Lymphocytic Choriomeningitis Virus — An Old Enemy up to New Tricks
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《新英格兰医药杂志》
Lymphocytic choriomeningitis virus (LCMV) was among the first human pathogenic viruses to be isolated. In the mid-1930s, Armstrong and Lillie obtained a filterable agent thought to be from the brain of a man who died during an epidemic of St. Louis encephalitis, Traub discovered a chronic infection in a mouse colony, and Rivers and Scott isolated a virus from the cerebrospinal fluid of patients with aseptic meningitis (see image).1 All three of these viruses were shown to have the same properties and serologic features, and LCMV became the type species characterizing the virus family Arenaviridae, established in 1970. In nature, each of the approximately 20 known arenaviruses chronically infects a single rodent species, with long-term shedding of virus, but with minimal or no overt disease.
Typical LCMV Virions.
This electron micrograph shows the spherical morphologic features and the granules within the virions that give the family, Arenaviridae, its name (arenosus is Latin for "sandy").
Courtesy of Cynthia Goldsmith, Centers for Disease Control and Prevention, Atlanta.
The study of mice infected with LCMV has led to Nobel Prize–winning advances in immunobiology. The chronic viremia that follows the infection of neonatal mice with LCMV was part of the inspiration for the clonal selection theory of immunity and tolerance, and studies of T-cell activity in the LCMV-infected mouse have deepened our understanding of the function of the major histocompatibility complex in immunologic tolerance and its effect on the interactions of T cells with other cells.2 The outcome of direct intracranial inoculation of the immunocompetent adult mouse is important to the understanding of human disease. The LCMV grows locally without overtly damaging brain or meningeal cells, but an immunopathologic CD8 T-cell–mediated choriomeningitis ensues. This histologic finding, which is the source of the name of the virus, led Rivers to seek the virus in patients with aseptic meningitis.1 Ablation of CD8 T cells or immunosuppression of the T-cell response prevents this syndrome, but the noncytopathic virus persists.
In this issue of the Journal, Fischer et al. (pages 2235–2249) report on the infection with LCMV of two groups of transplant recipients through organs obtained from common donors. Although there is no documentation of the infection in the donors, the coincidence in timing and the phylogenetic matching of the strains within each cluster leave little doubt about the interpretation. There were no clinical signs of LCMV infection in the donors, although both had hemorrhagic intracranial lesions when they died. The source of infection in one of the donors was identified definitively as a pet hamster, but the other source remains unknown. Seven of the eight infected recipients died.
Many human LCMV infections remain completely subclinical, but some result in debilitating febrile diseases, with central nervous system involvement in a minority of cases.3 The associated mortality is quite low, certainly less than 1 percent. Careful studies of febrile diseases involving the central nervous system conducted at the Walter Reed Army Medical Center between 1941 and 1958 revealed that about 10 percent of cases were due to LCMV. Population studies in the United States routinely show that about 5 percent of adults have antibodies indicating previous infection. The source is often not identified, and infection is presumed to occur through aerosols or other contamination from wild mice, pet mice, or pet hamsters.
The pathogenesis of typical disease from LCMV infections in humans is thought to be similar to that in adult mice that have been intracranially injected with the virus (see graph, top panel). In humans, there is a viremic, febrile syndrome, often with marked thrombocytopenia and leukopenia, and occasionally the virus invades the central nervous system. The host T cells attack the virus-infected cells in the meninges, causing a transient inflammatory response. The course is often more severe than those of typical enteroviral aseptic meningitides; the lymphocyte counts in the cerebrospinal fluid may reach into the hundreds and, occasionally, hypoglycorrachia suggests granulomatous meningitis. Usually the struggle between the virus and the host immune response is resolved in favor of the patient, who recovers without sequelae.
Pathogenesis of Human LCMV Infection.
