Multiple Viral Pathogenicity: Another Paradigm in Medical Research?

MULTIPLE VIRAL PATHOGENICITY: ANOTHER PARADIGM IN MEDICAL RESEARCH? JULIO SOTELO* The conceptual framework in scientific research on the causal mechanisms of disease has been based on the idea that a disease is either caused by a single agent or by a combination ofvarious agents. With this approach, the accomplishments ofbiomedical research are impressive for the majority of diseases endemic at the beginning of this century. One after another, the etiology of important disorders was discovered and the causal agents ofmost infectious diseases were elucidated and characterized; the same was done with metabolic diseases. With the discovery and isolation of several viral, bacterial and parasitic entities, as well as with the purification of hormones , vitamins, cytokines, enzymes, and peptides, the etiopathic mechanisms of several disorders were clearly defined. Thus, the specific and unique cause of infectious diseases like tuberculosis, syphilis, malaria, trypanosomiasis , rabies, smallpox, influenza, measles, etc., was elucidated. The same results were achieved with many metabolic diseases: vitamin deficiencies , endocrinopathies, immune deficiency diseases, inborn errors of metabolism, etc., that were shown to be caused either by the lack or by the excess of a single substance. These discoveries, made within the short timespan of a few decades, strengthened the concept that every disease was caused by a specific agent. Still, a few other diseases were shown to be secondary to the confluence of various factors, such as the disorders secondary to the combination of alcoholism and malnutrition; or to be the consequence ofcoinciding genetic, developmental, and environmental risk factors causing a defined disorder, as seems to be the case ofschizophrenia. All this accumulation of discoveries on the etiology of diseases reinforced the paradigm that was so successful in medical research: one agent —> one disease one agent <— various diseases Parallel to our usual thinking that a given disease is the result of the action of one or various factors, it seems quite possible that a given factor might also cause either one or various different diseases. At least in the field of virus-induced pathology, this appears to be a frequent event. Several viruses , with representatives from various families and categories, have been implicated either as the key player or as an important participant in the etiology of more than one disorder. 508 Julio Sotelo ¦ Multiple Viral Pathogenicity Multiple Pathogenesis Induced by a Single Virus Genre Measles virus, an RNA paramyxovirus, is the cause of one of the most frequent and classical viral diseases. It is highly infectious but moderately pathogenic. It originates, like most conventional viruses, an acute, selflimiting disorder: measles. However, the very same virus is also responsible for two other diseases, different from measles in every aspect: subacute sclerosing panencephalitis and measles encephalitis. The former is a chronic inflammatory disease of the brain, and the latter is an acute autoimmune disorder. In cases of subacute sclerosing panencephalitis, the virus changes its pathogenic mechanisms to become a neurotrophic agent, selective for oligodendrocytes; the infection becomes chronic; and the virus survives within the target cell, inducing a slow and incurable dementia. In cases of post-infectious measles encephalitis, the disorder is remarkable insofar as the pathogenic mechanisms correspond to a clear example of autoimmunity: the measles virus, by an ill-understood process, triggers a violent response against myelin proteins from the host, producing an aseptic case of immune-mediated demyelinating encephalitis [I]. Thus, the same virus is responsible for at least three disorders with diverse characteristics: an acute systemic infection, a chronic disease limited to a single organ, and an autoimmune disorder in which the virus plays a hit-and-run role. Retroviruses constitute a subgroup ofRNA infectious particles with a notorious capacity for the induction of diseases that almost in every instance defy the classical concepts ofclinical expression ofan infection. The human T cell lymphotropic virus type 1 (HTLV-I) was among the first to be recorded as an etiologic agent for a human cancer, T-cell leukemia [2] . Nevertheless , several decades earlier, in 1911, another retrovirus had been clearly shown to be the cause of an avian cancer: the Rous sarcoma. Although it was a breakthrough in biology, it remained for several years as an oddity, lacking clinical importance for the field of human pathology. A remarkable aspect of HTLV-I lies in its capacity to participate in two different and even opposite mechanisms of disease: a proliferative disorder of lymphocytes (leukemia), and a degenerative neurological disorder of the spinal cord (tropical spastic paraparesis) [3]. Retroviruses are a fair example in which the host cells are not significantly harmed by the viral replication . In the case of oncogenic retroviruses, cellular proto-oncogenes are incorporated into their genome, inducing in turn a malignant transformation ofcells infected by these new "defective" oncogene-containing retroviruses . Due to the increased