The Infectious Etiology of Chronic Diseases Defining the Relationship, Enhancing the Research, and Mitigating the Effects: Workshop Summary (2004) / Chapter Skim
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1 Defining the Relationship: An Examination of Infectious Agents Associated with Chronic Disease
1 Defining the Relationship: An Examination of Infectious Agents Associated with Chronic Disease
Pages 13-80
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From page 13... ...
Advances in numerous detection and diagnostic techniques have revealed that several chronic illnesses result from infectious agents. For example, the human papillomavirus causes more than 90 percent of cervical cancers.
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From page 14... ...
The case studies presented in this chapter were chosen to provide insight into the range of research under way in the field. The chronic diseases covered represent the full spectrum of those that have been linked in some degree, from "clearly proven" to "suspected," with infectious agents; they are caused by a variety of microorganisms; and their association with disease is supported variously by laboratory and epidemiological studies.
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From page 15... ...
Richard Johnson reviewed the various ways that viral infections are associated with demyelinating diseases in animals and humans, including such direct routes as oligodendrocytes or Schwann cells causing demyelination through cell lysis or alteration of cell metabolism; virus-induced immune-mediated reactions, such as incorporation of myelin antigens into the virus envelope or modification of antigenicity of myelin membranes; and viral disruption of regulatory mechanisms of the immune system. Human demyelinating diseases with known viral etiology include postinfectious encephalomyelitis, acute disseminated encephalomyelitis, and progressive multifocal leucoencephalopathy.
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From page 16... ...
is a contagious lung cancer of sheep. Tumor samples from animals with OPA consistently contain exogenous jaagsiekte sheep retrovirus (JSRV)
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Some of the well-studied models in cancer causation, such as tobacco smoking in lung cancer and chronic hepatitis B in liver carcinoma, are among the strongest epidemiologic associations that one can find, but they do not represent causal relations that are necessary. Lung cancers may occur in people who never smoked and had only minimal exposure to environmental tobacco smoke, frequently as a result of exposure to occupation-related carcinogens, and liver cancer may occur in individuals who never had hepatitis B, e.g., via aflatoxin exposure or hepatitis C
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From page 18... ...
Emergence of HPV Infection as the Main Etiologic Factor in Cervical Cancer Prominent among the risk factors for cervical cancer is the role of two measures of sexual activity, namely number of sexual partners and age at first intercourse (Herrero, 1996) , and also the sexual behavior of the woman's male partners (Brinton et al., 1989a)
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. Understanding the role of these cofactors is the subject of much ongoing research on the natural history of HPV infection and cervical cancer (see Figure 1-1)
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woman and her infection male partners Viral factors: Persistent HPV variants Co-factors : OC use, - infection with and viral parity, other STDs oncogenic types load Normal Invasive Low grade High grade cervical cervical lesions lesions epithelium cancer Co-factors : nutrition FIGURE 1-1 Etiologic model in cervical carcinogenesis showing the primary role of HPV infection, its relation with sexual activity, and the putative role of cofactors.
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. Latent genital HPV infection can be detected in 5 to 40 percent of sexually active women of reproductive age (IARC, 1995)
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Studies of viral load and intratypic variation of HPVs indicate that persistent infections tend to 1.0 .8 HPV 16/18 positive .6 HPV Nononcogenic .4 types remaining Oncogenic types other than 16/18 .2 Proportion 0.0 0 4 8 12 16 20 24 Time since enrollment (months) FIGURE 1-2 Actuarial curves showing clearance of prevalent HPV infection according to type present at enrollment in a cohort study of asymptomatic women presenting for cervical cancer screening.
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From page 23... ...
Similarly, concerning screening of cervical cancer by HPV testing, a main drawback is the low positive predictive value of a single test because of the relatively high prevalence of latent HPV infections in the population, particularly among young women. The predictive value would increase substantially if testing were to rely on repeated samplings, about 6 months apart, because of the aforementioned high prognostic value of persistent positivity.
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From page 24... ...
