda - binds the type 3 R, imp in epithelial cells.
the vast majority of mammalian viruses have at least one mech of blocking IFN action.


IFNalpha/beta binding to its R induces what?

induces the JAK-STAT signalling pathway - activates 'interferon stimulated gene factor 3 (ISGF-3). - binds interferon stimulated response element (ISRE) present in many interferon stimulated genes (ISGs).
proteins generated inc - PKR, OAS and the Mx protein.
PKR and OAS are activated by viral dsDNA and inhibit all cellular protein synthesis - cell death.


viral mechanisms of interfering with IFNs?

1 - blocking PRR signal cascades
2 - releasing soluble IFN binding proteins
3 - inhibiting JAK-STAT signalling to prevent ISG stimulation
4 - targeting the ISG proteins directly
poxviruses exhibit ALL of these


how can viruses block host cell apoptosis?

1 - block caspase action or target the Bcl-2 family of proapoptotic proteins


how do viruses block chemokines and cytokines

1 - myriad of ways. can stimulate production and secretion of proteins that bind them to neutralise. poxviruses and herpesviruses do this.
EBV expresses a viral cytokine (vIL-10) that drives the immune system to a Th2 rather than Th1 response.


contrast action of NK cells and Cytotoxic T cells briefly

NKs kill virally infected cells in an antigen independent manner. the missing self model. if class 1 MHC is absent the NK cell is disinhibited from killing the cell. some viruses have devised mechs to block the NKs.
Cytotoxic T cells instead kill in an antigen dependent manner.
NKs are hence v imp early in infection killing off many virally infected cells before they get the chance to start spreading.


Function of antibodies in viral infections?

bind to and neutralise viral particles to prevent infection or diminish spread. can be bound to complement too. mucosal IgA important is preventing viral infection of the respiratory system.


how do viruses block the action of cytotoxic T cells? 3 primary mechs. other NON-CD8 general mechs?

1 - block transport of peptides into the ER (HSV and adenoviruses)
2 - cause the degredation of MHC class 1 by inducing their transport back into the cytosol for proteolytic deg. (HCMV)
3 - prevent transport of MHC class 1 to the cell surface.
1 - latency - hide. (herpesviruses, retroviruses)
2 - express viral FcR to remove antibodies from circulation (herpes)
3 - antigenic variation - HIV, influenza and Hep C - all RNA so low fidelity replication.


possible outcomes of a viral infection of a cell

1 - cell death (common) - cell type infected gives rise to the specific disease
2 - cell transformation - cancer
3 - persistent infection - continues to replicate
4 - latent infection - virus remains dormant for long periods.


5 viral diseases caused by cell death outcome

1 - poliovirus - motor neurones (anterior horn in CNS) - paralysis. but only if it escapes the gut epithelium.
2 - Rotavirus - gut epithelial cells - diarrhoea
3 - HIV - CD4+ T helper cells - immunodeficiency
4 - Hepatitis B virus - Hepatocytes - acute hepatitis
5 - Rabies Virus - Perkinji cells in the cerebellum - hydrophobia and aggressive behaviour


4 viral diseases associated with latent or persistent infections of hbv, measles, hsv and vzv

1 - Hepatitis B virus - hepatocytes - chronic hepatitis predisposing for liver cancer
2 - measles virus - neurones - subacute schlerosing panencephalitis (SSPE) but this is rare (and fatal) occuring in around 1 in 300000 infections
3 - HSV-1,HSV-2 - neurones - cold sores and genital herpes
4 - Varicella-zoster virus - neurones - chickenpox and shingles


5 examples of virus induced cancers

1 - Hepatitis B virus - hepatocytes - hepatocellular carcinoma
2 - HPV 6 and 11 - epithelial cells - common warts
3 - HPV 16 and 18 - epithelial cells - cervical and penile carcinoma
4 - Epstein-barr virus - B cells - Burkitt's lymphoma and nasopharyngeal carcinoma
5 - Rous sarcoma virus - connective tissue - chicken sarcomas


