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1、Chapter 7: PathogenesisSlide 1/43PathogenesisLearning Objectives:On completing this session, you should be able to:Explain the concept of pathogenesis in the context of virus infections.Discuss the molecular basis for virus-induced immunodeficiency (including AIDS) & cell transformation by viruses.U
2、nderstand the ways in which virus infection may result in cellular injury.Chapter 7: PathogenesisSlide 2/43PathogenicityPathogenicity, the capacity of one organism to cause disease in another, is a complex & variable phenomenon.At the simplest level there is the question, what is disease? An all-emb
3、racing definition would be that it is a departure from the normal physiological parameters of an organism.This could range from a transient & very minor condition such as a slightly elevated temperature or rather subjective feelings of lethargy to chronic pathologic conditions which eventually resul
4、t in death.Any of these conditions may result from a large number of internal or external sources.However, there is rarely one single factor which causes a disease.Most disease states are multi-factorial at one level or another.Chapter 7: PathogenesisSlide 3/43Virus DiseasesTwo components are involv
5、ed:the direct effects of virus replicationthe effects of bodily responses to the infectionThe course of any virus infection is determined by a delicate & dynamic balance between the host & the virus, as is the extent & severity of virus pathogenesis.In some virus infections, most of the pathologic s
6、ymptoms observed are attributable not to virus replication, but to the side-effects of the immune response.Inflammation, fever, headaches & 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 & int
7、erleukins.In the most extreme cases, none of the pathologic effects of certain diseases are caused directly by the virus, except that its presence stimulates the activation of the immune system.Chapter 7: PathogenesisSlide 4/43Virus PathogenesisVirus pathogenesis is an abnormal & fairly rare situati
8、on - the majority of virus infections are silent & do not result in outward signs of disease.It is sometimes said that viruses would disappear if they killed their hosts - this is not necessarily true.It is possible to imagine viruses with a hit-and-run strategy, moving quickly from one dying host t
9、o the next & relying on continuing circulation for their survival.Nevertheless, there is a clear tendency for viruses not to injure their hosts if possible.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 o
10、f virus pathogenesis must be considered: direct cell damage resulting from virus replication, damage resulting from immune activation or suppression, & cell transformation caused by viruses.Chapter 7: PathogenesisSlide 5/43Mechanisms of Cellular InjuryVirus infection results in a number of changes w
11、hich are detectable by visual or biochemical examination of infected cells.These changes result from the production of virus proteins & nucleic acids, but also from alterations to the biosynthetic capabilities of cells.Intracellular parasitism by viruses sequesters cellular apparatus such as ribosom
12、es & raw materials which would normally be devoted to synthesizing molecules required by the cell.Eukaryotic cells must carry out constant macromolecular synthesis, whether they are growing & dividing or in a state of quiescence.Chapter 7: PathogenesisSlide 6/43Mechanisms of Cellular InjuryA growing
13、 cell clearly needs to manufacture more proteins, more nucleic acids & more of all of its myriad components to increase its size before dividing.The function of all cells is regulated by controlled expression of their genetic information & the subsequent degradation of the molecules produced.Such co
14、ntrol relies on a delicate & dynamic balance between synthesis & decay which determines the intracellular levels of all the important molecules in the cell.This is particularly true of the control of the cell cycle, which determines the behaviour of dividing cells.Chapter 7: PathogenesisSlide 7/43Me
15、chanisms of Cellular InjuryA number of common phenotypic changes can be recognized in virus-infected cells.These changes are often referred to as the cytopathic effects (c.p.e.) of a virus & include:1)Altered shape2)Detachment from the substrate3)Lysis4)Membrane fusion5)Membrane permeability6)Inclus
16、ion bodies7)ApoptosisChapter 7: PathogenesisSlide 8/43ShutoffA number of viruses which cause cell lysis exhibit a phenomenon known as shutoff early in infection.Shutoff is the sudden & dramatic cessation of most host cell macromolecular synthesis.In poliovirus-infected cells, this is the result of p
17、roduction of the virus 2A protein.This molecule is a protease which cleaves the p220 component of eIF-4F, a complex of proteins required for cap-dependent translation of messenger RNAs by ribosomes.Since poliovirus RNA does not have a 5 methylated cap but is modified by the addition of the VPg prote