Primary Prevention by HPV Vaccination Two main types of HPV vaccines are currently being developed: prophylactic vaccines to prevent HPV infection and associated diseases, and therapeutic vaccines to induce regression of precancerous lesions or remission of advanced cervical cancer. DNA-free virus-like particles (VLP)
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From page 25... ...
While the benefits of vaccination against HPV infection as a cervical cancer prevention tool are at least a decade into the future, the potential benefits of HPV testing in screening for this disease can be realized now in most populations. Primary prevention of cervical cancer can also be achieved through prevention and control of genital HPV infection.
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From page 26... ...
After 20 years, we have reached the point where preventing cervical cancer via vaccination against HPV infection is in the foreseeable future. It would be disastrous, however, if countries relaxed their cervical cancer screening programs in anticipation of a successful HPV vaccine.
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1998. The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescent and young women.
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2001. Persistent human papillomavirus infection as a predictor of cervical intraepithelial neoplasia.
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From page 29... ...
Transmission Transmission is parenteral, requiring exposure to the blood or blood-contaminated materials of infected individuals. The most common mode of exposure leading to chronic infection occurs at birth when the mother is chronically infected, or during the first year of life.
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According to WHO, there are now 350 million chronically infected individuals worldwide. Of these, 60 million are expected to die prematurely of liver cancer or cirrhosis, at a rate of approximately 1 million per year (5,000 per year in the United States)
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How can chronic infections be cured? Will eliminating the virus reduce the risk of liver cancer and premature death from liver disease?
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. In addition to characterizing infections and therapies, the animal models have also provided, along with clinical studies, a better understanding of the difficulties of treating chronic infections with nucleoside analogs.
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1993. The woodchuck hepatitis virus X gene is important for establish ment of virus infection in woodchucks.
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2001. Noncytolytic control of viral infections by the innate and adaptive immune response.
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1994b. Woodchuck hepatitis virus X protein is required for viral infection in vivo.
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. Interest in the role of infection in atherosclerosis was renewed with the observation that patients with coronary artery disease were more likely than matched controls to have an elevated antibody titer to Chlamydia pneumoniae (Saikku et al., 1988)
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pneumoniae antibody titers and the prevalence of coronary artery disease, over thirty additional studies have been performed and multiple review articles published. These studies used different antibody detection assays with different titer
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From page 38... ...
pneumoniae are associated with a three-fold increase in the likelihood of having coronary artery disease. The association identified in seroepidemiologic studies using titers to predict the incidence, distinct from the prevalence, of heart disease, however, only variably detect an association and, when positive, only in the range of a 2040 percent increased risk (Dunne, 2000)
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From page 39... ...
. There are limitations to the interpretation of animal models of atherosclerosis.
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From page 40... ...
pneumoniae infection to this inflammatory state. Clinical Trials with Antibiotics Even with continued gaps in our understanding of the association between infection and atherosclerosis, the significance of coronary artery disease as an unmet medical need has driven interest in conducting antibiotic intervention studies.
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While several risk factors for coronary artery disease are already well established, the relationship between these risk factors and C pneumoniae infection has not been fully examined.
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artery disease for 20% vs. 45% claudication aSome combination of either recurrent MI, hospitalization for angina, coronary artery intervention, stroke, or death.
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1999. Randomized secondary prevention trial of azithromycin in patients with coronary artery disease and serological evidence for Chlamydia pneumoniae infection: the azithromycin in coronary artery disease: elimination of myocardial infection with chlamydia (ACADEMIC)
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2000. Monocyte-endothelial cell coculture enhances infection of endothelial cells with Chlamydia pneumoniae.
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From page 45... ...