A normal human volunteer shows an initial period of viremia associated with fever, leukopenia, and systemic symptoms (top panel). This period is followed by the onset of the cellular immune response, with meningeal inflammation that results in mild, transient disease of the central nervous system. The virus was isolated from the cerebrospinal fluid (CSF). The course of infection in a patient with immunosuppression caused by Hodgkin's disease and chemotherapy is shown in the bottom panel. The patient was inoculated with LCMV in hopes of causing remission of the lymphoma. Viremia developed and was sustained; no indirect fluorescent, complement-fixing, or neutralizing antibodies developed; and there was no overt disease of the central nervous system. At the time of death, possibly caused by bacterial pneumonia and LCMV infection, there were high titers of the virus present in brain (B), spleen (S), and tumor (T) tissue. Adapted from Peters3 with the permission of the publisher. The dagger symbol denotes death.
However, another pattern was suggested early on by observations of LCMV. A monkey was inoculated with brain tissue from a patient thought to have St. Louis encephalitis. One of the persons who conducted the autopsy on the monkey became fatally infected with LCMV, as did one of the persons performing the autopsy on that patient. In retrospect, these two fatal cases resembled a viral hemorrhagic fever syndrome typical of another arenavirus disease, Lassa fever from Africa. LCMV strains inoculated into macaques or marmosets result in a fatal infection with an apparently similar pathogenesis. The same pathogenetic process was seen again in three patients with lymphoma in whom chemotherapy had failed, after they were inoculated with a strain of LCMV in an attempt to induce tumor remission (see graph, bottom panel). These patients had sustained viremia; the virus was isolated from multiple organs, and they died two to six weeks later. As in the transplant recipients discussed by Fischer et al., the microscopic lesions in the three patients were not substantial, and inflammatory infiltrates were not prominent. Thus, the pathogenesis of these syndromes is dependent on sustained viremia and not on the T-cell immune response to virus in tissues, as are meningeal syndromes in mice and humans. Indeed, immunosuppression is not protective against these syndromes but, rather, predisposes humans to the hemorrhagic fever-like syndrome as it does in the experimental animal models of arenaviral hemorrhagic fevers.
LCMV has been administered to patients in the hope that it will cause tumor regression. It can infect transplanted cells and cause chronic infection, with LCMV antigens serving as transplantation antigens. Under proper experimental conditions, the T-cell response to these antigens can result in the regression of tumors, particularly lymphoid tumors. In the single survivor among the eight infected solid-organ recipients in the study by Fischer et al., immunosuppressive medications were tapered at the same time as treatment with ribavirin — an antiviral drug known to be effective against LCMV — was initiated. Presumably, the balance between the reduction of viral infection and the increase in the immune response permitted clearance of the virus without an immune attack on the patient's own organs or his transplanted kidney, as might occur with an experimental tumor or infected meninges.
What should be done about controlling LCMV in organ transplantation? The testing of potential donors by means of polymerase chain reaction or immunohistochemical analysis is theoretically possible but would be extremely expensive and, judging from these two donors, not necessarily effective. The determination of a history of ownership of a pet rodent is neither sensitive nor specific to LCMV infection. One obvious way to reduce the risk of human infection with LCMV is to have suppliers of pet rodents screen their colonies for the infection. Mice are known to carry silent, vertically transmitted LCMV infection. Hamsters and possibly other pet rodents, although not hosts in the wild, can sustain continuous transmission under breeding-colony conditions, with disastrous consequences.4 Wild mice can introduce LCMV into colonies of either hamsters or mice. Thus, regulations to ensure the absence of virus in rodent colonies would reduce the risk of LCMV infection posed to pet owners and decrease the risk of transmission from transplanted organs. Such screening seems justified, given the serious nature of LCMV disease and the particular risk to fetuses: LCMV infection in pregnant women is an increasingly recognized cause of hydrocephalus, mental retardation, and chorioretinitis in newborns.5
Dr. Peters reports having received consulting fees from Acambis, a vaccine manufacturer.
Source Information
Dr. Peters is a professor of tropical and emerging virology and director of biodefense at the Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston.
References
Lehmann-Grube F. Lymphocytic choriomeningitis virus. New York: Springer-Verlag, 1971.
Zinkernagel RM. Lymphocytic choriomeningitis virus and immunology. Curr Top Microbiol Immunol 2002;263:1-5.
Peters CJ. Arenavirus diseases. In: Porterfield JS, ed. Exotic viral infections. London: Chapman & Hall Medical, 1995:227-46.