5 factors affecting whether or not a viral infection causes disease

1 - virus dose - obv raise dose increase chance of overwhelming innate immune response
2 - route of entry - eg variola virus (poxvirus causing smallpox) if given by dermal infection (variolation) rather than inhaled it wont cause a stable infection.
3 - age and sex - VZV (causes chickenpox) if infected during childhood then the infection is usually mild, but in adults it can be very serious.
- EBV - usually in chilldhood and asympotomatic, but if acquired in the young adult it can cause glandular fever (infectious mononucleosis)
- HBV - if infects the neonate from the mother it has a much greater chance of establishing a chronic infection. in the adult it is more likely to be acute. sex - male born with HBV, no action = 90% chance of chronic infection, and 50% chance of dying from HBV induced liver cancer.
5 - physiological state - stress and immunological deficiency increase likelihood of severe infection/ herpesvirus reactivation.


some infections are grouped by target organ. 5 groups and examples. often not a helpful mech as some are contracted by the respiratory route but dont cause disease here (measles, rubella, VZV, FMDV)

1 - respiratory - common cold (rhinovirus), influenza (influenza virus), chest infection (respiratory syncytial virus)
2- enteric - infantile diarrhoea (rotavirus),paralysis (poliovirus
3 - CNS - rabies, herpes encephalitis (HSV), poliomyelitis (poliovirus)
4 - hepatitis - acute hepatitis (HAV,HEV), chronic hepatitis (HBV,HCV)
5 - haemorrhagic fever - yellow fever (YFV), dengue haemorrhagic fever (dengue virus), ebola (ebola virus)


infections can be superficial (local) or systemic. describe

local - contained to epithelium, acute, short incubation period and duration. eg common cold, influenza, gastroenteritis (rotavirus)
systemic - replicates a portal of entry, spreads (lymph, blood, nerves), amplification at secondary sites. longer incubation period, more severe, outcome very dependent on specific immune responses (esp CTL) eg smallpox, chickenpox, Foot and mouth.
- factors determining each are largely unnown but its known that rhinoviruses (common cold) grow well at 32degrees but not at 37 so replicate only in the upper respiratory tract epithelium. several viruses that go systemic grow well in macrophages (YFV and ectromelia virus).


define primary viraemia

the first time a virus enters the bloodstream to infect multiple organs from entry site.


in addition to superficial and systemic infections , viruses can be divided into 3 groups based on persistence.

1 - acute - normal outcome in normal host. measles mutants can infect CNS and cause chronic demyelination (SSPE) but about 1 in a million.
2 - persitent (chronic infection) - years or lifetime of host. HIV HCV, HBV in 10% adults or 90% male neonates.
3 - persistent (latent) - disappears after primary infectio but reactivates causing recurrence. herpesvirus does this and is never cleared. VZV is dramatic example - chickenpox in acute but genome latent in neurones of sensory ganglia for life, can reoccur to cause shingles.


explain recurrence for HSV,VZV, HCMV, EBV

a host cell can be permissive or non permissive for viral gene expression. acute infection expressed in permissive cells then is resolved. infected non-permissive cells are the location of latency. a later stimulus can then cause these cells to be permissive and seed a recurrence of the infection.
1 - HSV and VZV - permissive site in mucosal or cutaneous epithelium - latent in sensory neurones
2 - Human cytomegalovirus - tissue macrophage and glandular epithelium - pre-monocyte, differentiation of this into a macrophage results in HCMV production and seeding.
3 - EBV - activated B cell, oral epithelium - memory B cell


generally a virus reaches highest titre in the organ from which it is shed. often the portal of entry and exit is the same. give 8 portals of exit and some virus examples for each.