The pathogenesis of the demyelination is different with different infections; these mechanisms range from direct infection and lysis of oligodendrocytes to immune destruction of myelin or supporting cells by cell-mediated immune responses, antibody, or cytokines (see Box 1-1)
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in macaque monkeys TABLE 1-3 Animal Models of Demyelinating Diseases Virus Family Virus Host Animal Proposed Mechanism Papoavirus SV40 Monkeys Opportunistic infection of oligodendrocytes in immunodeficient animals Coronavirus Mouse Hepatitis Virus Mice Persistent oligodendrocyte Rats infection and probable humoral immune responses Picornaviruses Theiler's virus Mice Persistent infection of oligodendrocytes and macrophages and immune responses Encephalomyocarditis Mice ? Rhabdovirus Chandipura Mice Cell-mediated immune responses Vesicular stomatitis virus Mice Togavirus Semiliki Forest virus Mice Neuronal infection and immune Venezuelan equine Mice mediated demyelination encephalitis virus Ross River virus Mice Direct lysis of oligodendrocytes Paramyxovirus Canine distemper virus Dogs Predominantly astrocytic infection with probable indirect demyelination Lentivirus Visna virus Sheep Macrophage and monocyte infection with cytokine Caprine arthritis-encephalitis Goats mediated demyelination virus SOURCE: Johnson (1998)
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From page 47... ...
In these lentivirus diseases, infection is limited to macrophages and microglia, and demyelination is thought to result from cytokines released by infected cells. Human Demyelinating Diseases of Known Viral Etiology Postinfectious Encephalomyelitis or Acute Disseminated Encephalomyelitis (ADEM)
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From page 48... ...
For example, in measles, virus is seldom recoverable after the rash which corresponds with the humoral immune response. In measles, deaths occurring at or before the time of rash, measles virus has been found in cerebrovascular endothelial cells by in situ PCR; but no virus antigen or nucleic acid has been found in cells of the CNS in patients dying of encephalomyelitis.
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From page 49... ...
in the genesis of multiple sclerosis, and natural history studies have related "virus-like illnesses" to exacerbations of the disease. Second, studies of human and animal viral infections have documented that these infections can have incubation periods of years, cause remitting and relapsing disease and can cause myelin destruction mediated by a variety of mechanisms.
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From page 50... ...
Specific viral infections have been suggested by serological and virus isolation studies. Over 30 studies have documented the higher levels of antibody to measles in serum and spinal fluid in multiple sclerosis patients than in controls.
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From page 51... ...
Recent interest has focused on Chlamydia pneumoniae, herpesvirus 6, Epstein-Barr virus, and endogenous retroviruses as latent or persistent agents implicated in multiple sclerosis. While they are all normal flora of the human body, they seem to change in quantity or topography in multiple sclerosis.
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From page 52... ...
2001. Presence of Chlamydia pneumoniae DNA in the cerebral spinal fluid is a common phenomenon in a variety of neurological diseases and not restricted to multiple sclerosis.
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From page 53... ...
, and neonatal sepsis-like disease. Enterovirus infections result in 30,000 to 50,000 hospitalizations per year in the United States, with aseptic meningitis cases accounting for the vast majority of the hospitalizations (Pallansch and Roos, 2001)
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From page 54... ...
Since the enterovirus serotype is rarely relevant to clinical case management, many clinical virology laboratories are bypassing virus isolation entirely, in favor of PCR detection of viral nucleic acid directly in clinical specimens such as cerebrospinal fluid, nasopharyngeal swabs, or tissue specimens (Rotbart and Romero, 1995)
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Despite the advantages of enterovirus detection by RT-PCR, challenges remain. In the case of chronic diseases, the virus may act indirectly (e.g., through immune-mediated pathology)
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Enterovirus infection elicits a serotype-specific immune response directed against epitopes on the surface of the viral capsid. Mucosal immunity is most important.
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. These molecular detection and typing methods, when coupled with well-designed prospective studies, will be useful in addressing the potential causal relationship between enterovirus infection and development of prediabetic autoimmunity or progression from persistent autoimmunity to clinical diabetes.
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Pp. 291351 in Human Enterovirus Infections, HA Rotbart, ed.
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From page 59... ...
Pp. 353 385 in Human Enterovirus Infections, HA Rotbart, ed.
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From page 60... ...
This approach derives its rationale from a number of epidemiological studies which indicate that environmental factors may contribute to the risk of schizophrenia in some individuals. Many of these studies identify environmental events occurring during fetal development and early infancy as risk factors for the development of schizophrenia in adult life.
