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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary 1 Defining the Relationship: An Examination of Infectious Agents Associated with Chronic Diseases OVERVIEW Chronic diseases cause 70 percent of all deaths in the United States. Yet the factors that cause many of these conditions have been poorly understood until recently. 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. The hepatitis B virus accounts for more than 60 percent of liver cancer. The Epstein-Barr virus produces in people simultaneously infected with malaria a cancer known as Burkitt’s lymphoma, a leading cause of childhood cancer deaths globally. The bacterium Helicobacter pylori has been linked to a number of disorders, including duodenal ulcers, gastric cancer, and certain types of lymphomas. Other connections between infections and chronic diseases are suspected, but not proven. Epstein-Barr virus, for example, has been found in patients with Hodgkin’s disease and with aggressive breast cancers. Multiple sclerosis acts suspiciously like an infection, with patients experiencing high antibody levels as well as exacerbations and remissions. Juvenile-onset diabetes may arise when a Coxsackie B enterovirus elicits an immune response that damages the pancreas. Identifying and confirming an infectious cause of a chronic disease is complicated by several factors: in some cases, microorganisms may act in a hit-and-run fashion, being undetectable by the time the disease process becomes apparent (e.g., Reiter’s syndrome, Guillian-Barré syndrome, rheumatic heart disease); infection may be in a persistent state at the time of diagnosis;
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary acute, chronic, or recurrent infections may be involved in pathogenesis; detection and culture of microbes in a variety of tissues may be difficult; a number of factors, including environmental and genetic (host and microbe) factors, may be involved in the disease etiology; and adequate methods may be lacking to identify novel or rare microorganisms. 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. Although other diseases and studies might have been included, some limits were imposed by time constraints and the availability of speakers. Eduardo Franco reviewed the evidence that human papillomavirus (HPV) infection is a cause of cervical cancer. HPV infection precedes lesion development and appears to be necessary for cervical cancer to occur. This is one of the first examples in which an infectious agent has been identified to be necessary for cancer development. This causal relationship was revealed through the use of improved diagnostic tools that enabled more accurate identification of HPV. As the role of infection by certain types of HPV is better elucidated as the cause of cervical cancer, HPV testing in cervical cancer screening programs becomes an important part of a primary prevention strategy. Another component of this strategy may be increased use of a recently developed vaccine. Clinical studies indicate that the new HPV 16 VLP vaccine was 100 percent effective in preventing acquisition of persistent infection with HPV 16, and was 90 percent effective in preventing any incident HPV 16 infection, transient or persistent. Immunization against HPV may have greatest value in developing countries, where 80 percent of the global burden of cervical cancer occurs each year. William Mason presented the association between hepatitis B virus infection and liver disease. Infection with the virus remains a worldwide problem, with more than 350 million people chronically infected. Although a vaccine has been available for the past 20 years, its high cost prevents universal vaccination. Current research, therefore, has focused on the development of effective therapies to cure those individuals chronically infected with the virus. Mason described the research presently being conducted in a number of animal model systems, including the woodchuck. Along with clinical studies, these models have been able to characterize infections and evaluate therapies, as well as better elucidate the difficulties of treating chronic infections with nucleoside analogs. Michael Dunne described the relationship between infection and cardiovascular disease. There is a tight association between hypercholesterolemia and atherosclerosis; recent research has examined how inflammation within the plaque
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary accumulated on arterial walls might drive atherosclerosis. Several pathophysiologic hypotheses have been formulated: Local infection might lead through a variety of pathways to arterial wall atherogenic effects. Local infection might produce a systemic inflammatory mediator that travels to the atherosclerotic plaque and produces expression of adhesion molecules along the endothelium, foam cell formation, and other proinflammatory reactions. Local infection might produce bacteremia or viremia from a variety of pathogens that infect the arterial wall and induce those same inflammatory changes. There is a long list of potential causes: Chlamydia pneumoniae, cytomegalovirus, various dental disease organisms, H. pylori, and herpes simplex virus. Anything leading to increased foam cell function in the plaque is a potential culprit. This is an example where many different etiologic causes or multiple causes might be involved in the same chronic condition either individually, synergistically, or multifactorially. 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. A viral cause for multiple sclerosis has been postulated for more than 100 years, and epidemiologic studies support this supposition and clearly show an environmental factor. In addition, several studies show multiple sclerosis patients to have elevated levels of various antiviral antibodies compared to controls. Mark Pallansch discussed some of the difficulties in addressing the association of chronic diseases with infectious diseases, using diabetes and enteroviruses as examples. Type 1 diabetes is clearly a multifactorial disease: there is both a clear genetic predisposition and an autoimmune component. The major manifestation is the loss of beta cells in the pancreas and the associated loss of capacity to produce insulin. There are more than 65 different enteroviruses, which include the most common human viral infections. All individuals may have multiple infections every year with at least one of these viruses. Because the standard enterovirus diagnostics are extremely labor-intensive, efforts are being made to develop diagnostic tools based on reverse transcriptase-polymerase chain reaction (RT-PCR). A semi-nested PCR method is available to determine presence or ab-
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary sence of enteroviruses, but ways of identifying specific enteroviruses remain to be developed using this technology. Robert Yolken and Fuller Torrey examined associations between infectious agents and schizophrenia. Epidemiologic studies indicate that environmental events during fetal development and early infancy may contribute to the risk of schizophrenia in some individuals. Yolken and Torrey hypothesized that most cases of schizophrenia are caused by infections and other environmental events occurring in genetically susceptible individuals. The activation of endogenous retroviruses within the central nervous system may possibly be one of several mechanisms by which infections can lead to the disease. If this is the case, then medications controlling these infections could play a major role in treating schizophrenia. Hung Fan examined evidence from an animal model supporting the possibility that an infectious agent may be involved in human lung adenocarcinoma. Ovine pulmonary adenocarcinoma (OPA) is a contagious lung cancer of sheep. Tumor samples from animals with OPA consistently contain exogenous jaagsiekte sheep retrovirus (JSRV), which has an envelope gene with oncogenic potential. JSRV-induced OPA is histologically very similar to human adenocarcinoma. The lack of association of this cancer with tobacco smoking, together with the disease’s increasing incidence, suggests the possibility of viral involvement. David Persing discussed the pathogenesis of acne, a dermatologic inflammatory disease unique to humans and the most common dermatological complaint of adolescents and young adults. In addition to the role played by the bacteria Propionibacterium acnes in the development of the inflammatory acne lesion, Persing explained how P. acnes has been implicated as a source of heart valve infections, postoperative implant infections, and prostheses failure. Recently P. acnes has been implicated as a possible cause of chronic inflammation in sciatica. Persing described his approaches to developing a vaccine for acne that could also benefit other P. acnes-related chronic diseases. Studies in each of these areas are advancing our understanding of the role that infections play in chronic diseases. But the path from suspecting a microorganism to proving its association with a specific disease can be long. The discovery that H. pylori can cause duodenal ulcer disease is often cited as case in point of both the hurdles and the rewards. The medical establishment in the United States and worldwide remained skeptical of this link for years. Finally, the evidence became overwhelming, and the discovery is credited with galvanizing research for the entire field of infection and chronic disease. Medical treatment also has evolved accordingly, with therapies shifting from surgery to blocking hyperacidity and, ultimately, to the use of antibiotics directed against H. pylori.