18、in, virus RNA continues to be translated.In poliovirus-infected cells, the dissociation of mRNAs & polyribosomes from the cytoskeleton can be observed & this is the reason for the inability of the cell to translate its own messages.A few hours after translation ceases, lysis of the cell occurs.Chapt
19、er 7: PathogenesisSlide 9/43Cell Damage by AdenovirusesIn the case of adenoviruses, the penton protein (part of the virus capsid) has a toxic effect on cells.Although its precise action on cells is not known, addition of purified penton protein to cultured cells results in their rapid death.Toxin pr
20、oduction by pathogenic bacteria is a common phenomenon, but this is the only well-established case of a virus-encoded molecule with a toxin-like action.The adenovirus E3-11.6K protein is synthesized in small amounts from the E3 promoter at early stages of infection & in large amounts from the major
21、late promoter at late stages of infection.E3-11.6K is required for the lysis of adenovirus-infected cells & the release of virus particles from the nucleus.Chapter 7: PathogenesisSlide 10/43Membrane FusionMembrane fusion is the result of virus-encoded proteins required for infection of cells, typica
22、lly 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) glycoprot
23、eins have been characterised regarding their role in virus replication.A number of these proteins are involved in fusion of the virus envelope with the cell membrane & also in cell penetration.Production of fused syncytia is a common feature of HSV infection.Chapter 7: PathogenesisSlide 11/43Cell Fu
24、sion by HIVInfection of CD4+ cells with some but not all isolates of HIV causes cell-cell fusion & the production of syncytia or giant cells.The protein responsible for this is the transmembrane envelope glycoprotein of the virus (gp41) & the domain near the amino terminus responsible for this fusog
25、enic activity has been identified by molecular genetic analysis.Because HIV infects CD4+ cells & it is the reduction in the number of these crucial cells of the immune system which is the most obvious defect in AIDS, it was initially believed that direct killing of these cells by the virus was the b
26、asis for the pathogenesis of AIDS.Although direct cell killing by HIV undoubtedly occurs in vivo, it is now believed that the pathogenesis of AIDS is considerably more complex.Many animal retroviruses also cause cell killing & in most cases, it appears that the envelope protein of the virus is requi
27、red, although there may be more than one mechanism involved.Chapter 7: PathogenesisSlide 12/43Cell Fusion by HIVChapter 7: PathogenesisSlide 13/43Viruses & ImmunodeficiencyAt least two groups of viruses, herpesviruses & retroviruses, directly infect the cells of the immune system.This has important
28、consequences for the outcome of the infection & for the immune system of the host.Herpes simplex virus (HSV) establishes a systemic infection, spreading via the bloodstream in association with platelets, but does not show particular tropism for cells of the immune system.However, Herpes saimirii & M
29、areks disease virus are herpesviruses which cause lymphoproliferative diseases (but not clonal tumours) in monkeys & chickens, respectively.The most recently discovered human herpesviruses, human herpesvirus-6 (HHV-6), HHV-7 & HHV-8 all infect lymphocytes.Chapter 7: PathogenesisSlide 14/43Infection
30、of Immune cells by HerpesvirusesEpstein-Barr virus infection of B-cells leads to immortalization & proliferation, resulting in glandular fever or mononucleosis, a debilitating but benign condition.EBV was first identified in a lymphoblastoid cell line derived from Burkitts lymphoma and, in rare inst
31、ances, EBV infection may lead to the formation of a malignant tumour.While some herpesviruses such as HSV are notably cytopathic, most of the lymphotropic herpesviruses do not cause a significant degree of cellular injury.Infection of the delicate cells of the immune system may perturb their normal
32、function.Because the immune system is internally regulated by complex networks of interlinking signals, relatively small changes in cellular function can result in its collapse.Alteration of the normal pattern of production of cytokines could have profound effects on immune function.The trans-regula
33、tory proteins involved in the control of herpesvirus gene expression may also affect the transcription of cellular genes - the effects of herpesviruses on immune cells are more complex than just cell killing.Chapter 7: PathogenesisSlide 15/43Retrovirus PathogenesisRetroviruses cause a variety of pat
34、hogenic conditions including paralysis, arthritis, anaemia & malignant cellular transformation.A significant number of retroviruses infect the cells of the immune system.Although these infections may lead to a diverse array of diseases & haematopoetic abnormalities such as anaemia & lymphoproliferat