rate ofintragenomic rearrangements ofretroviruses , their possiblities for multiple pathogenic changes wihin the cell must be high. Different changes in the same virus genre might bring different pathologies of proliferative, degenerative, or autoimmune nature, with no Perspectives in Biology and Medicine, 39, 4 ¦ Summer 1996 | 509 physiopathological or clinical similarities between them, except for the fact that they all are caused by the same virus [2-4] . On the side ofDNAviruses, some agents from the herpes family, particularly the Epstein-Barr virus (EBV) and cytomegalovirus, have a remarkable ability for multiple pathogenesis. They are clear examples of virus persistence within the host for several years. EBV is a lymphotropic virus responsible for infectious mononucleosis, an acute disease, usually benign and selflimited . But the infection may also persist and cause a chronic inflammatory disorder of the lymph nodes. On the other hand, EBV has been postulated as one ofthe most conspicuous viruses involved in the pathogenesis of human cancer: Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's disease, immunoblastic lymphoma, and other rare forms of cancer have been associated with EBV [5, 6] . Moreover, EBV has also been implicated in the genesis of an autoimmune disorder, autoimmune hepatitis [7]. In the case of cancer-associated EBV, it seems that the expression ofviral proteins during latency have the ability to deregulate the control ofcell growth, which, associated with additional genetic, hormonal, or immunological factors in the host, can lead to malignant transformation. Autoimmune-hepatitis associated to EBV appears to be a virus-induced defect in the immunoregulatory functions of the suppressor/inducer T-lymphocyte subset, triggering an autoimmune response against a glycoprotein on the hepatocyte surface. Interestingly, this form of virus-induced autoimmunity is another case of a hit-and-run event, in which both the virus and EBV antibodies are not found when the autoimmune hepatitis develops, making it difficult to detect EBV-triggered cases [7]. Another herpesvirus has also been implicated as a causative agent in Kaposi sarcoma, a rare form of cancer that develops with peculiar frequency in immunocompromised hosts, especially victims of another viral disorder, the acquired immunodeficiency syndrome (AIDS) . A possible synergic action of both viruses in the genesis of Kaposi sarcoma is currently been studied [8]. Papovaviruses are the oldest viruses known for inducing proliferative changes within the cell [9] . In the forties, viruses from the genes papilloma were recognized as the cause of benign neoplasms of the skin or mucous membranes. These viruses are ubiquitous and do not seem to produce a typical viral infection. However, the SJ virus from the genus polyoma has been found as the cause of a chronic degenerative disease of the brain, progressive multifocal leukoencephalopathy, in which the virus infects oligodendrocytes leading to progressive demyelination, dementia, and death. Progressive multifocal leukoencephalopathy characteristically develops in immunosuppressed patients. Both genera from the Papovavirus family, papilloma and polyoma, have been demonstrated as causal or associated factors of cancer in animals. In humans there is circumstantial evidence linking them to cancer from the uterine cervix and malignant transformation of papillomas. 510 Julio Sotelo ¦ Multiple Viral Pathogenicity Hepatitis B virus causes an acute and very frequent viral disorder; however , in rare cases it also seems to be responsible for the development of hepatocellular carcinoma [5]. In these cases it is possible that the chronic persistence of the virus, associated with genetic or nutritional factors from the host, might coincide with the malignant transformation ofhepatic cells. Unconventional viruses, different in several biological, chemical, and physical characteristics from all known viruses, induce, in animals and humans , pathology of a characteristically degenerative nature: espongiform encephalopathy secondary to the intracellular replication of infectious amyloid molecules [10]. The uncoventional virus, are apparently devoid of nucleic acids and produce fibrillar polymerization of the amyloid protein, leading to neuronal degeneration [10] . Similar changes in the amyloid subunit are found in one of the most conspicuous degenerative disturbances, Alzheimer's disease, although every attempt to explore infectious agents in Alzheimer's disease has failed. Viral Participation in Autoimmunity, Cancer, and Degenerative Diseases Autoimmune reactions have long been recorded in several viral infections either caused by conventional or even by unconventional viruses known for their ability to bypass the mechanisms of immune recognition of the host [11, 12]. The large amount of lymphotrophic viruses, many of them responsible for alterations in the highly complex mechanisms of the immune response, supports the idea that some viral disorders may induce disturbances in the immune system leading to autoimmune responses against self-antigens [13] . Some of these mechanisms ofvirus-induced autoimmunity could implicate a rather peculiar viral participation in the genesis ofdisease: only as triggeringfactors ofa pathological