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Pathogenesis
Learning Objectives:
Chapter 7: Pathogenesis
Pathogenicity
Pathogenicity, the capacity of one organism to cause
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Chapter 7: Pathogenesis
Virus Diseases
The course of any virus infection is determined by a balance between the host and the virus, as is the extent and severity of virus pathogenesis. In some virus infections, most of the symptoms observed are attributable not to virus replication, but to the side-effects of the immune response. Inflammation, fever, headaches and skin rashes are not usually caused by viruses themselves, but by the cells of the immune system due to the release of potent chemicals such as interferons and interleukins.
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Chapter 7: Pathogenesis
Virus Pathogenesis
Virus pathogenesis is an abnormal and fairly rare situation - the majority of virus infections do not result in disease. It is sometimes said that viruses would disappear if they killed their hosts - this is not necessarily true. Ideally, a virus would not even provoke an immune response from its host, or at least be able to hide to avoid the effects. Three major aspects of virus pathogenesis must be considered: direct cell damage resulting from virus replication damage resulting from immune activation or suppression cell transformation caused by viruses
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Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
Shutoff
A number of viruses which cause cell lysis exhibit a phenomenon known as shutoff early in infection: the sudden cessation of host cell macromolecular synthesis. In poliovirus-infected cells, this is the results from the virus 2A protein, a protease which cleaves the p220 component of eIF-4F, required for cap-dependent translation of messenger RNAs. Since poliovirus RNA does not have a 5' methylated cap but is modified by the addition of the VPg protein, virus RNA continues to be translated. A few hours after translation ceases, lysis of the cell occurs.
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Chapter 7: Pathogenesis
E3-11.6K is required for the lysis of adenovirusinfected cells and the release of virus particles from the nucleus.
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Chapter 7: Pathogenesis
Membrane Fusion
Membrane fusion is the result of virus-encoded proteins required for infection of cells, typically the glycoproteins of enveloped viruses. One of the best known examples of such a protein comes from Sendai virus (a paramyxovirus), which has been used to induce cell fusion during the production of monoclonal antibodies. At least nine of the eleven known herpes simplex virus (HSV/HHV-1) glycoproteins have been characterised regarding their role in virus replication.
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Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
Elsevier, 2005.
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Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
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Chapter 7: Pathogenesis
Retrovirus Pathogenesis
Retroviruses cause a variety of pathogenic conditions including paralysis, arthritis, anaemia and malignant cellular transformation. Although these infections may lead to a diverse array of diseases and haematopoetic abnormalities such as anaemia and lymphoproliferation, the most commonly recognized consequence of retrovirus infection is the formation of lymphoid tumours. However, some degree of immunodeficiency is a common consequence of interference with the immune system resulting from the presence of a lymphoid or myeloid tumour.
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Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
AIDS Pathogenesis
It is still not clear how much of the pathology of AIDS
Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
Elsevier, 2005.
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Chapter 7: Pathogenesis
Elsevier, 2005.
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Chapter 7: Pathogenesis
T-Cell Anergy:
Anergy is a condition in which lymphocytes are present but not functionally active. In AIDS, anergy could be induced due to HIV infection, e.g. interference with cytokine expression. There is experimental evidence that gp120-CD4 interactions result in anergy due to interference with signal transduction. Many AIDS patients are anergic, i.e. fail to mount a delayed-type hypersensitivity (DTH) response to skintest antigens. There is no strong evidence that this phenomenon is directly related to any aspect of HIV infection rather than to general depletion of immune functions.
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Chapter 7: Pathogenesis
Apoptosis:
Apoptosis could potentially be induced in large numbers of uninfected cells by factors released from a much smaller number of HIV-infected cells. HIV infection of T-cells induces an activated phenotype which suggests that these cells may be doomed due to activation of the apoptosis pathway. Several HIV proteins have been identified as both inducers and repressors of apoptosis under various circumstances. The proportion of CD4+ T cells in the later stages of apoptosis is about twofold higher in HIV-1 infected individuals than in uninfected people.
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Chapter 7: Pathogenesis
Superantigens:
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Chapter 7: Pathogenesis
TH1/TH2 Imbalance:
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Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
AIDS Pathogenesis
Contrary to what was initially believed, there is a very dynamic situation in HIV-infected people involving continuous infection, destruction and replacement of CD4+ cells. Highly active antiretroviral therapy (HAART) has a dramatic effect on suppressing virus production and temporarily restores CD4 cell populations. Unfortunately, because of the long half life of latentlyinfected cells, the estimated time to completely eradicate HIV from the body is roughly 12-60 years something which is not presently achievable due to the failure of therapy as a result of drug toxicity and virus resistance.