35、ion, the most commonly recognized consequence of retrovirus infection is the formation of lymphoid tumours.However, some degree of immunodeficiency, ranging from very mild to quite severe, is a common consequence of the interference with the immune system resulting from the presence of a lymphoid or
36、 myeloid tumour.Chapter 7: PathogenesisSlide 16/43Acquired Immunodeficiency Syndrome (AIDS)The most prominent aspect of virus-induced immunodeficiency is acquired immunodeficiency syndrome (AIDS), a consequence of infection with Human immunodeficiency virus (HIV), a member of the genus Lentivirus of
37、 the Retroviridae.There are a number of similar lentiviruses which cause immunodeficiency diseases in animals.Unlike infection by other types of retrovirus, HIV infection does not directly result in the formation of tumours.Some tumours such as B-cell lymphomas are sometimes seen in AIDS patients bu
38、t these are consequence of the lack of immune surveillance which is responsible for the destruction of tumours in healthy individuals.The clinical course of AIDS is long & very variable.A great number of different abnormalities of the immune system are seen in AIDS.As a result of the biology of lent
39、ivirus infections, the pathogenesis of AIDS is highly complex.Chapter 7: PathogenesisSlide 17/43AIDS PathogenesisIt is still not completely clear how much of the pathology of AIDS is caused directly by the virus & how much is caused by the immune system.There are numerous models that have been sugge
40、sted to explain how HIV causes immunodeficiency.These mechanisms are not mutually exclusive & it is probable that the underlying loss of CD4+ cells in AIDS is multifactorial.Chapter 7: PathogenesisSlide 18/43Direct Cell Killing:This was the earliest mechanism suggested, based on the behaviour of lab
41、oratory isolates of HIV.Cell fusion resulting in syncytium formation is one of the major mechanisms of cell killing by HIV in vitro.However, different isolates of HIV vary considerably in the extent to which they promote the fusion of infected cells.Subsequent experiments suggested there may not be
42、sufficient virus present in AIDS patients to account for all the damage seen, although killing of CD4+ cells may contribute to the overall pathogenesis of AIDS in some circumstances.Recently, it has become clear that up to half of the CD4+ cells in the body may be infected with HIV, so the idea of d
43、irect cell killing has been re-examined, but in light of induction of apoptosis rather than by cell fusion.Chapter 7: PathogenesisSlide 19/43Indirect Killing of HIV-Infected Cells:Indirect effects of infection, e.g. disturbances in cell biochemistry & cytokine production, may also affect the regulat
44、ion of the immune system.However, the expression of virus antigens on the surface of infected cells leads to indirect killing by the immune system - effectively a type of autoimmunity.The extent of this activity is dependent on the virus load & replication kinetics in infected individuals.Chapter 7:
45、 PathogenesisSlide 20/43Antigenic DiversityThis theory proposes that the continual generation of new antigenic variants eventually swamps & overcomes the immune system, leading to its collapse.There is no doubt that new antigenic variants of HIV constantly arise during the long course of AIDS becaus
46、e of the low fidelity of reverse transcription.It is envisaged that there might be a ratchet effect, with each new variant contributing to the slight but irreversible decline in immune function.Because of the way virus infections are handled by the immune system, it is probable that variation of T-c
47、ell epitopes on target proteins recognized by CTL are more important than B-cell epitopes which generate the antibody response to a foreign antigen.Recently, it has been shown that there is a simple relationship between virus load & survival time, & that a patient can withstand only 1,300 viral year
48、s of HIV (i.e. copies of the virus genome/ml x survival time in years).Chapter 7: PathogenesisSlide 21/43Antigenic Diversity of HIVChapter 7: PathogenesisSlide 22/43T-Cell Anergy:Anergy is an immunologically unresponsive state in which lymphocytes are present but not functionally active.This is usua
49、lly due to incomplete activation signals & may be an important regulatory mechanism in the immune system, e.g. tolerance of self antigens.In AIDS, anergy could be induced due to HIV infection, e.g. interference with cytokine expression.There is experimental in vitro evidence that gp120-CD4 interacti
50、ons 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 skin-test antigens.Impaired DTH responses are directly related to decreasing CD4+ T-lymphocyte counts.However, there is no strong evi
51、dence that this phenomenon is directly related to any aspect of HIV infection in vivo rather than to general depletion of immune functions.Chapter 7: PathogenesisSlide 23/43Apoptosis:Like T-cell anergy, apoptosis could potentially be induced in large numbers of uninfected cells by factors released f
