L9. Pathogenesis of Viruses 1

Question 1

What must a virus do to cause an infection in a host?

Answer 1

Gain entry, find its target tissue, multiply and spread

Question 2

What are the four methods that viruses facilitate their survival and hence be maintained evolutionarily?

Answer 2

Direct spread to new hosts
Shed into the environment
Taken up by arthropod vectors or injections
Congenital spread

Question 3

What is the course of infection determined by?

Answer 3

The immune response of the host

Question 4

What are the outcomes of acute infection in response to viral infection?

Answer 4

Clearance

Spread and/or Persistence

Question 5

What is meant by Tropism?

Answer 5

The anatomical localisation of an infection. Viruses are only able to infect cells they can gain entry to (based on receptors)

Question 6

What is the most common route of entry for viruses?

Answer 6

Epithelial cells of the mucosa of the RT, GIT and UT.

Question 7

Is it common for viruses to enter via the skin?

Answer 7

No. The skin is quite robust against virus penetration especially because it is covered by a layer of dead (keratinised) skin. It requires abrasion or breakage of the skin for viruses to penetrate.

Question 8

What determines where in the Respiratory tract viruses initially deposit?

Answer 8

The size of the viral droplet: larger tend to be in the upper airways while smaller are able to penetrate a little further down.

Question 9

What are the barriers to infection in the respiratory tract?

Answer 9

Mucous (trapping)
cilia (pushing up and out)
IgA (mucosal neutralisation)
Alveolar macrophages
Temperature gradient

Question 10

What are the common localised vs. systemic RT viruses?

Answer 10

Local:
Rhinovirus
Respiratory Synctital Virus (RSV)
Influenza Virus

Systemic:
Mumps and Measles
Rubella
Varicella Zoster Virus

Question 11

Describe the RSV infection

Answer 11

A localised infection where the virus replicates in the URT causing inflammation, some of the inflammatory infiltrate fuse and become multinucleate (syncitia)

Question 12

Describe the measles virus infection

Answer 12

Primary replication occurs in the RT in epithelial cells but infection by local macrophages, lymphocytes and DCs which drain into the lymph nodes and have access to the rest of the body.
Infected APCs amplify in lymphoid tissue and return to epithelial cells - highly infectious disease.
Also leads to transient immunosuppresion

Question 13

What are the barriers to infection [8] of the alimentary tract?

Answer 13

Sequestration of the intestinal contents
Stomach acidity pH < 2
Mucous
Bile acid secretions with lipolytic activity
Proteolytic enzymes released by the pancreas
Resident macrophages (scavenging)
Intestinal alkalinity
IgA

Question 14

What is the common characteristic of viruses that infect the alimentary tract?

Answer 14

Are often acid and bile resistant
Non-enveloped
Very robust and hardy

Question 15

What is a major symptom of viral infection in the gut? How does this occur and why?

Answer 15

Diarrhoea.
Caused by destruction of the lining of the intestines leading to malabsorption of fluids. Some viruses (like rotavirus) have a protein that promotes fluid secretion.
Diarrhoea is favourable to (1) allow internal spread of the virus and (2) to promote the faecal-oral route.

Question 16

What are M cells? Where are they and what are their functions? What is their significance to viruses?

Answer 16

M cells are in between enterocytes (joined by tight junctions) and they ingest and deliver antigens to underlying lymphoid cells and tissue by transcytosis.
Some enteric viruses gain entry through this pathway or by directly infecting (and killing) these cells.

Question 17

Describe the Rotavirus infection

Answer 17

Localised GIT infection. A hardy and robust (triple capsid) virus that is able to survive passage to the gut. It infects and destroys epithelial cells and M cells causing inflammation, malabsorption. It is able to secrete a protein NSP4 that promotes secretion.

Question 18

Describe the Enterovirus infection

Answer 18

A systemic virus that enters via the respiratory route with primary replication occurring in the oropharynx which mucous is swallowed and more replication occurs in Peyer’s patch (lymphatic tissue) of the small intestine. Secondary viremia occurs in different tissues

• CNS
• Meninges
• Skin
• Muscle

Question 19

What are the transcutaneous routes of infection [3] and what are some examples of viruses entering in these ways?

Answer 19

1. Trauma: papillomavirus
2. Injection via needles: Hepatitis B, C, HIV
3. Insect/Animal bites: Dengue from mosquitos

Question 20

What are some common viruses that infect the genital tract?

Answer 20

Papillomavirus, HSV, HIV, Hepatitis B

Question 21

What are some common viruses that infect the conjunctiva?

Answer 21

A rare route of infection.