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Chapter 7: Pathogenesis
Virus-Related Diseases
There are a number of diseases for which virus infections are believed to be a necessary prerequisite. In some instances, the link between a particular virus and a pathological condition is well established, but the pathogenesis of the disease is complex and also involves the immune system of the host. In other cases, the pathogenic involvement of a particular virus is less certain, and in a few instances, rather speculative.
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Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
Dengue Virus
Dengue virus is a flavivirus which is transmitted from one human host to another via mosquitoes. The primary infection may be asymptomatic or result in dengue fever, a self-limited illness. Following primary infections, patients carry antibodies to the virus. There are four serotypes of dengue virus and the presence of antibody against one type does not give cross-protection against the other three. Antibodies can enhance the infection of peripheral blood mononuclear cells by Fc-receptor mediated uptake of antibody-coated dengue virus particles.
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Chapter 7: Pathogenesis
Dengue Virus
Dengue haemorrhagic fever (DHF) is a life-threatening disease. Hypovolemic shock (dengue shock syndrome, DSS) also occurs, which is frequently fatal. DHF and DSS following primary dengue virus infections occur in approximately 1 in 14,000 and 1 in 500 patients respectively. After secondary dengue virus infections, the incidence of DHF is 1 in 90 and DSS 1 in 50, since cross-reactive but non-neutralizing antibodies to the virus are present.
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Chapter 7: Pathogenesis
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Chapter 7: Pathogenesis
Virus-Associated Diseases
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Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
Stx Toxins
Meat is infected by faecal contamination, usually at the time of slaughter. Ground meat such as hamburger is particularly dangerous since surface bacterial contamination may become buried deep within the meat where it may not be inactivated by cooking. The Stx1 and Stx2 toxin genes are encoded in the genome of lysogenic lambda-like prophages within the bacteria. Stimuli such as UV light or mitomycin C are known to induce these prophages to release a crop of phage particles which can infect and lysogenize other susceptible bacteria within the gut.
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Chapter 7: Pathogenesis
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Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
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Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
Oncogenes
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Chapter 7: Pathogenesis
Oncogenes
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Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
These additional sequences may alter the function or the cellular localization of the protein and these abnormal attributes result in transformation.
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Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
Insertional Activation
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Chapter 7: Pathogenesis
Trans-Activating Retroviruses
Human T-cell leukaemia virus (HTLV) and related animal viruses encode a transcriptional activator protein - the tax gene. The tax protein acts in trans to stimulate transcription from the virus LTR. The tax protein also activates transcription of cellular genes by interacting with transcription factors. Cell transformation and tumour formation are not one and the same - additional events are required for the development of leukaemia. Chromosomal abnormalities which may occur in the population of HTLV-transformed cells are also required to produce a malignant tumour.
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Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
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Chapter 7: Pathogenesis
p53
p53 forms complexes with SV40 T-antigen and other DNA virus oncoproteins, including those of adenoviruses and papillomaviruses. The gene encoding p53 is mutated or altered in the majority of tumours. p53 plays a central role in controlling the cell cycle. p53 is a transcription factor which activates the expression of cellular genes, causing the cell cycle to arrest at the G1 phase. Since these viruses require ongoing cellular DNA replication for their own propagation, this explains why their transforming proteins target p53.
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Chapter 7: Pathogenesis
Rb
Rb was discovered in tumours of the optic nerve known as retinoblastomas. The Rb protein forms complexes with a transcription factor called E2F. E2F is required for the transcription of adenovirus genes, but is also involved in the transcription of cellular genes. The formation of inactive E2F-Rb complexes has the same overall effect as the action of p53 - arrest of the cell cycle at G1. Release of E2F by replacement of E2F-Rb complexes with E1A-Rb, T-antigen-RB or E7-RB complexes stimulates cellular and virus DNA replication.
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Chapter 7: Pathogenesis
SV40 T-Antigen
SV40 T-antigen is one of the known virus proteins which binds p53. Infection of cells by SV40 or other polyomaviruses can result in two possible outcomes: Productive (lytic) infection Non-productive (abortive) infection The outcome of infection appears to be determined primarily by the cell type infected. T-antigen is also involved in SV40 genome replication, initiated by binding of large T-antigen to the origin region of the genome.
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Chapter 7: Pathogenesis
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Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
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Chapter 7: Pathogenesis
1. EBV immortalizes a large pool of B-lymphocytes. Malaria causes T-cell immunosuppression. There is a large pool of target cells in which a third event (e.g. a chromosomal translocation) results in the formation of a malignantly transformed cell. 2. Malaria results in polyclonal B-cell activation. EBV subsequently immortalizes a cell containing a preexisting c-myc translocation. 3. EBV is just a passenger virus!