52、rom a much smaller number of HIV-infected cells.In addition to clonal deletion as a normal part of the evolution of the T-cell repertoire, apoptosis may be induced following T-cell activation as a negative regulatory mechanism to control the strength & duration of the immune response.HIV infection o
53、f T-cells induces an activated phenotype, e.g. surface expression of CD45 & HLA-DR markers, which suggests that these cells may be inevitably doomed due to activation of the apoptosis pathway.Because HIV establishes a persistent infection, it is by no means clear that apoptosis has an entirely negat
54、ive effect - induction of cell death may well limit virus production & slow down the course of infection.Several HIV proteins have been identified as both inducers & repressors of apoptosis under various circumstances. However, the proportion of CD4+ T cells in the later stages of apoptosis is about
55、 twofold higher in HIV-1 infected individuals than in uninfected people.Chapter 7: PathogenesisSlide 24/43Superantigens:Superantigens are molecules which short-circuit the immune system, resulting in massive activation of T-cells rather than the usual, carefully controlled response to foreign antige
56、ns.It is believed that they do this by binding to both the variable region of the b b-chain of the T-cell receptor (Vb b) & to MHC class II molecules, cross-linking them in a non-specific way.This results in polyclonal T-cell activation rather than the usual situation where only the few clones of T-
57、cells responsive to a particular antigen presented by the MHC class II molecule are activated.The over-response of the immune system produced results in autoimmunity as whole families of T-cells which bind superantigens are activated, & immunosuppression as the activated cells are killed by other ac
58、tivated T-cells or undergo apoptosis.No superantigen has been conclusively identified in HIV, despite intensive investigation, thus the practical relevance of superantigens in AIDS is in doubt.Chapter 7: PathogenesisSlide 25/43Superantigens:Chapter 7: PathogenesisSlide 26/43TH1/TH2 Imbalance:Immunol
59、ogical theory suggests that there are two types of CD4+ T-helper (TH) cell: TH1 cells which promote the cell mediated response & TH2 cells which promote the humoral response.This theory suggests that early in HIV infection, TH1-responsive T-cells predominate & are effective in controlling (but not e
60、liminating) the virus.At some point, a (relative) loss of the TH1 response occurs & TH2 HIV-responsive cells predominate.The hypothesis is therefore that the TH2-dominated humoral response is not effective at maintaining HIV replication at a low level & the virus load builds up, resulting in AIDS.Al
61、though this is largely a theoretical proposal which has not been proved, this thinking is shaping our understanding of the immune response to many different pathogens, not just HIV.However, no experimental study has demonstrated an actual switch from the TH1 to TH2 pattern of cytokine expression & s
62、ecretion that is associated with disease progression, so there is no evidence for the involvement of these mechanisms in AIDS.Chapter 7: PathogenesisSlide 27/43TH1/TH2 Imbalance:Chapter 7: PathogenesisSlide 28/43Virus Load & Replication Kinetics:Experiments involving accurate quantitation of the amo
63、unt of virus in infected individuals have revealed that much higher virus loads are present than was originally measured by less sensitive techniques.Using quantitative polymerase chain reaction (PCR) methods to accurately measure the amount of virus present & determine how these levels change when
64、patients are treated with drugs which inhibit HIV replication, it has been shown that:Continuous & highly productive replication of HIV occurs in all infected individuals, although the rates of virus production vary by up to 70-fold in different individuals.The average half-life of an HIV particle i
65、n vivo is 2.1 days.Up to 109-1010 HIV particles are produced each day.An average of 2x109 new CD4+ cells are produced each day.Chapter 7: PathogenesisSlide 29/43AIDS PathogenesisContrary to what was initially believed, there is a very dynamic situation in HIV-infected people involving continuous inf
66、ection, destruction & replacement of CD4+ cells. Billions of new CD4+ cells are produced, infected & killed each day.A better understanding of the pathogenesis of AIDS and, in particular, the role of the immune system in the early stages of the disease is vital to permit the development of more appr
67、opriate therapies for AIDS.Highly active antiretroviral therapy (HAART) has a dramatic effect on suppressing virus production & temporarily restores CD4 cell populations.Unfortunately, because of the long half life of latently-infected cells, the estimated time to completely eradicate HIV from the b