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary THE ROLE OF VIRUSES IN ONCOGENESIS: HUMAN PAPILLOMAVIRUSES AND CERVICAL CANCER AS A PARADIGM Eduardo L. Franco, M.P.H., Dr.P.H.* Departments of Oncology and Epidemiology, McGill University, Montreal, Canada Like other malignant neoplasms of humans, cervical cancer is a disease with multifactorial causes and long latency. Unlike most other cancers, however, in which multiple environmental, biologic, and lifestyle determinants contribute independently or jointly to carcinogenesis, cervical cancer has been shown to have a central causal agent, human papillomavirus (HPV) infection, whose contribution to the risk of the disease is much greater than that of any other recognized determinant (IARC, 1995). Recently, there has been much attention to the fact that it is virtually impossible to find cervical carcinoma specimens devoid of traces of HPV DNA, which strongly suggests that HPV infection could be a necessary cause for this malignancy (Franco et al., 1999a; Walboomers et al., 1999). If this is really the case, then it would be a first in cancer research; no human cancer has yet been shown to have a necessary cause, so clearly identified. 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. The implications of this finding are substantial and have spawned new approaches to preventing cervical cancer on two fronts: (i) via screening for HPV infection as the biological surrogate that reveals asymptomatic cervical cancer precursor lesions and (ii) via primary immunization against HPV infection to prevent the onset of such precursor lesions. While there is now intense research in these two fronts the debate still continues concerning issues related to the etiologic mechanism whereby HPV infection initiates cervical carcinogenesis. This brief overview addresses the epidemiologic characteristics of HPV infection and cervical cancer and the recent progress using new approaches to preventing cervical cancer. * The author’s research on the epidemiology of HPV infection and prevention of cervical cancer is funded by grants from the Canadian Institutes of Health Research (CIHR) and from the U.S. National Institutes of Health.
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary Global Importance of Cervical Cancer Cervical cancer is one of the most common malignant diseases of women. In the US each year there are approximately 12,800 new cases of invasive cervical cancer with 4,600 deaths due to this disease (Ries et al., 2000). On average during the last decade, an estimated 371,000 new cases of invasive cervical carcinoma were diagnosed annually worldwide, representing nearly 10 percent of all female cancers. Its incidence is the third among women, after breast and colorectal cancer (Parkin et al., 1999). The highest risk areas are in Central and South America, Southern and Eastern Africa, and the Caribbean, with average incidence rates around 40 per 100,000 women per year. While risk in western Europe and North America is considered relatively low at less than 10 new cases annually per 100,000 women, rates are 10 times higher in some parts of Northeastern Brazil, where the cumulative lifetime risk can approach 10 percent (Muir et al., 1987). Every year, an estimated 190,000 deaths from cervical cancer occur worldwide, with over three-fourths of them in developing countries, where mortality from this disease is the highest among deaths caused by neoplasms (Pisani et al., 1999). Less than 50 percent of women affected by cervical cancer in developing countries survive longer than five years whereas the 5-year survival rate in developed countries is about 66 percent (Pisani et al., 1999). Moreover, cervical cancer generally affects multiparous women in the early post-menopausal years. In high-fertility developing countries these women are the primary source of moral values and education for their children. The premature loss of these mothers has important social consequences for the community. 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). The consistency of the sexually-transmitted disease model for cervical neoplasia led much of the laboratory and epidemiologic research in attempting to identify the putative microbial agent or agents acting as etiologic factor. Research conducted during the late 1960s and 1970s attempted to unveil an etiologic role for the Herpes simplex viruses (HSV). Although HSV was proven to be carcinogenic, in vitro and in vivo clinical studies eventually demonstrated that only a fraction of cervical carcinomas contained traces (viral DNA) of HSV infection and epidemiologic studies failed to demonstrate that the association between HSV and cervical cancer was the primary causal element (Franco, 1991). In the 1980s, a solid research base emerged implicating HPV infection as the sexually-transmitted cause of cervical cancer and its precursors. In 1995, the In-
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary ternational Agency for Research on Cancer at the World Health Organization (WHO), in its monograph series of carcinogenicity evaluation classified HPV types 16 and 18 as carcinogenic to humans, HPV types 31 and 33 as probably carcinogenic, and other HPV types (except 6 and 11) as possibly carcinogenic (IARC, 1995). This classification was conservatively made on the basis of the available published evidence until 1994. Subsequent research has permitted a more inclusive grouping of genital HPV types on the basis of the presumed oncogenic potential. HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 are considered to be of high oncogenic risk because of their frequent association with cervical cancer and cervical intraepithelial neoplasia (CIN), the precursor, pre-invasive lesion stage. The remaining genital types, e.g., HPV types 6, 11, 42–44, and some rarer types are considered of low or no oncogenic risk (Bosch et al., 1995). The latter types may cause subclinical and clinically visible benign lesions known as flat and acuminate condylomata, respectively. Today, it is well established that infection with high oncogenic risk HPV types is the central causal factor in cervical cancer (IARC, 1995; Koutsky et al., 1992; Nobbenhuis et al., 1999). Relative risks for the association between HPV and cervical cancer are in the 20–70 range, which is among the strongest statistical relations ever identified in cancer epidemiology. Both retrospective and prospective epidemiologic studies have demonstrated the unequivocally strong association between viral infection and risk of malignancy, both as CIN or invasive disease (Bosch et al., 2002). Table 1-1 shows that HPV infection satisfies nearly all of standard causal criteria in chronic disease epidemiology. However, not all infections with high risk HPVs persist or progress to cervical cancer, thus suggesting that, albeit necessary, HPV infection is not sufficient to induce this disease; other factors, environmental or host-related, are also involved. Among these co-factors are: smoking (Ho et al., 1998a), high parity (Brinton et al., 1989b), use of oral contraceptives (Moreno et al., 2002), diets deficient in vitamins A and C (Potischman and Brinton, 1996), and genetic susceptibility traits, such as specific HLA alleles and haplotypes (Maciag et al., 2000) and polymorphisms in the p53 gene (Makni et al., 2000). 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). Human Papillomaviruses HPVs are small, double-stranded DNA viruses of approximately 55 nanometers (nm) with an icosahedral protein capsid containing 72 capsomers. The genome is circular and contains 7500–8000 base pairs (bp). HPVs have the following characteristics: ~8 kilobase (kb) DNA virus from Papillomaviridae family Species- and tissue-specific