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Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
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Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
Poliomyelitis
In rural communities with primitive sanitation facilities, poliovirus circulated freely. More than 90% of children have antibodies to at least one of the three serotypes of poliovirus. Even the most virulent strains of poliovirus cause 100-200 subclinical infections for each case of paralytic poliomyelitis seen. In such communities, infants experience subclinical immunizing infections while still protected by maternal antibodies - a form of natural vaccination. The relatively few cases of paralysis and death which do occur are likely to be overlooked, especially in view of high infant mortality rates.
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Chapter 7: Pathogenesis
Poliomyelitis
During the nineteenth century, industrialization and urbanization changed the pattern of poliovirus transmission. Dense urban populations and increased travelling afforded opportunities for rapid transmission of the virus. Improved sanitation broke the natural pattern of virus transmission. Children were likely to encounter the virus for the first time at a later age without the protection of maternal antibodies. The widespread use of poliovirus vaccines has since brought the situation under control, and global eradication of poliovirus is anticipated by 2008.
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Chapter 7: Pathogenesis
It has been suggested that it was not until human populations in China and the Roman Empire reached a critical density that these viruses were able to propagate in an epidemic pattern and cause recognizable outbreaks of disease.
Before this time, the few cases that did occur could easily have been overlooked.
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Chapter 7: Pathogenesis
Smallpox
Smallpox reached Europe from the Far East in 710 AD and in the eighteenth century, achieved plague proportions. Smallpox was (accidentally) transferred to the Americas by Hernando Corts in 1520. In the next two years, 3.5 million Aztecs died from the disease and the Aztec empire was decimated by disease rather than conquest. Although not as highly pathogenic as smallpox, epidemics of measles subsequently finished off the Aztec and Inca civilizations. More recently, the first contacts with isolated population groups have had similarly devastating results.
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Chapter 7: Pathogenesis
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Chapter 7: Pathogenesis
Dengue Fever
Dengue fever is primarily an urban disease of the tropics, transmitted by Aedes aegypti, a domestic, day-biting mosquito that prefers to feed on humans. Some outbreaks of dengue fever have involved more than a million cases with attack rates of up to 90% of the population. There are over 40 million cases of Dengue virus infection worldwide each year. This is not a new virus, but the frequency of Dengue virus infection has increased dramatically in the last 30 years.
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Chapter 7: Pathogenesis
Dengue Fever
Population movements and into new arthropod habitats, particularly tropical forests Deforestation Irrigation, especially primitive systems without arthropod control Uncontrolled urbanization Increased long-distance air travel Increased long-distance livestock transportation New routing of long-distance bird migration brought about by new man-made water impoundments Cessation of mosquito control programmes and political upheaval resulting in degraded primary medical services
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Chapter 7: Pathogenesis
Chapter 7: Pathogenesis
vectors (whiteflies).
These viruses cause a great deal of crop damage and their spread may be directly linked to the worldwide
Chapter 7: Pathogenesis
Zoonoses
Many emergent virus diseases are zoonoses (transmitted from animals to humans). Severe acute respiratory syndrome (SARS) is a type of viral pneumonia. The first SARS outbreak originated in China in 2003. The cause was a novel coronavirus, SARS-CoV. Where did the SARS virus come from? Coronaviruses with 99% sequence similarity to human SARS isolates have been isolated from apparently healthy masked palm civets. It is believed that humans became infected as they raised and slaughtered these animals rather than by consumption of infected meat.
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Chapter 7: Pathogenesis
Bioterrorism
Many governments devoted considerable resources to the development of viruses as weapons of war before deciding that their military usefulness was limited. The U.S. Centers for Disease Control (CDC) only recognises two types of virus as potentially dangerous terrorist weapons: smallpox and agents causing haemorrhagic fevers such as filoviruses and arenaviruses. Emerging viruses such as Nipah virus and hantaviruses are also recognized as possible future threats; however, this is in contrast to a much larger number of bacterial species and toxins.
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Chapter 7: Pathogenesis
Summary
Virus pathogenesis is a complex, variable and relatively rare state. Pathogenesis is also determined by the balance between host and virus factors. Not all of the pathogenic symptoms seen in virus infections are caused directly by the virus - the immune system also plays a part in causing cell and tissue damage. Viruses can transform cells so that they continue to grow indefinitely. In some cases, this can lead to the formation of tumours. New pathogenic viruses are being discovered all the time and changes in human activities result in the emergence of new or previously unrecognized diseases.
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