68、ody is roughly 12-60 years - something which is not presently achievable due to the failure of therapy as a result of drug toxicity & virus resistance.Chapter 7: PathogenesisSlide 30/43Virus-Related DiseasesThere are a number of human disease syndromes for which virus infections are believed to be a
69、 necessary prerequisite.In some instances, the link between a particular virus & a pathological condition is well established, but it is clear that the pathogenesis of the disease is complex & also involves the immune system of the host.In other cases, the pathogenic involvement of a particular viru
70、s is less certain, & in a few instances, rather speculative.Chapter 7: PathogenesisSlide 31/43Subacute Sclerosing Panencephalitis (SSPE)Although the incidence of measles virus infection has been reduced sharply by vaccination, measles still causes hundreds of thousands of deaths each year.The normal
71、 course of measles virus infection is an acute febrile illness during which the virus spreads throughout the body, infecting many tissues.The vast majority of people spontaneously recover from the disease without any lasting harm.In rare cases (about 1 in 2000), measles may progress to a severe ence
72、phalitis.This is still an acute condition which either regresses or kills the patient within a few weeks.There is however, another, much rarer late consequence of measles virus infection which occurs many months or years after initial infection of the host.This is the condition known as subacute scl
73、erosing panencephalitis (SSPE).Chapter 7: PathogenesisSlide 32/43Subacute Sclerosing Panencephalitis (SSPE)Evidence of prior measles virus infection (antibodies or direct detection of the virus) is found in all patients with SSPE, whether they can recall having a symptomatic case of measles or not.I
74、n about 1 in 300,000 cases of measles, the virus is not cleared from the body by the immune system, but establishes a persistent infection in the CNS.In this condition, virus replication continues at a low level, but defects in the envelope protein genes prevent the production of extracellular infec
75、tious virus particles.The lack of envelope protein production causes the failure of the immune system to recognize & eliminate infected cells. However, the virus is able to spread directly from cell to cell, bypassing the usual route of infection.It is not known to what extent damage to the cells of
76、 the brain is caused directly by virus replication, or whether there is any contribution by the immune system to the pathogenesis of SSPE.Vaccination against measles virus & the prevention of primary infection should ultimately eliminate this condition.Chapter 7: PathogenesisSlide 33/43Dengue VirusA
77、nother well-established case where the immune system is implicated in pathogenesis concerns dengue virus infections.Dengue virus is a flavivirus which is transmitted from one human host to another via mosquitoes.The primary infection may be asymptomatic, or may result in dengue fever.Dengue fever is
78、 normally a self-limited illness from which patients recover after 7-10 days without further complications.Following primary infections, patients carry antibodies to the virus.Unfortunately, there are four serotypes of dengue virus & the presence of antibody against one type does not give cross-prot
79、ection against the other three; worse still is the fact that antibodies can enhance the infection of peripheral blood mononuclear cells by Fc-receptor mediated uptake of antibody-coated dengue virus particles.Chapter 7: PathogenesisSlide 34/43Dengue VirusIn a few cases, the consequences of dengue vi
80、rus infection are much more severe than the usual fever.Dengue haemorrhagic fever (DHF) is a life-threatening disease.In the most extreme cases, so much internal haemorrhaging occurs that hypovolemic shock (dengue shock syndrome, DSS) occurs. This is frequently fatal.The cause of shock in dengue & o
81、ther haemorrhagic fevers is partly due to the virus, but largely due to immune-mediated damage of virus-infected cells.DHF & DSS following primary dengue virus infections occur in approximately 1 in 14,000 & 1 in 500 patients respectively.However, after secondary dengue virus infections, the inciden
82、ce of DHF is 1 in 90 & DSS 1 in 50, since cross-reactive but non-neutralizing antibodies to the virus are now present.Chapter 7: PathogenesisSlide 35/43Dengue Virus InfectionChapter 7: PathogenesisSlide 36/43Reyes SyndromeReyes syndrome is a neurological condition involving acute cerebral oedema & o
83、ccurs almost exclusively in children.It is well known as a rare post-infection complication of a number of different viruses, but most commonly influenza virus & VZV (chicken pox).Symptoms include frequent vomiting, painful headaches, behavioural changes, extreme tiredness & disorientation.The chanc