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary TABLE 1-1 Causality Criteria in HPV and Cervical Cancer Causal Criterion Degree of Evidence Findings Strength of the association ++ Relative risks among the highest in cancer epidemiology Consistency ++ Association confirmed in multiple epidemiologic studies Temporality + Infection precedes lesion development Biological gradient + Viral persistence and viral load affect disease risk in dose-dependent manner Coherence ++ Epidemiology does not conflict with molecular pathogenesis data Biological plausibility ++ Overwhelming body of evidence from laboratory studies Experimental evidence + HPV vaccination reduces short-term risk of cervical cancer precursor lesions Necessary factor? + HPV DNA found in virtually all cervical cancers 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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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary Cannot be cultivated Over 150 genotypes identified, of which more than 40 infect the anogenital tract High risk (oncogenic) types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68 Induces both benign (caused by low risk types) and malignant (caused by high risk types) diseases Two major viral oncogenes: E6 (binds to p53) and E7 (binds to retinoblastoma [Rb] protein) Taxonomically, papillomaviruses used to be a subfamily in the Papovaviridae family but are now grouped independently as a family, the Papillomaviridae. As infectious agents, they are highly specific to their respective hosts. Different HPVs are classified as types on the basis of DNA sequence homology in the E6, E7, and L1 genes. More than 150 different HPV types have been catalogued so far (zur Hausen, 2000). The epithelial lining of the anogenital tract is the target for infection by over 40 different mucosotropic HPV types. Clinical, subclinical, and latent HPV infections are the most common sexually-transmitted viral diseases today (Cox, 1995). Latent genital HPV infection can be detected in 5 to 40 percent of sexually active women of reproductive age (IARC, 1995). In most cases, genital HPV infection is transient or intermittent (Hildesheim et al., 1994; Ho et al., 1998b; Moscicki et al., 1998; Franco et al., 1999b; Liaw et al., 2001); the prevalence is highest among young women soon after the onset of sexual activity and falls gradually with age, possibly as a reflection of accrued immunity and decrease in sexual activity (meaning a decrease in number of sexual partners). The carcinogenic mechanism following HPV infection involves the expression of two major viral oncogenes, E6 and E7, which produce proteins that interfere with tumor suppressor genes controlling the cell cycle. Once viral DNA becomes integrated into the host’s genome, E6 and E7 become upregulated. While E7 complexes with the cell growth regulator Rb protein, causing an uncontrolled cell proliferation (Chellappan et al., 1992), the binding of E6 to p53 protein promotes the degradation of the latter, thus exempting the deregulated cell to undergo p53-mediated control (Thomas et al., 1996). The degradation of p53 by E6 leads to loss of DNA repair function and prevents the cell from undergoing apoptosis. The infected cell can no longer stop further HPV-related damages and becomes susceptible to additional mutations and genomic instability. Interestingly, the effect of the E6 and E7 proteins on p53 and Rb has been shown to occur only with high-risk HPVs but not with low-risk HPVs (Dyson et al., 1989).
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary Persistent HPV Infection as the Precursor Event in Cervical Carcinogenesis Most women who engage in sexual activity will probably acquire HPV infection over a lifetime. As mentioned above, the vast majority of these infections will be transient with only a small proportion becoming persistent. We have found in our ongoing cohort study of Brazilian women that only 35 percent of the subjects who were infected at enrollment retain their infections after 12 months, with the mean duration being affected by the viral oncogenic potential (see Figure 1-2). Infections with oncogenic HPVs tend to last longer on average (13.5 months) than those with non-oncogenic types (8.2 months) (Franco et al., 1999b). A substantial increase in risk of CIN (see Figure 1-3) and cancer exists for women who develop persistent, long-term infections with oncogenic HPV types (Koutsky et al., 1992; Ho et al., 1998b; Nobbenhuis et al., 1999; Ylitalo et al., 2000; Moscicki et al., 2001; Schlecht et al., 2001). There is currently great interest in defining persistent infection and in obtaining additional markers of pathogenesis for predictive purposes. Studies of viral load and intratypic variation of HPVs indicate that persistent infections tend to 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. SOURCE: Adapted from Franco et al. (1999b).
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary FIGURE 1-3 Actuarial curves showing the cumulative incidence of cervical squamous intraepithelial lesions (SIL) according to HPV infection in the first two visits in a cohort study of asymptomatic women presenting for cervical cancer screening. SOURCE: Adapted from Schlecht et al. (2001). yield higher viral loads than transient ones (Caballero et al., 1999) and those with non-European variants of HPVs 16 and 18 tend to be associated with higher risk of CIN as compared with those caused by European variants (Villa et al., 2000). Defining viral persistence is critical because trials of HPV vaccine efficacy rely on the reduction of the risk of persistent infection as one of the primary outcomes. 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. However, population screening cannot rely on repeated testing to be cost-effective and realistic as a public health measure. It would be highly desirable if one could, with a single HPV test, collect enough ancillary information on the virus and on the host that would allow determining whether or not a single instance of HPV positivity is likely to represent a persistent infection.
