Mechanisms of Viral Infection and Pathogenesis

Question 1

do most viruses infect us?

Answer 1

no, they haven’t adapted to infect us

• we have thick skin and mucosal barriers, protects us from infection
• our adaptive immune system more often than not has seen something similar try and infect the body before, so it protects us

Question 2

Sites of Microbe Entry

Answer 2

conjunctiva
respiratory tract
alimentary tract
capillary
scratch, injury
urinogenital tract

Question 3

Common virus diseases of man

Answer 3

Influenza			
Common cold		
Measles				
Mumps
Chicken pox/Shingles
Glandular fever
Hepatitis
Papillomas (Warts)
AIDS
Kaposi’s sarcoma
COVID-19?

Question 4

General patterns of viral infection

Answer 4

During an acute infection:

• virus load is what we detect in us, either it is cleared by the immune system or we die
• disease symptoms occur when the virus load is at its highest, it will make us sick
• generally you develop long lasting immunity

Latent, reactivating infection:

• throughout your life, episodic reactivations of the virus
• if host immunity breaks down even slightly, you can get reactivation.

Chronic infection:
-virus persists throughout life, and the main function of the immune system is keeping it under control

Persistant infection:
-you won’t see symptoms for a long time, and then you have an eruption of symptoms

Question 5

Latent/reactivating infections - examples

Answer 5

Human Herpes Viruses

• Herpes simplex virus type 1
• Herpes simplex virus type 2
• Varicella zoster virus (chickenpox)
• Epstein-Barr virus (glandular fever)
• Cytomegalovirus
• Human herpesvirus 6, 7, 8 (8 - Kaposi’s sarcoma)

Life-long infection, controlled by immunity

Question 6

Herpes Simplex virus = HHV-1

Answer 6

Cold Sore
Primary Gingivostomatitis

Facial rash, temperature for about a day

This virus hangs around, evidence by the fact that people get cold sores – immune stress can reactivate the virus, but you don’t get a facial rash, you get these specific localised things

Question 7

Varicella Zoster Virus (VZV)

Answer 7

Varicella zoster virus – the later you get it, the worse it is

As you get older and your immune system wanes, it can reactivate the same virus, and you can get painful blistering explosions that are highly septic -shingles

Question 8

Herpes Simplex & VZV latency

Answer 8

these viruses travel up neurones and establish a persistent infection where the virus is largely switched off

a secondary stimulus will cause them to burst out and travel down neurons and causes infection in more localised regions

Question 9

Examples of persistent infections

Answer 9

HIV: Virus infects CD4+ cells and weakens immune system

HCV: Virus infects hepatocytes and damages liver, slowly destroys adaptive immune system

Congenital Rubella: if infected in utero, virus is seen as self, baby is born immunotolerant and virus continues to replicate (and cause damage) in neonatal tissues

Question 10

How does virus infection of a host lead to disease?

Answer 10

many infections are apathogenic or associated with relatively mild symptoms

it is important to realize that from the virus’ point of view these are not always failed or resolved infections – a successful virus is one that replicates well enough to spread to the next host

Question 11

in inapparent infections, what are 2 qualities viruses have?

Answer 11

non-cytopathic
-viruses often replicate to a high copy number, and it isn’t associated with any cell damage

host-adapted
–replicate in 1 or 2 hosts

Question 12

How does virus infection of a host lead to disease?

Answer 12

Pathogenesis results from cell and tissue damage caused by the viral infection, which will alert the immune system and is usually resolved quickly. Or, the immune system cannot cope and you die

On most occasions the damage is limited by the host’s immune system

Question 13

give an example of Cytopathic damage

Answer 13

1. EBOLA targets Vascular Endothelial Cells
   - Ebola targets a receptor only found on vascular endothelia, replicates in blood vessels
2. Influenza A virus targets lung epithelia
   - respiratory epithelia lined with cilia and beat in order to expel mucus or move it around so you have something to cough up to get rid of things that shouldn’t be there (dust, pathogens)
   - influenza infection destroys the cilia so you can’t clear the virus

Question 14

immunopathology

Answer 14

on some occasions the relative limited damage caused by the virus is made worse or even caused by the host’s immune system

Question 15

Hep C outcomes?

Answer 15

20% of cases, immune system permanently cures you

80% of people progress to chronic liver inflammation, fibrotic liver, leading to cirrhosis or even cancer

Question 16

Immunopathology: Hepatitis C Virus (HCV)

Answer 16

-non-cytopathic - this means although it causes no damage to the cells its infected, its broken down by the normal function of the immune system, and peptides from it get presented on the surface on hepatocytes through MHC class I. Immune system attacks it. The liver kills up with inflammatory response cells and attempt to clear the infected cells which actually wouldn’t cause damage

• extensive liver infiltration of leukocytes
• high levels of pro-inflammatory cytokines
• viral clearance and disease is associated with generation and infiltration of CD8+ cells which attack infected cells and destroy them
• HCV persistence is associated with the generation of HCV variants that are not recognised by CD8+ cells

persistent HCV infection causes chronic hepatitis (severe liver damage and loss of hepatocytes)

Question 17

Dengue Fever

Answer 17

mosquito-borne infection

4 serotypes which all have the same clinical manifestations, greatest risk is a previous infection with a different serotype

Bitten, and in primary infection you get mild symptoms (fever, rash, headache etc., similar to flu)
But, if get infected a second time (by a different strain – heterotypic), you develop much more serious disease

antibodies formed in response to a dengue infection are not cross-protective against other subtypes of the virus. ADE occurs - antibodies bind to the viral protein and rather than neutralise it they create a target that can be taken up into macrophages – and dengue viruses replicate in macrophages.

fixation of complement results in release of products of the complement cascade leading to sudden increased vascular permeability, shock and death

Question 18

Influenza

Answer 18

people of all ages infected, usually only a serious problem in the old or children with asthma

Pathology:
Mild URTI to severe LRTI
Lower respiratory tract infection causing damage to lung epithelia and viral pneumonia, often secondary pneumonia
Fever, often prolonged
Neurological (headache, malaise)
Myalgia

Infection generates powerful, long-live immunity
Easy to vaccinate against if you know what’s coming

Question 19

Antigenic Shift

Answer 19

Flu can switch what is presents on its surface by antigenic shift – people are extremely susceptible