84、es of contracting Reyes syndrome are increased if aspirin is administered during the initial illness.The basis for the pathogenesis of this condition is completely unknown, but some of the most unfortunate cases have followed the administration of experimental influenza virus vaccines.Chapter 7: Pat
85、hogenesisSlide 37/43Guillain-Barr Syndrome& Kawasaki DiseaseGuillain-Barr syndrome is a mysterious condition in which demyelination of nerves results in partial paralysis & muscle weakness.The onset of Guillain-Barr syndrome usually follows an acute virus-like infection, but no single agent has ever
86、 been firmly associated with this condition.Kawasaki disease is similar to Reyes syndrome in that it occurs in children, but distinct in that it results in serious damage to the heart.Like Guillain-Barr syndrome, Kawasaki disease appears to follow acute infections.The disease itself is not infectiou
87、s but does appear to occurs in epidemics, which suggests an infectious agent as the cause.A large number of bacterial & virus pathogens have been suggested to be associated with the induction of Kawasaki disease, but the underlying cause of the pathology is unknown.It would appear that acute infecti
88、on itself rather than a particular pathogen may be responsible for the onset of these diseases.Chapter 7: PathogenesisSlide 38/43Bacteriophages & Human DiseaseCan bacteriophages, viruses which are only capable of infecting prokaryotic cells, play a role in human disease?Surprisingly, the answer is y
89、es.Shiga toxin (Stx)-producing Escherichia coli (STEC) are able to cause intestinal foodborne diseases such as diarrhoea & haemorrhagic colitis.STEC serotype O157:H7, the hamburger bug, has received much attention in recent years.STEC infections can lead to fatal complications such as haemolytic-ura
90、emic syndrome, & neurological disorders.The major virulence characteristics of these strains of bacteria are the ability to colonize the bowel (a natural trait of Escherichia coli) & the production of secreted Shiga toxins, which can damage endothelial & tubular cells & may result in acute kidney fa
91、ilure.Chapter 7: PathogenesisSlide 39/43Stx ToxinsAt least 100 different E. coli serotypes produce Stx toxins, & STEC bacteria occur frequently in the bowels of cattle & other domestic animals such as sheep, goats, pigs & horses.Meat is infected by faecal contamination, usually at the time of slaugh
92、ter.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.Various types of Stx are known, but they fall into two main types, Shiga toxin 1 (Stx1) & Shiga toxin 2 (Stx2).The Stx1
93、& 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 & lysogenize other susceptible bacteria within the gut, accounting for
94、 the high prevalence of STEC bacteria (up to 50% of cattle in some herds).Chapter 7: PathogenesisSlide 40/43Bacteriophages & Human DiseaseRecent research has shown that the scandalous overuse of antibiotics as growth promoters in animal husbandry & even antibiotic treatment of infected people can st
95、imulate the production of phage particles & contributes to the increased prevalence of STEC bacteria & growing human death toll.Other bacterial virulence determinants are also encoded by lysogenic phages (e.g. Diphtheria toxin, Strepococcus erythrogenic toxins, Staphylococcus enterotoxins), although
96、 the selective pressures that maintain these arrangements are not yet understood.Emerging bacterial genome sequence data strongly indicates that phages have been responsible for spreading virulence determinants across a wide range of pathogens.Chapter 7: PathogenesisSlide 41/43Bacteriophages & Human
97、 DiseaseThe other area where bacteriophages may influence human illness is phage therapyphage therapy - the use of bacteriophages as antibiotics.This is not a new idea, with initial experiments having been performed (unsuccessfully) shortly after the discovery of bacteriophages almost 100 years ago.
98、However, with increasing resistance of bacteria to antibiotics & the emergence of superbugs immune to all effective treatments, this idea has undergone a resurgence of interest.Chapter 7: PathogenesisSlide 42/43Bacteriophages & Human DiseaseAlthough attractive in theory, phage therapy suffers from a
99、 number of defects:Bacteriophages are quite specific in their receptor usage & hence the strains of bacteria they can infect - they are narrow spectrum antibacterial agents.Bacteria exposed to bacteriophages rapidly develop resistance to infection by downregulating or mutating the phage receptor.Lib
100、eration of endotoxin as a consequence of widespread lysis of bacteria within the body can lead to toxic shock.Repeated administration of bacteriophages results in an immune response which neutralizes the phage particles before they can act.However, it may be that this is a useful therapy for certain bacterial infections which cannot be treated by conventional means.Chapter 7: PathogenesisSlide 43/43PathogenesisPart 2 (click on this link)