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. Based on this background, we have devised the working hypothesis that most cases of schizophrenia are caused by infections and other environmental events occurring in genetically susceptible individuals (Torrey and Yolken, 2000)
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From page 62... ...
. Since they share properties of both genes and infectious agents, they are a potential link between genetic and environmental causes of human disease (Yolken et al., 2000)
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From page 63... ...
The transcription of endogenous retroviruses can be activated by a number of infectious agents and other environmental factors. We have examined the prevalence of potential activating infections in different stages of schizophrenia.
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From page 64... ...
If this is the case, it is possible that the treatment of infectious agents which activate retroviral transcription may be capable of modulating the course of disease at different times in the lifelong course of disease. For example, the treatment of active infection with herpes simplex virus might prevent endogenous retrovirus activation due to this organism.
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From page 65... ...
The definitive establishment of the role of infectious agents in the etiopathogenesis of schizophrenia may lead to new methods for the diagnosis, prevention, and treatment of this devastating disease. REFERENCES Buka SL, Tsuang MT, Torrey EF, Klebanoff MA, Bernstein D, Yolken RH.
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From page 66... ...
2001. Multiple sclerosis retrovirus particles and recombinant envelope trigger on abnormal immune response in vitro, by inducing polyclonal Vbetal 6 T-lymphocyte activation.
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From page 67... ...
, human papillomavirus (cervical cancer) , hepatitis virus types B and C (hepatocellular carcinoma)
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From page 68... ...
This RNA was then reverse transcribed in vitro using purified reverse transcriptase and an oligodT primer, and a series of overlapping partial cDNA clones was obtained. Sequencing of the cDNA clones and overlapping the resulting sequences revealed a novel complete retroviral sequence; this retrovirus was designated jaagsiekte sheep retrovirus or JSRV.
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From page 69... ...
, taking advantage of the prior work. Most notably, the availability of the complete JSRV sequence, and the PCR-based diagnosis for exogenous JSRV were important.
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From page 70... ...
. In vivo transfection of JSRV DNA was accomplished by incorporating a plasmid form of JSRV21, pJS21, into liposomes containing a lipid that favors DNA transfer into lung epithelial cells.
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From page 71... ...
Mutation of the critical tyrosine for methionine residues in the PI3K docking site led to loss of transformation. It is noteworthy that all exogenous JSRV envelopes sequenced so far contain the PI3K binding domain, while endogenous JSRV-related envelope genes do not.
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From page 72... ...
In light of the lack of association of human BAC with tobacco smoking and its increasing incidence, the possibility of a viral involvement in human lung adenocarcinoma has also been raised. Several investigators have specifically explored whether a human virus related to JSRV might be associated with human lung cancer.
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From page 73... ...
2001. An association between chronic infection with Chlamydia pneumoniae and lung cancer.
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From page 74... ...
1999. Jaagsiekte sheep retrovirus is necessary and sufficient to induce a contagious lung cancer in sheep.
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acnes, were commonly used to stimulate the innate immune response against cancer in mice and human cells (Cantrell and Wheat, 1979; Davies, 1982)
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From page 76... ...
These studies are important for differentiating bacterial antigens that lead healthy controls to generate a protective immune response and those that might be involved in pathogenesis. Antibody against P
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From page 77... ...
and various cerebrospinal fluid shunt infections (Thompson and Albright, 1998)
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From page 78... ...
Knowing the physiological function of our targets allows us to tailor in-vitro and in-vivo assays to evaluate the potential of specific immune components to limit or abolish the events that lead to inflammatory acne. Since the antigens of choice will be delivered under a recombinant protein format, they will require a strong adjuvant that induces an adequate immune response at the correct site.
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1993. Detection of Propionibacterium acnes polypeptides which have stimulated an immune response in acne patients but not in normal individuals.
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From page 80... ...
1995. Induction of proinflammatory cytokines by a soluble factor of Propionibacterium acnes: implications for chronic inflammatory acne.
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