35.5 Cellular and Systemic Consequences of Infection Flashcards
Are all viruses pathogenic?
No
What does the outcome of an infection rely on?
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)
Why do viral infections cause disease in the organism as a whole?
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.
What does infection usually result in?
The death of cells
What are cytopathic effects and what are they caused by?
Morphological changes within the host cells as side effects of the viral life cycle.
What are the cytopathic effects of polio on motor neurons?
- 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.
What are the cytopathic effects of HIV on CD4+ T-cells?
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
Which part of human immunity is important in hepatitis pathogenesis?
Cell-mediated immunity -> This is leads to bystander cell death and therefore damage to the liver, as well as inflammation.
Is cellular transformation by DNA viruses common?
No, it is a comparatively rare and atypical consequence of viral infection.
What can EBV cause?
*Infectious mononucleosis
aka glandular fever.
How does EBV cause glandular fever?
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
How can EBV lead to cancer development?
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
What is EBV a predisposing factor for?
*Burkitt’s Lymphoma
*Nasopharyngeal carcinoma
There is a requirement for other factors.
What does Papilloma virus cause?
common warts (benign tumours)
What is Papilloma virus a predisposing factor for?
*carcinoma of the uterine cervix + other carcinomas by certain serotypes.
- e.g. ano-genital carcinomas/ head and neck squamous cell carcinomas.
*by 6 strains
How does Papilloma virus predispose to carcinomas?
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.
What can cause Hepatocellular carcinoma?
Chronic Hepatitis B Virus and Hepatitis C Virus infection
*in cases of severe chronic infection.
How do DNA viruses with small genomes and some RNA viruses transform cells?
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.
What is cellular latency?
The persistence of viral genomes in cells without overt expression of new viruses.
Give examples of viruses that display cellular latency
Herpes virus and retroviruses
What is clinical latency?
The temporary absence of symptoms in spite of infection, resulting from cellular latency, active immunity etc.
Describe how latency of HIV works.
- 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
What are some potential approaches to curing HIV?
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
How can dissemination be classified?
Local or systemic
What does dissemination depend on?
Dose received, virulence, lifecycle of viral strain, viral tropism.
How does local spread affect symptom presentation?
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
Give examples of viruses with local spread
*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
What is another way that local spread can take place?
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
What does systemic infection depend upon?
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.
What does viraemia enable?
Spread of infection to distant sites.
How does presentation of symptoms in systemic infection compare to local spread?
The effect of the virus on distant tissue becomes evident after a longer period.
Give an example of a virus with systemic infection.
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
What do the majority of symptoms from viruses result from?
Most symptoms result form the release of mediators of inflammation
What are the symptoms commonly associated with a viral infection?
Fever/ malaise/ myalgia/ headache/ nausea/ dizziness
What is fever caused by?
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
What is Malaise and other symptoms caused by?
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.
How are acute infections resolved?
*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
How is re-infection of acute infections prevented?
By plasma IgG and secretory IgA
What can persistent infection of HBV lead to?
Possibly liver cancer
How can HIV remain a chronic infection?
Attack on CD4+ T-lymphocytes leading to immunodeficiency if left untreated.
Also antigenic variation.
How can EBV remain a chronic infection?
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)
How can EBV become latent?
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
Describe how EBV can lead to tumours.
- 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