1 - blood - YFV, HIV, HBV, HCV
2 - skin - HPV 6 and 11, VZV, HSV, measles
3 - alimentary canal - Poliovirus, HAV, rotavirus, calicivirus (winter vomiting disease)
4 - Respiratory system - rhinovirus, influenza virus, VZV, measles, variola virus.
5 - saliva - EBV, rabies virus, mumps virus, HCMV
6 - genital tract - HIV, HBV, HPV 16 and 18
7 - breast milk - HCMV
8 - placenta - rubella virus, HCMV


what factors affect viral transmission?

particle stability, duration of shedding, concentration of virus shed, availability of susceptible hosts.
1 - enveloped are less stable than non as the lipid is fragile and contains attachment proteins hence often spread by close contact ie measles, influenz, HSV. non enveloped = long distances, 1981 FMDV epidemic in southern england due to cirus blown across the english channel from france. picornaviruses spread by oro-faecal route (poliovirus and HAV) are v stable in water.
2 - acute infections have only a short time to shed so shed higher amounts to ensure host transfer. acute vs persistant ie influenza vs HSV
3 - acute vs chronic. rotavirus - acute - watery diarrhoea of conc up to 10^9 pfu/ml
4 - two factors are imp here, pop size and availability of other host species.


measles transmission in populations vs YFV and rabies

1 - eg measles - physically unstable, only infects humans, antigenically stable, immunity is lifelong so herd immunity is high. every few years epidemic in young school children, between these its maintained in a few susceptable hosts. in isolated pops of less than 100,00 it's eliminated. in the faroe islands the virus disappears after an epidemic only returning when there are sufficient susceptible hosts and the virus is reintroduced by an external source.
YFV and rabies infects multiple hosts so human infection is incidental and herd immunity has no impact on virus survival. infections like this with an animal reservoir are called zoonotic infections and are v hard to eliminate.


Classifications of vertical transmission

1 - congenital
2 - perinatal
3 - germ line transmission
1 - virus crosses placenta into foetus. (HIV, rubella, HCMV)
2 - infection during birth or via breast milk. HSV in birth canal, HCMV in birth canal and breast milk, HBV probably blood during birth
3 - provirus in germ line. called endogeneous retrovirus. usually silent but may reactivate (hence concerns about them in xenographs). make up 8% of genome with retrotransposons


HCMV multiple entry and exit portals

1- congenitally, perinatally, oral contact, sexual transmission, blood transfusion, organ transplantation. always goes systemic and grows at multiple exit portals.


general characteristics of a virus transmitted by respiratory aerosol?

1 - usually highly contageous, cause widespread epidemics
2 - high herd immunity so new epidemics need intro of sufficient suceptable individuals (measles) or appearance of new antigenic variants (influenza)


general characteristics of a virus transmitted by saliva?

1 - from oropharynx, less contageous, require contact (HSV, EBV)


general characteristics of a virus transmitted by food/water bourne?

1- sporadic outbreaks associated with contaminated source (HAV, often community with no clean water, poor food hygene. causes high incidence of infection and high viral load in community. polio and water.


why do most viruses cause little disease, which cause high disease and generally how? myxomatosis?

1 - co-evolved with host to reach balance, evolution favours low virulence.
2 - most with high morbidity/mortality are zoonoses - AIDS, SARS, influenza and rabies. we are the abnormal host.
3 - myxomatosis (myxoma virus - poxvirus), natural host is south american rabbit (little disease caused), introduced to australia to control the european rabbit which was introduced from europe and was out of control and consuming all vegetation. fatal to european rabbit but rapidly mutated over 5 years to become less virulent - fewer and slower deaths therefore enhanced chance of transmission.
4 - disease usually caused by destruction of specific cell types causing symptoms, or from an immune system pathology from inappropriate response (TB).


define morbidity

the incidence or prevalence of a disease or of all diseases in a population


define zoonoses

Zoonosis, also called zoonotic disease refers to diseases that can be passed from animals, whether wild or domesticated, to humans