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary transfections in newborn lambs. In vivo transfection of retroviral DNA was first demonstrated for bovine leukemia virus (Willems et al., 1993). 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. The pJS21 liposomes were injected intratracheally into newborn lambs, and PBMCs were tested for the presence of JSRV DNA at different times post-transfection. Nested PCR amplifications revealed the presence of exogenous JSRV DNA in PBMCs from the transfected animals at various times up to nine months, when the animals were sacrificed. These results indicated that the JSRV21 was an infectious provirus. However, at necropsy (9 months), no tumors were observed, so this experiment did not indicate if JSRV21 was an oncogenic clone. The failure to observe tumors in the pJS21-transfected animals might have been due to the relative inefficiency of in vivo DNA transfection. Therefore, a method for generating genuine JSRV virus from the pJS21 clone was developed. Ultimately, we were able to prepare significant amounts of JSRV virus from a version of the pJS21 plasmid in which the human cytomegalovirus immediate early promoter drives expression of the JSRV sequences. Transient transfection of pJS21 into human 293T cells resulted in the production of JSRV particles. When concentrated JSRV stocks prepared in this way were inoculated intratracheally into four newborn lambs, two lambs developed classic OPA within four months. The resulting tumors were positive for viral CA antigen and DNA (Palmarini et al., 1999). This proved that JSRV is the causative agent of OPA. The availability of an infectious and oncogenic molecular clone of JSRV has opened up several avenues of research that are being pursued. Two features of JSRV molecular biology are particularly noteworthy. First, JSRV is unusual among retroviruses in that its expression is highly restricted in vivo. In infected animals, JSRV DNA sequences can be detected in various cells, including different lineages of hematopoietic cells in the PBMCs (Holland et al., 1999). The level infection is low—detection requires a nested PCR—and this infection is apparently not productive, since CA antigen-positive cells cannot be detected in PBMCs. Even in lungs of animals with end-stage OPA, CA antigen is only detected in the tumor cells. In particular, other lung cells (even normal lung epithelial cells) do not typically express the CA antigen (Sharp and DeMartini, 2003). Thus, lung epithelial cells may be the only cell types in which JSRV infection is productive. The basis for the expression specificity is the enhancer sequences in the JSRV long terminal repeat (LTR). Retroviral LTRs containing enhancer sequences in the U3 region that are responsible for driving transcription of the provirus. We showed that the JSRV LTR is quite specific for lung epithelial cells in transient transfection assays using a JSRV LTR-driven luciferase reporter gene in mouse cell lines of different differentiation lineages (Palmarini et al., 2000b). Deletional analysis indicated that the JSRV enhancers function in lung epithelial-derived cell lines, while they are inactive in most other cell types.
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary FIGURE 1-13 Foci of transformation induced by the transfection of clone JSRV DNA into mouse NIH 3T3 cells. Such transfection is a standard assay for detecting viral and cellular oncogenes. Panels (a) and (c) show untransfected NIH3T3 cells. Panel (b) shows a focus of transformed cells resulting from transfection with CMV-driven plasmid DNA (pCMV2JS21). Panel (d) shows a pCMV2JS21 transfected culture that had been passaged several times prior to plating under focus-forming conditions. Detailed analysis of the factors responsible for the lung epithelial-specific expression is in progress. The second interesting feature of JSRV biology is that the viral genome appears to contain a transforming gene. In fact, JSRV is an extremely potent carcinogen in the laboratory setting. Experimentally inoculated newborn animals develop end-stage OPA with a mean time of six weeks, and in some cases tumors have been observed as early as 10 to 14 days. The rapid oncogenesis, coupled with the multi-focal pattern of the tumors is consistent with a direct transforming function (oncogene) in the virus. We showed that transfection of clone JSRV DNA into mouse NIH 3T3 cells could induce foci of transformation, a standard assay for detection of viral and cellular oncogenes (see Figure 1-13) (Maeda et al., 2001). Further studies indicated that the envelope gene of JSRV is responsible for the transformation. Transformation appears to occur through the cytoplasmic tail of the envelope transmembrane (TM) protein (Palmarini et al., 2001a). The cytoplasmic tail contains a docking site for PI 3 kinase, an important cellular kinase involved in signal transduction and oncogenic transformation. 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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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary The finding that the JSRV envelope gene contains oncogenic potential is unusual for replication-competent retroviruses. Most other replication-competent retroviruses do not normally cause tumors by a direct mechanism (i.e., oncogenes). More typically, oncogenesis is a byproduct of the replication cycle (e.g., insertional activation of cellular proto-oncogenes). However, the fact that all exogenous JSRVs have a transforming envelope suggests that this property is important for replication of the virus. We have proposed a hypothesis to explain this. In studies of the endogenous JSRV-related proviruses, we found that the endogenous JSRV LTRs do not show transcriptional specificity for lung epithelial cells (Palmarini et al., 2000a). The endogenous viruses provide a view into the primordial progenitor of JSRV, since they reflect the JSRV progenitor from 1 million to 5 million years ago. (Mutation rates of retroviral DNAs decrease markedly when they are transmitted in the proviral [DNA] form.) Thus the progenitor to exogenous JSRV likely replicated through different cells in the animals than lung epithelial cells. Indeed, the endogenous JSRV proviruses in current day sheep are not expressed in lung epithelial cells, but they are expressed in cells of the female reproductive tract (Palmarini et al., 2001b). During evolution of exogenous JSRV, presumably alterations in the enhancer sequences in the LTR arose that conferred transcriptional specificity for lung epithelial cells. However, in the normal adult lung there is relatively little division and growth of Type II pneumocytes and close cells. Most retroviruses require cell division for efficient infection and production. Thus during evolution of exogenous JSRV, the mutation in the cytoplasmic tail of the envelope TM protein would allow for more efficient infection and expression in lung epithelial cells, to which JSRV is transcriptionally restricted. As mentioned above, JSRV-induced OPA is histologically very similar to human adenocarcinoma and BAC. 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. In particular, De las Heras and colleagues recently reported a study in which they screened a series of human lung cancers and other tumors for immunological staining with a polyclonal antibody to JSRV CA protein (De las Heras et al., 2000). They found that approximately 30 percent of human BACs and nearly 25 percent of human lung adenocarcinomas showed immunohistochemical staining with the JSRV CA antibody. In contrast, little or no reactivity was detected in squamous cell carcinomas of the lung and other tumors. Thus the reactivity appears to be rather specific for human lung adenocarcinomas and BACs. Another laboratory has been able to replicate these immunohistochemistry findings (J. DeMartini, personal communication). On the other hand, several investigators have attempted to clone a JSRV-related retrovirus from these human tumors by using PCR amplification with degenerative oligonucleotide primers. So far no one has succeeded.
