35.5 Cellular and Systemic Consequences of Infection

Question 1

Are all viruses pathogenic?

Answer 1

No

Question 2

What does the outcome of an infection rely on?

Answer 2

A wide range of host and viral factors
*e.g. age/ health/ state of immune system/ dose of virus (likely due to extent of spread/ cell death)

Question 3

Why do viral infections cause disease in the organism as a whole?

Answer 3

Symptoms are generally due to the limitations of viral tropism.
*to infect a cell lineage, viruses must be able to enter host cells w/out evoking a strong immune response so they target specific surface proteins.
Therefore, systemic consequences of infection generally linked to the cell lineages that are affected.

Question 4

What does infection usually result in?

Answer 4

The death of cells

Question 5

What are cytopathic effects and what are they caused by?

Answer 5

Morphological changes within the host cells as side effects of the viral life cycle.

Question 6

What are the cytopathic effects of polio on motor neurons?

Answer 6

• Inhibition of cell protein synthesis (by cleavage of eukaryotic translation initiation factor eIF4G by viral protein 2A).
• Inhibition of cell transcription by all three classes of RNA polymerases.
• Cytoskeletal changes, cell rounding and detachment from substratum.
• Cell lysis.

Lots of the pathogenesis of polio also results from apoptosis of cells.

Question 7

What are the cytopathic effects of HIV on CD4+ T-cells?

Answer 7

HIV-1 is also known to have a direct, cytopathic effect on CD4+ T-cells, leading to membrane ballooning and rupture for the lytic death thought to be a primary cause of T-cell depletion in the course of the disease

Question 8

Which part of human immunity is important in hepatitis pathogenesis?

Answer 8

Cell-mediated immunity -> This is leads to bystander cell death and therefore damage to the liver, as well as inflammation.

Question 9

Is cellular transformation by DNA viruses common?

Answer 9

No, it is a comparatively rare and atypical consequence of viral infection.

Question 10

What can EBV cause?

Answer 10

*Infectious mononucleosis
aka glandular fever.

Question 11

How does EBV cause glandular fever?

Answer 11

fever, a sore throat, enlargement of the lymph nodes of the neck and fatigue due to replication within the pharyngeal epithelium acutely (fever, sore throat) before moving on to infect B-cells via CD21 and leading to swelling of the lymph nodes as CTLs begin to target these infected lymphocytes

Question 12

How can EBV lead to cancer development?

Answer 12

production of the viral protein EBNA-1, which is used in opposition to antigen presentation and improving replication of the virus in a host, is known to increase DNA replication and BART/EBER/LMP gene expression (which causes the likelihood of apoptosis to decrease), thus increasing the likelihood of somatic mutation and development of cancers from infected cells

Question 13

What is EBV a predisposing factor for?

Answer 13

*Burkitt’s Lymphoma
*Nasopharyngeal carcinoma
There is a requirement for other factors.

Question 14

What does Papilloma virus cause?

Answer 14

common warts (benign tumours)

Question 15

What is Papilloma virus a predisposing factor for?

Answer 15

*carcinoma of the uterine cervix + other carcinomas by certain serotypes.
- e.g. ano-genital carcinomas/ head and neck squamous cell carcinomas.
*by 6 strains

Question 16

How does Papilloma virus predispose to carcinomas?

Answer 16

Proteins E6 and E7 are linked to the development of cancer. They up-regulate the cell cycle.
*E6 interferes w/ normal p53 signalling that suppresses cellular survival signals.
*E7 activates E2F transcription factors that help u[regulate genes necessary for mitosis. Also RB1 inhibition so cell can immediately progress from G1 to S phase.

Question 17

What can cause Hepatocellular carcinoma?

Answer 17

Chronic Hepatitis B Virus and Hepatitis C Virus infection
*in cases of severe chronic infection.

Question 18

How do DNA viruses with small genomes and some RNA viruses transform cells?

Answer 18

These acute viruses benefit from the rapid replication of host cells to increase their own numbers further without needing to account for the longer-term effects to the host, they can carry genetic material that can be integrated into the host cell to alter replication.
*e.g. RSV injects a proto-oncogene which is transcribed to promote host cell replication + directly and rapidly induces tumour development.

Question 19

What is cellular latency?

Answer 19

The persistence of viral genomes in cells without overt expression of new viruses.

Question 20

Give examples of viruses that display cellular latency

Answer 20

Herpes virus and retroviruses

Question 21

What is clinical latency?

Answer 21

The temporary absence of symptoms in spite of infection, resulting from cellular latency, active immunity etc.

Question 22

Describe how latency of HIV works.

Answer 22

• HIV-1 can infect macrophages and T-cells (which can become memory T cells)
• When these cells are in long-term reservoirs, they are not active and therefore there is no transcription of the viral genome -> Thus, there is no immune response against the viral proteins and the virus is latent
• These viruses in these cells are resistant to drugs and the immune system

Question 23

What are some potential approaches to curing HIV?