process thatfuels itself with no further participation of the causal agent [1, 7]. If this mechanism operates in other disorders of viral origin, and in fact this seems to be the case [6, 14], researchers would have to incorporate to their hypothetical reasoning the possibility of a virus playing a crucial but ephemeral role within the longitudinal process of disease, particularly at its genesis, the most difficult stage to be discovered. In cancer, for instance, it could explain why so many intracellular disturbances are observed with no apparent alien intromission. The virus may inactivate tumor suppressor proteins [5] , and initiate a sustained cell proliferation with little or no further participation of the virus in the pathophysiology of the tumor. Whereas in cases of degenerative disorders, the virus might enhance genes related with arrest of the cell cycle and subsequent apoptosis [15, 16], where the cell undergoes programmed death and reabsorption; again, this would make difficult the discovery of the virus that originated the event. Although diverse pathologies are caused by bacteria and parasites in relaPerspectives in Biology and Medicine, 39, 4 ¦ Summer 1996 | 511 tion with the tissue infected, they depend only on topography. Thus, tuberculosis bacilli produces meningeal, pulmonary, peritoneal, or renal tuberculosis ; each constitutes a different clinical entity, however, they do not correspond to multiple pathogenicity of the tuberculosis bacillus but to multiple tissue affinity. In viral disorders, the case of multiple pathogenicity is demonstrated by the fact that infection to the same cell type by the same virus can lead to different and even contrasting cell pathologies. The above examples ofviruses that cause two or more different diseases, some of them within the boundaries of autoimmunity, cancer, and degenerative processes, represent only scattered cases among large lists of disorders ofobscure etiology [3, 5, 6, 8, 9, 17, 18] . Modern techniques ofmolecular biology, particularly for gene-sequencing analysis and experimental models ofvirus-induced pathology, will define whether multiple viral pathogenicity is a common cause of various diseases or only a biological rarity [19,20], REFERENCES 1.Johnson, R. T.; Griffin, D. E.; Hirsch, R. L.; et al. Measles encephalomyelitis : Clinical and Immunological studies. N. Engl. J. Med. 310:137-141, 1984. 2.Poiesz, B. J.; Ruscetti, F. W.; Gazdar, A. F.; et al. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc. Natl. Acad. Sci. USA 77:74157419 , 1980. 3.Yanagihara, R. Geographic-specific genotypes or topotypes of human Tcell lymphotropic virus type I as markers for early and recent migrations of human populations. Advances in Virus Research 43:147-186, 1994. 4.Krieg, A. M. F.; Gourley, M., and Steinberg, A. D. 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Spontaneous generation of infectious nucleating amyloids in the transmissible and nontransmissible cerebral amyloidoses. MoI. Neurobiol . 8:1-13, 1994. 11.Toh, B. H.; Yildiz, A.; Sotelo, J.; et al. Viral infections and IgM autoantibodies to cytoplasmic intermediate filaments. Clin. Exp. Immunol. 37:76-82, 1979. 512 Julio Sotelo ¦ Multiple Viral Pathogenicity 12.Sotelo, J.; Gibbs, C. J.; and Gajdusek, D. C. Autoantibodies against axonal neurofilaments in patients with Kuru and Creutzfeldt-Jakob disease. Science 210:190-193, 1980. 13.Zinkernagel, R. M. Immunity to viruses. In Fundamental Immunology, 3rd ed., edited by W. E. Paul. New York: Raven Press, 1993. 14.Rady, P. L.; Yen, A.; Rollefson, J. L; et al. Herpesvirus-like DNA sequences in non-Kaposi's sarcoma skin lesions of transplant patients. Lancet 345: 1339-1340, 1995. 15.Kaufmann, Y; Many, A.; Rechavi, G.; et al. Lymphoma with recurrent cycles of spontaneous remission and relapse. Possible role of apoptosis. JV. Engl. J. Med. 332:507-510, 1995. 16.Carson, D. A., and Ribeiro, J. M. Apoptosis and disease. Lancet 341: 12511254 , 1993. 17.Gubersky, D. L.; Thomas, V. A.; Shek, W. R.; et al. Induction of type I diabetes by Kilham's rat virus in diabetes-resistant BB/Wor rats. Science 254: 1010, 1991. 18.Britton, S. EBV and rheumatoid arthritis. Immunol. Today 3:127, 1982. 19.Sherman, M. P.; Amin, R. M.; Rodgers-Johnson, P. E. B.; et al. Identification of human T cell leukemia/lymphoma virus type I antibodies, DNA, and protein in patients with polymyositis. Arthritis Rheum. 38:690-698, 1995. 20.Godec, M. S.; Asher, D. M.; Murray, R. S.; et al. Absence of measles, mumps, and rubella viral genomic sequences from multiple sclerosis brain tissue by polymerase chain reaction. Ann. Neurol. 32:401-404, 1992. PAVLOV LOSES HIS BOOTS In later years, when Pavlov described freedom and slavery as reflex actions, his critics said he had become dogmatic, relying too heavily on conditioned reflex. Old Pavlov traveled with his son Vladimir to America. Used to staying in European hotels, they left their shoes outside the door to be spirited away and shined overnight. Upon waking, they found them gone. Pavlov's lost orthopedic boots were custom-made, expensive, his only pair. They recovered the boots: Don't do that again, die manager told them, we have a shoeshine parlor in the lobby here. NoraJacobson Perspectives in Biology and Medicine, 39, 4 ¦ Summer 1996 | 513 ...