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary The antigenic cross-reactivity to JSRV observed in some human lung adenocarcinomas might result from two possibilities. First, it could reflect infection with an exogenous human retrovirus with some relationship to JSRV. Alternatively, it could reflect expression of a human endogenous retrovirus (HERV) with antigenic cross-reactivity to JSRV. The human genome contains many copies of HERVs, divided into several classes. It has been shown that different HERVs are expressed in normal versus malignant tissues. It has been noted that the JSRV sequence has some similarity to the HERV-K class, so it is possible that these tumors are expressing a HERV-K (J. DeMartini, personal communication). A third possibility is that the antigenic cross-reactivity could reflect a human cellular protein unrelated to a retrovirus. Identification of the nucleic acid encoding the JSRV antigenic cross-reactivity in the human lung adenocarcinomas and BACs is a goal of primary importance, and several laboratories are actively pursuing this. Once the genetic material encoding the cross-reactivity is identified, if it corresponds to an exogenous or endogenous human retrovirus, the next important issue will be to ascertain whether it has a causal role in lung carcinogenesis. For such experiments, the JSRV OPA system and sheep will provide a valuable framework for designing experiments to address this question. REFERENCES De las Heras M, Barsky SH, Hasleton P, Wagner M, Larson E, Egan J, Ortin A, Gimenez-Mas JA, Palmarini M, Sharp JM. 2000. Evidence for a protein related immunologically to the jaagsiekte sheep retrovirus in some human lung tumors. The European Respiratory Journal 15:330–332. DeMartini J, Carlson J, Leroux C, Spencer T, Palmarini M. 2003. Endogenous retroviruses related to jaagsiekte sheep retrovirus. Pp. 117–137 in Jaagsiekte Sheep Retrovirus and Lung Cancer, H Fan, ed. Berlin: Springer-Verlag. Fan H, ed. 2003. Jaagsiekte Sheep Retrovirus and Lung Cancer, Vol. 275. Berlin: Springer-Verlag. Hecht SJ, Stedman KE, Carlson JO, DeMartini JC. 1996. Distribution of endogenous type B and type D sheep retrovirus sequences in ungulates and other mammals. Proceedings of the National Academy of Sciences 93:3297–3302. Holland MJ, Palmarini M, Garcia-Goti M, Gonzalez L, de las Heras M, McKendrick I, Sharp JM. 1999. Jaagsiekte retrovirus is widely distributed both in T and B lymphocytes and in mononuclear phagocytes of sheep with naturally and experimentally acquired pulmonary adenomatosis. Journal of Virology 73:4004–4008. Jackson LA, Wang SP, Nazar-Stewart V, Grayston JT, Vaughan TL. 2000. Association of Chlamydia pneumoniae immunoglobulin A seropositivity and risk of lung cancer. Cancer Epidemiology Biomarkers and Prevention 9:1263–1266. Koyi H, Branden E, Gnarpe J, Gnarpe H, Steen B. 2001. An association between chronic infection with Chlamydia pneumoniae and lung cancer. A prospective 2-year study. APMIS 109:572–580. Laurila AL, Anttila T, Laara E, Bloigu A, Virtamo J, Albanes D, Leinonen M, Saikku P. 1997. Serological evidence of an association between Chlamydia pneumoniae infection and lung cancer. International Journal of Cancer 74:31–34. Maeda N, Palmarini M, Murgia C, Fan H. 2001. Direct transformation of rodent fibroblasts by jaasiekte sheep retrovirus DNA. Proceedings of the National Academy of Sciences 98:4449–4454.
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary Mornex JF, Thivolet F, de las Heras M, Leroux C. 2003. Pathology of human bronchioloalveolar carcinoma and its relationship to the ovine disease. Pp. 225–248. In Fan H, editor. Jaagsiekte Sheep Retrovirus and Lung Cancer. Berlin: Springer-Verlag. Palmarini M, Cousens C, Dalziel RG, Bai J, Stedman K, DeMartini JC, Sharp JM. 1996. The exogenous form of Jaagsiekte retrovirus is specifically associated with a contagious lung cancer of sheep. Journal of Virology 70:1618–1623. Palmarini M, Sharp JM, de las Heras M, Fan H. 1999. Jaagsiekte sheep retrovirus is necessary and sufficient to induce a contagious lung cancer in sheep. Journal of Virology 73:6964–6972. Palmarini M, Hallwirth C, York D, Murgia C, de Oliveira T, Spencer T, Fan H. 2000a. Molecular cloning and functional analysis of three type D endogenous retroviruses of sheep reveal a different cell tropism from that of the highly related exogenous jaagsiekte sheep retrovirus. Journal of Virology 74:8065–8076. Palmarini M, Datta S, Omid R, Murgia C, Fan H. 2000b. The long terminal repeat of Jaagsiekte sheep retrovirus is preferentially active in differentiated epithelial cells of the lungs. Journal of Virology 74:5776–5787. Palmarini M, Maeda N, Murgia C, De-Fraja C, Hofacre A, Fan H. 2001a. A phosphatidylinositol 3-kinase docking site in the cytoplasmic tail of the jaagsiekte sheep retrovirus transmembrane protein is essential for envelope-induced transformation of NIH 3T3 cells. Journal of Virology 75:11002–11009. Palmarini M, Gray CA, Carpenter K, Fan H, Bazer FW, Spencer TE. 2001b. Expression of endogenous betaretroviruses in the ovine uterus: effects of neonatal age, estrous cycle, pregnancy and progersterone. Journal of Virology 75:11319–11327. Sharp J and DeMartini J. 2003. Natural history of JSRV in sheep. Pp. 55–79. In Fan H, editor. Jaagsiekte Sheep Retrovirus and Lung Cancer. Berlin: Springer-Verlag. Sharp JM and Herring AJ. 1983. Sheep pulmonary adenomatosis: demonstration of a protein which cross-reacts with the major core proteins of Mason-Pfizer monkey virus and mouse mammary tumour virus. The Journal of General Virology 64:2323–2327. Willems L, Kettmann R, Dequiedt F, Portetelle D, Voneche V, Cornil I, Kerkhofs P, Burny A, Mammerickx M. 1993. In vivo infection of sheep by bovine leukemia virus mutants. Journal of Virology 67:4078–4085. York D and Querat G. 2003. A history of ovine pulmonary adenocarcinoma (Jaagsiekte) and experiments leading to the deduction of the JSRV nucleotide sequence. Pp. 1–23. In Fan H, editor. Jaagsiekte Sheep Retrovirus and Lung Cancer. Berlin: Springer-Verlag. York DF, Vigne R, Verwoerd DW, Querat G. 1991. Isolation, identification, and partial cDNA cloning of genomic RNA of jaagsiekte retrovirus, the etiological agent of sheep pulmonary adenomatosis. Journal of Virology 65:5061–5067. York DF, Vigne R, Verwoerd DW, Querat G. 1992. Nucleotide sequence of the jaagsiekte retrovirus, an exogenous and endogenous type D and B retrovirus of sheep and goats. Journal of Virology 66:4930–4939. PROPIONIBACTERIUM ACNES AND CHRONIC DISEASES Ajay Bhatia, Ph.D.; Jean-Francoise Maisonneuve, Ph.D.; and David H. Persing, M.D., Ph.D. Corixa Corporation, Seattle, WA Propionibacterium acnes is a gram-positive human skin commensal that prefers anaerobic growth conditions and is involved in the pathogenesis of acne (Kirschbaum and Kligman, 1963). Acne is one of the most common skin diseases, affecting more than 45 million individuals in the United States. It is esti-