Answer 23

The problem with HIV is that a latent infection is very difficult to treat. The approaches include:

• ‘Berlin’ and ‘London’ patients, who received bone marrow transplants from individuals with no CCR5 receptors on their cells -> This resulted in there being no detectable virus for many years, making these patients essentially cured. However, this is not widely viable for every HIV patient.
• ‘Kick and kill’ approach, where latency is reversed by activating transcription in infected memory T-cells (so that they can be killed by cytotoxic T-cells) and then re-infection of new cells is prevented using strong anti-retroviral drugs

Question 24

How can dissemination be classified?

Answer 24

Local or systemic

Question 25

What does dissemination depend on?

Answer 25

Dose received, virulence, lifecycle of viral strain, viral tropism.

Question 26

How does local spread affect symptom presentation?

Answer 26

In local spread, replication and emergence of the virus from infected cells allows for the presentation of cytopathic symptoms in the specific tissue (with the cell lineage to which the virus exhibits tropism resent) after a short period of clinical latency known as the incubation period

Question 27

Give examples of viruses with local spread

Answer 27

*Influenza - cytopathic effects being on epithelial cells following entry through sialic acid sugars using haemagglutinin
*rotavirus - cytopathic effects being on enterocytes following entry via binding to glycans on the epithelial cell surfaces

Question 28

What is another way that local spread can take place?

Answer 28

Local spread can also take place via the delivery of viruses to local lymph nodes through the lymphatic drainage – either freely within the lymph or within macrophages as occurs for HIV-1 to allow entry to the CD4+ T-cells in these areas

Question 29

What does systemic infection depend upon?

Answer 29

Viraemia (the presence of viruses in the blood) which can be due to direct entry or a secondary viraemia following release of virions from earlier sites of infection.

Question 30

What does viraemia enable?

Answer 30

Spread of infection to distant sites.

Question 31

How does presentation of symptoms in systemic infection compare to local spread?

Answer 31

The effect of the virus on distant tissue becomes evident after a longer period.

Question 32

Give an example of a virus with systemic infection.

Answer 32

Poliomyelitis.
*the virus initially enters through the gastrointestinal system before using the blood to migrate to the CNS where it can cause its effects following a clinical latency period of up to a few days

Question 33

What do the majority of symptoms from viruses result from?

Answer 33

Most symptoms result form the release of mediators of inflammation

Question 34

What are the symptoms commonly associated with a viral infection?

Answer 34

Fever/ malaise/ myalgia/ headache/ nausea/ dizziness

Question 35

What is fever caused by?

Answer 35

signalling of cytokines on the hypothalamus, resetting the baseline body temperature at a higher level to reduce inhibitory drive to the neurons stimulating brown adipose tissue and skeletal muscle so that both shivering and non-shivering thermogenesis processes are increased to elevate the body temperature.
*makes it harder for replication of pathogens to take place + helps to control the growth of infections within the body.
*increased temperatures can improve the function of the immune system and help it to resolve the issue

Question 36

What is Malaise and other symptoms caused by?

Answer 36

generally the result of cytokine signals; the mediators of inflammation are able to act on the brain and its vasculature to alter normal physiology downstream.

Question 37

How are acute infections resolved?

Answer 37

*Restriction of viral replication by local production of type 1 alpha/beta interferons
*Clearance of virus-infected cells by the immune system (mainly CD8+ T-cells)
*Clearance of free virus by Ab and complement

Question 38

How is re-infection of acute infections prevented?

Answer 38

By plasma IgG and secretory IgA

Question 39

What can persistent infection of HBV lead to?

Answer 39

Possibly liver cancer

Question 40

How can HIV remain a chronic infection?

Answer 40

Attack on CD4+ T-lymphocytes leading to immunodeficiency if left untreated.
Also antigenic variation.

Question 41

How can EBV remain a chronic infection?

Answer 41

Most infections are chronic and controlled w/in nasopharynx or throat area.
Initial asymptomatic or glandular fever, both followed by latent infection.
*Re-emergence if immune surveillance is lacking (e.g. HIV and AIDS)

Question 42

How can EBV become latent?

Answer 42

Latent infection of B cells is enabled by circularisation of the virus’ genome and decreased viral gene expression, which confers resistance to host adaptive immunity

Question 43

Describe how EBV can lead to tumours.

Answer 43

• EBV stimulates proliferation and inhibits apoptosis of host cells
• If co-factors are present, it may proceed to tumours:
  
  • Malaria is a co-factor that leads to Burkitt lymphoma (cancer of the B cells)
  • Environmental co-factors lead to nasopharyngeal carcinoma