Adenovirus, enterovirus 70 and HSV

Question 22

What are the mechanisms of spread from the epithelia?

Answer 22

Local spread on epithelial surfaces, sub-epithelial invasion and lymphatic spread, into the blood (viraemia) and neural spread

Question 23

What is meant by the term viraemia?

Answer 23

Free floating viral particles in the blood stream (plasma) with the potential to infect new cells.

Question 24

Once in the epithelium, some viruses spread to cause secondary infections. What is the major route for spread into the blood?

Answer 24

Epithelial tissues drain fluid into the lymphatic system, through which they have access to many parts of the body including the lymph nodes. From here they drain into the blood stream where they cause systemic infection. (Injection or arthropod spread of disease is the exception: directly into the blood).

Question 25

Describe the difference between primary and secondary viraemia

Answer 25

Primary viraemia is when the virus is IN THE BLOOD | Secondary viraemia is the infection of other organs leading to ENMASS AMPLIFICATION

Question 26

What is an important consideration with secondary viraemia?

Answer 26

It often occurs asymptomatically or quietly leading to large numbers of viral particles without the host knowing until they cause widespread damage and terrible symptoms.

Question 27

What is the main mechanism of the host to combat varaemia?

Answer 27

By the production of antibodies against the viral antigen leading to neutralization. These take approximately 1-2 weeks to develop.

Question 28

Define what is meant by cell-associated viremia. Give exampless

Answer 28

This is when the viruses are in the plasma but are associated with cells flowing through it (ie. Intracellular) Eg. HIV in T cells and Dengue and Malaria virus in monocytes.

Question 29

What is a common feature of cell-associated viruses that make them dangerous to the host?

Answer 29

They are able to survive intracellularly and persist for many months and years as a latent infection (to avoid CTL attack)

Question 30

Describe the congenital routes of viral infection [4] and their consequences. Give examples.

Answer 30

Viruses can pass through the placental wall from the mother and cause death of the foetus (abortion). = Smallpox Viruses can also cross through the placental wall and cause impairments in development (non-cytocydal) = Rubella and CMV. The baby can be infected in the birthing process: HSV, Varicella, CMV or cocsakie B (faecal contamination) Transplacental spread leading to a carrier state of immunological tolerance (HBV)

Question 31

What are the determinants of Tropism? [6]

Answer 31

1. Available of receptors for the virus 2. Optimal temperatures for replication (eg. rhinovirus) 3. Stability in extremes of pH (eg. Rotavirus) 4. Ability to replicate in macrophages and lymphocytes: provides access to other tissues (Eg. HIV, measles) 5. Polarised release: apical vs. basal release. Basal released viruses are more likely to cause systemic infections. 6. Presence of Activating enzymes (eg. influenza requires tryptase clara secreted by clara cells of the large airways)

Question 32

How do viruses cause DIRECT damage to tissues and organs? [4]

Answer 32

1. Cytocidal (viral death due to overwhelming amplification of viral particles) 2. Toxicity of viral products 3. Imitation of apoptosis by causing dysfunction to the cell 4. Loss of function to infected cells damaging the overall tissue (eg. rhinoviruses cause cilia stasis)

Question 33

Why do viruses cause immunopathology, immunsuppresion and/or autoimmunity?

Answer 33

Very potent stimulators of the inflammatory response Are able to infiltrate lymphocytes and macrophages and release cytokines and inflammation Cuase symptoms like fever (IL-1 and TNF) and enlarged lymph nodes on an immunological basis.

Question 34

What are the three major antibody mediated responses to viruses? How do they cause pathology?

Answer 34

When antibody binding to viral antigens and Fc binding-mediated uptake into immune cells amplifies the infection (Eg. dengue leading to hemorrhagic shock syndrome) Antigen-antibody complex deposition: glomerulonephritis or vasculitis (Hep B) T cell mediated pathology: induction of cytokines that recruit eosinophils for rashes (measles) or infection of cytotoxic CD8 cells that contribute to organ damaga (eg. liver damage by Hepatitis)

Question 35

How are viruses believed to be involved in autoimmunity? [2 hypothesised mechanisms]

Answer 35

1. Antigen mimicry: viral particles mimicking the host (eg. Myelin basic protein and proteins of influenza) 2. EBV is able to infect B cells (latency) and once a non-specific trigger activates them they are able to produce a polyclonal B cell activation that is self reactive

Question 36

How do viral infections lead to immunosuppression?

Answer 36

By infecting immunologically important cell like CD4 (HIV) and Measles (cause temporary suppression from non-productive replication in T cells and macrophages). There can be an indirect suppression (to secondary infections) due to inflammation and damage caused by the virus.