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary mated that nearly 20 percent of all visits to dermatologists are related to the treatment of acne. Acne often debuts during changes in hormonal levels in pre-teens; however, it is also very common as an adult-onset condition, often associated with hormonal fluctuation during the menstrual cycle and pregnancy. While not life-threatening, acne can persist for years and is known to have serious psychosocial effects such as decreased self-esteem, depression, frustration, and social withdrawal. In addition to dermatological pathology, P. acnes is also suspected to be discreetly involved in post-operative infections, prostheses failure, and more recently, in inflammation of lumbar nerve roots leading to sciatica. P. acnes, previously known by the name Corynebacterium parvum, has been studied extensively by immunologists for its ability to stimulate the reticuloendothelial system (Adlam and Scott, 1973). Not too long ago, an important cytokine, interleukin (IL)-18 was cloned from the liver of mice primed with P. acnes followed by challenge with LPS (Okamura et al., 1995). In the early eighties, certain bacteria, including BCG and P. acnes, were commonly used to stimulate the innate immune response against cancer in mice and human cells (Cantrell and Wheat, 1979; Davies, 1982). One of the great ironies of this organism is that it is a powerful nonspecific immune stimulant that resides naturally in the skin; its role as an immunostimulant in humans is appreciated when cases of severe acne also develop adjuvant-type arthritis. Some investigators have gone so far as to suggest that severe acne, by virtue of the nonspecific immunostimulatory effects of P. acnes, might have played a role in natural protection against life-threatening diseases such as malaria and plague. In contrast, the acquired immune response to P. acnes has received little attention in humans. Pathogenesis of Acne Chronic inflammatory acne cannot be defined as an infectious disease, since the bacteria are normally present on the skin of a vast majority of individuals, irrespective of the presence of acne lesions. P. acnes apparently only triggers the disease when it meets favorable dermatophysiological terrain; P. acnes colonization of the skin is therefore necessary but not sufficient for the establishment of the pathology. The 4 major recognized pathophysiological features of acne include androgen stimulated seborrhea, hyperkeratinization and obstruction of the follicular epithelium, proliferation of P. acnes, and then inflammation. Comedogenesis, the transformation of the pilosebaceous follicle into the primary acne lesion, the comedone, is the product of abnormal follicular keratinization related to excessive sebum secretion. During this process, P. acnes often gets trapped in layers of corneocytes and sebum and rapidly colonizes the comedonal kernel, resulting in a microcomedone, a structure invisible to the naked eye (Plewig and Kligman, 2000). A microcomedone can develop into larger structures, called comedones. Comedones can be a closed structure (whitehead) that
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary appears like a colored bump on the skin or an open structure (blackhead). Unlike open comedones, closed comedones cannot evacuate the thread-looking conglomerate of cell debris, sebum, P. acnes and its products to the skin surface, and this makes them more prone to inflammation and rupture. In inflammatory acne, comedones rupture and the follicular material becomes dispersed in the dermis rather than on the skin surface. Depending on the extent of the damage to the comedone wall, various types of inflammatory lesions are produced and these are classified as papules, pustules, or nodules. Nodules are the most severe types of acne lesions and scarring may be associated with any form of severe inflammatory acne. A break in the lining of the comedone was initially attributed to free fatty acids generated by P. acnes-mediated triglyceride hydrolysis, but for several reasons, it is now thought that substances produced by P. acnes are directly involved in the rupture the comedone epithelial lining (Holland et al., 1981). The bacteria secrete many polypeptides, among which are numerous extracellular enzymes such as proteases, hyaluronidases, neuraminidases, and others that could be involved in epithelium permeabilization and inflammatory infiltration (Noble, 1984). P. acnes is also known to produce chemotactic factors (Puhvel and Sakamoto, 1977), proinflammatory cytokine inducing-factors (Vowels et al., 1995), and to activate both the direct and indirect complement pathways (Webster et al., 1978). The infiltrate of an early inflamed lesion consists of polymorphonuclear cells that certainly contribute to the lining breakage, but eventually, as time goes by and infection becomes chronic, these cells attract and are replaced by mononuclear cells, predominantly T-cells of the CD4 phenotype (Norris and Cunliffe, 1988; Layton et al., 1994). As the inflammation propagates to the lining of adjacent sebaceous follicules, it can start a chain reaction that results in multiple lesions connected together and called a sinus. Studies by Hoffler et al. (1985) have revealed differences in the production of various enzymes by Propionibacterium isolates of acne lesions versus bacteria isolated from healthy controls. 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. acnes antigenic determinants are found in the blood of most adults, whether they have had acne or not (Ingham et al., 1987); amounts may vary between the two populations, and possibly the nature of the determinants the antibodies recognize (Holland et al., 1993). Recent investigations by our group suggest that differential recognition might involve surface molecules with physiological functions. P. acnes specific IgG and IgA are also found at the level of the follicular infudibulum (Knop et al., 1983); these antibodies might be of great importance in limiting or preventing P. acnes proliferation, and maybe more importantly, in preventing comedonal lining destruction by P. acnes-derived soluble factors. Our preliminary data suggests that a robust P. acnes specific T-cell response is also common in adult donors, but its specificity at the
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary antigen level is currently under investigation. We like to think that there possibly exists a P. acnes-specific protective immunity against acne. This hypothesis is supported by the fact that some people never get acne, as well as by the observation that acne is mostly a disease of young people, (although there are numerous exceptions), and that even in countries where people are unable to afford sophisticated medications, chronic disease of adolescents eventually resolves with age. Finally, there have been successful human trials of therapeutic vaccination against P. acnes, and although the rate of success has not been high, some individuals refractory to conventional approaches experienced remission (Goldman et al., 1979; Vymola et al., 1970). Role of P. acnes in Chronic Inflammation and Systemic Infections The chronic inflammatory condition of the pilosebaceous follicle caused by P. acnes is generally considered non-pathogenic. However, there is a growing body of evidence that point to the bacterium as being low virulence pathogen in several types of postoperative infections and other chronic conditions. P. acnes have been associated with endocarditis of prosthetic (Lazar and Schulman, 1992) and native aortic valves (Mohsen et al., 2001), corneal infections (Underdahl et al., 2000) and postoperative endophthalmitis (Clark et al., 1999). It has also been recognized as a source of infection in focal intracranial infections (Chu et al., 2001) and various cerebrospinal fluid shunt infections (Thompson and Albright, 1998). A recent study from Japan (Ishige et al., 1999) has shown that P. acnes DNA can be detected in lymph nodes of Japanese individuals with sarcoidosis. Sarcoidosis is a granulomatous disease that results in the inflammation of lymph nodes, lungs, eyes, liver, and other tissues. P. acnes have also been implicated in sciatica, a chronic inflammatory condition of the lower back. Stirling et al. (2001) have isolated P. acnes from intervertebral disc material of patients with severe sciatica and they hypothesize that low virulent organisms such as P. acnes can gain access to the injured spinal disc and initiate chronic inflammation. However, until confirmatory data is available, the proposed role of P. acnes in sarcoidosis and sciatica should be considered intriguing but preliminary. It also appears to be significant that P. acnes have been isolated from several orthopedic infections, silicone breast prosthesis, and prosthetic joint infections (Yu et al., 1997; Tunney et al., 1999). The infected prostheses have been shown to contain bacterial biofilms of P. acnes and/or Staphylococcus epidermidis. The adhesion of P. acnes to the surface of the prostheses has been postulated to be a result of binding of propionibacterial cell surface proteins or adhesion molecules to host plasma or connective tissue proteins such as fibronectin (Yu et al., 1997). Evidence for this hypothesis comes from the studies of Herrmann et al. (1988), who show that fibronectin, fibrinogen, and laminin are mediators of adherence of staphylococcal isolates to polymer surfaces in intravenous device infection.
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary Corixa Acne Vaccine Program The gamut of acne treatments range from topical and systemic antibiotics to oral and topical isotretinoins, chemicals like benzoyl peroxide, oral contraceptives and corticosteroids. Antibiotics have been in use for several decades as one of the most common treatments for acne. Antibiotics, both topical and systemic, take a relatively long time to reduce the numbers of P. acnes bacteria in the skin and do not address other causative factors of acne. More recently, vitamin A derivatives called retinoids have been used effectively for acne treatment since these drugs help unclog pores, reduce sebum production and help normalize skin shedding and growth. However, oral isotretinoins are also known to cause severe side effects including elevated serum triglyceride levels, acute pancreatitis, hepatotoxicity, clinical depression, and birth defects in pregnant women. To help identify components of P. acnes involved in pathogenesis or a protective immune response and develop a therapeutic vaccine for acne, we recently sequenced the genome of P. acnes. The genome is approximately 2.6 Mb and organized into 100 contigs. It shares similarity with the genomes of other bacteria, including Streptomyces coelicor, Mycobacterium tuberculosis, and other gram-positive cocci. Numerous homologues to virulence factors of other grampositive pathogens have been found in the P. acnes genome, including homologues of known vaccine targets. Whole genome sequencing of microbial pathogens has been used successfully to predict vaccine candidates in Streptococcus pneumoniae and Haemophilus influenzae (Adamou et al., 2001; Wizemann et al., 2001; Chakravarti et al., 2000). We are using a multifaceted approach that combines traditional immunological and biochemical antigen discovery strategies along with a genomics approach to identify antigens for use as vaccine targets. This approach includes serological expression cloning, proteomics, and CD4 T-cell expression cloning. We are further enhancing antigen discovery methods by using in-silico approaches to predict targets for antibody-based vaccines and antimicrobial agents. The products of these various research strategies provide attractive antigen candidates, i.e., a polypeptide that is detected by serum from adult individuals who never suffered acne, and predicted to be extracellular and involved in P. acnes metabolism, or an immunogenic extracellular enzyme potentially involved in epithelial destruction. Such antigens may prove to be valuable vaccine candidates for the other chronic diseases associated with P. acnes as well. 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. Recent data indicates that Corixa’s proprietary adjuvants, MPL® and AGPs (aminoalkyl glucosaminide phosphates), induce strong mucosal and systemic
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary immunity when administered mucosally. Adjuvants such as these would be useful to prime a local immune system against P. acnes at the pilosebaceous level. Lastly, the molecules discovered by immunological methods could be used in immunodiagnostic assays. For example, we might be able to develop serological markers to predict in early adolescence the likelihood of future acne flares. In addition, since many of the studies of the involvement of P. acnes outside of the skin have so far relied on culture-based and molecular techniques that are prone to false positive results, future studies of disease associations of P. acnes might be facilitated by the availability of a specific immunoassay comprising recombinant P. acnes proteins. REFERENCES Adamou JE, Heinrichs JH, Erwin AL, Walsh W, Gayle T, Dormitzer M, Dagan R, Brewah YA, Barren P, Lathigra R, Langermann S, Koenig S, Johnson S. 2001. Identification and characterization of a novel family of pneumococcal proteins that are protective against sepsis. Infection and Immunity 69:949–958. Adlam C and Scott MT. 1973. Lympho-reticular stimulatory properties of Corynebacterium parvum and related bacteria. Journal of Medical Microbiology 6:261–274. Cantrell JL and Wheat RW. 1979. Antitumor activity and lymphoreticular stimulation properties of fractions isolated from Corynebacterium parvum. Cancer Research 39:3554–3563. Chakravarti DN, Fiske MJ, Fletcher LD, Zagursky RJ. 2000. Application of genomics and proteomics for identification of bacterial gene products as potential vaccine candidates. Vaccine 19:601–612. Chu RM, Tummala RP, Hall WA. 2001. Focal intracranial infections due to Propionibacterium acnes: report of three cases. Neurosurgery 49:717–720. Clark WL, Kaiser PK, Flynn HW Jr, Belfort A, Miller D, Meisler DM. 1999. Treatment strategies and visual acuity outcomes in chronic postoperative Propionibacterium acnes endophthalmitis. Ophthalmology 106:1665–1670. Davies M. 1982. Bacterial cells as anti-tumour agents in man. Reviews on Environmental Health 4:31–56. Goldman L, Michael JG, Riebel S. 1979. The immunobiology of acne. A polyvalent proprionibacteria vaccine. Cutis 23:181–184. Herrmann M, Vaudaux PE, Pittet D, Auckenthaler R, Lew PD, Schumacher-Perdreau F, Peters G, Waldvogel FA. 1988. Fibronectin, fibrinogen, and laminin act as mediators of adherence of clinical staphylococcal isolates to foreign material. The Journal of Infectious Diseases 158:693–701. Hoffler U, Gehse M, Gloor M, Pulverer G. 1985. Enzyme production of propionibacteria from patients with acne vulgaris and healthy persons. Acta Dermato-Venereologica 65:428–432. Holland KT, Ingham E, Cunliffe WJ. 1981. A review, the microbiology of acne. The Journal of Applied Bacteriology 51:195–215. Holland KT, Holland DB, Cunliffe WJ, Cutcliffe AG. 1993. Detection of Propionibacterium acnes polypeptides which have stimulated an immune response in acne patients but not in normal individuals. Experimental Dermatology 2:12–16. Ingham E, Gowland G, Ward RM, Holland KT, Cunliffe WJ. 1987. Antibodies to P. acnes and P. acnes exocellular enzymes in the normal population at various ages and in patients with acne vulgaris. The British Journal of Dermatology 116:805–812. Ishige I, Usui Y, Takemura T, Eishi Y. 1999. Quantitative PCR of mycobacterial and propionibacterial DNA in lymph nodes of Japanese patients with sarcoidosis. Lancet 354:120–123.
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary Kirschbaum JO and Kligman AM. 1963. The pathogenic role of Corynebacterium acnes in acne vulgaris. Archives of Dermatology 88:832–833. Knop J, Ollefs K, Frosch PJ. 1983. Anti-P. acnes antibody in comedonal extracts. The Journal of Investigative Dermatology 80:9–12. Layton AM, Henderson CA, Cunliffe WJ. 1994. A clinical evaluation of acne scarring and its incidence. Clinical and Experimental Dermatology 19:303–308. Lazar JM and Schulman DS. 1992. Propionibacterium acnes prosthetic valve endocarditis: a case of severe aortic insufficiency. Clinical Cardiology 15:299–300. Mohsen AH, Price A, Ridgway E, West JN, Green S, McKendrick MW. 2001. Propionibacterium acnes endocarditis in a native valve complicated by intraventricular abscess: a case report and review. Scandinavian Journal of Infectious Diseases 33:379–380. Noble WC. 1984. Skin microbiology: coming of age. Journal of Medical Microbiology 17:1–12 Norris JF and Cunliffe WJ. 1988. A histological and immunocytochemical study of early acne lesions. The British Journal of Dermatology 118:651–659. Okamura H, Nagata K, Komatsu T, Tanimoto T, Nukata Y, Tanabe F, Akita K, Torigoe K, Okura T, Fukuda S. 1995. A novel costimulatory factor for gamma interferon induction found in the livers of mice causes endotoxic shock. Infection and Immunity 63:3966–3972. Plewig G and Kligman AM, eds. 2000. Acne and Rosacea, 3rd ed., 744 pages. New York: Springer-Verlag. Puhvel SM and Sakamoto M. 1977. Chemoattractant properties of Corynebacterium parvum and pyran copolymer for human monocytes and neutrophils. Journal of the National Cancer Institute 58:781–783. Stirling A, Worthington T, Rafiq M, Lambert PA, Elliott TS. 2001. Association between sciatica and Propionibacterium acnes. Lancet 357:2024–2025. Thompson TP and Albright AL. 1998. Propionibacterium [correction of Proprionibacterium] acnes infections of cerebrospinal fluid shunts. Childs Nervous System 14:378–380. Tunney MM, Patrick S, Curran MD, Ramage G, Hanna D, Nixon JR, Gorman SP, Davis RI, Anderson N. 1999. Detection of prosthetic hip infection at revision arthroplasty by immunofluorescence microscopy and PCR amplification of the bacterial 16S rRNA gene. Journal of Clinical Microbiology 37:3281–3290. Underdahl JP, Florakis GJ, Braunstein RE, Johnson DA, Cheung P, Briggs J, Meisler DM. 2000. Propionibacterium acnes as a cause of visually significant corneal ulcers. Cornea 19:451–454. Vymola F, Buda J, Lochmann O, Pillich J. 1970. Successful treatment of acne by immunotherapy. Journal of Hygiene, Epidemiology, Microbiology, and Immunology 14:135–138. Vowels BR, Yang S, Leyden JJ. 1995. Induction of proinflammatory cytokines by a soluble factor of Propionibacterium acnes: implications for chronic inflammatory acne. Infection and Immunity 63:3158–3165. Webster GF, Leyden JJ, Norman ME, Nilsson UR. 1978. Complement activation in acne vulgaris: in vitro studies with Propionibacterium acnes and Propionibacterium granulosum. Infection and Immunity 22:523–529. Wizemann TM, Heinrichs JH, Adamou JE, Erwin AL, Kunsch C, Choi GH, Barash SC, Rosen CA, Masure HR, Tuomanen E, Gayle A, Brewah YA, Walsh W, Barren P, Lathigra R, Hanson M, Langermann S, Johnson S, Koenig S. 2001. Use of a whole genome approach to identify vaccine molecules affording protection against Streptococcus pneumoniae infection. Infection and Immunity 69:1593–1598. Yu JL, Mansson R, Flock JI, Ljungh A. 1997. Fibronectin binding by Propionibacterium acnes. FEMS Immunology and Medical Microbiology 19:247–253.
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