Gregg MB. Recent outbreaks of lymphocytic choriomeningitis in the United States of America. Bull World Health Organ 1975;52:549-553.
Mets MB, Barton LL, Khan AS, Ksiazek TG. Lymphocytic choriomeningitis virus: an underdiagnosed cause of congenital chorioretinitis. Am J Ophthalmol 2000;130:209-215.(C.J. Peters, M.D.)
Typical LCMV Virions.
This electron micrograph shows the spherical morphologic features and the granules within the virions that give the family, Arenaviridae, its name (arenosus is Latin for "sandy").
Courtesy of Cynthia Goldsmith, Centers for Disease Control and Prevention, Atlanta.
The study of mice infected with LCMV has led to Nobel Prize–winning advances in immunobiology. The chronic viremia that follows the infection of neonatal mice with LCMV was part of the inspiration for the clonal selection theory of immunity and tolerance, and studies of T-cell activity in the LCMV-infected mouse have deepened our understanding of the function of the major histocompatibility complex in immunologic tolerance and its effect on the interactions of T cells with other cells.2 The outcome of direct intracranial inoculation of the immunocompetent adult mouse is important to the understanding of human disease. The LCMV grows locally without overtly damaging brain or meningeal cells, but an immunopathologic CD8 T-cell–mediated choriomeningitis ensues. This histologic finding, which is the source of the name of the virus, led Rivers to seek the virus in patients with aseptic meningitis.1 Ablation of CD8 T cells or immunosuppression of the T-cell response prevents this syndrome, but the noncytopathic virus persists.
In this issue of the Journal, Fischer et al. (pages 2235–2249) report on the infection with LCMV of two groups of transplant recipients through organs obtained from common donors. Although there is no documentation of the infection in the donors, the coincidence in timing and the phylogenetic matching of the strains within each cluster leave little doubt about the interpretation. There were no clinical signs of LCMV infection in the donors, although both had hemorrhagic intracranial lesions when they died. The source of infection in one of the donors was identified definitively as a pet hamster, but the other source remains unknown. Seven of the eight infected recipients died.
Many human LCMV infections remain completely subclinical, but some result in debilitating febrile diseases, with central nervous system involvement in a minority of cases.3 The associated mortality is quite low, certainly less than 1 percent. Careful studies of febrile diseases involving the central nervous system conducted at the Walter Reed Army Medical Center between 1941 and 1958 revealed that about 10 percent of cases were due to LCMV. Population studies in the United States routinely show that about 5 percent of adults have antibodies indicating previous infection. The source is often not identified, and infection is presumed to occur through aerosols or other contamination from wild mice, pet mice, or pet hamsters.
The pathogenesis of typical disease from LCMV infections in humans is thought to be similar to that in adult mice that have been intracranially injected with the virus (see graph, top panel). In humans, there is a viremic, febrile syndrome, often with marked thrombocytopenia and leukopenia, and occasionally the virus invades the central nervous system. The host T cells attack the virus-infected cells in the meninges, causing a transient inflammatory response. The course is often more severe than those of typical enteroviral aseptic meningitides; the lymphocyte counts in the cerebrospinal fluid may reach into the hundreds and, occasionally, hypoglycorrachia suggests granulomatous meningitis. Usually the struggle between the virus and the host immune response is resolved in favor of the patient, who recovers without sequelae.
Pathogenesis of Human LCMV Infection.
A normal human volunteer shows an initial period of viremia associated with fever, leukopenia, and systemic symptoms (top panel). This period is followed by the onset of the cellular immune response, with meningeal inflammation that results in mild, transient disease of the central nervous system. The virus was isolated from the cerebrospinal fluid (CSF). The course of infection in a patient with immunosuppression caused by Hodgkin's disease and chemotherapy is shown in the bottom panel. The patient was inoculated with LCMV in hopes of causing remission of the lymphoma. Viremia developed and was sustained; no indirect fluorescent, complement-fixing, or neutralizing antibodies developed; and there was no overt disease of the central nervous system. At the time of death, possibly caused by bacterial pneumonia and LCMV infection, there were high titers of the virus present in brain (B), spleen (S), and tumor (T) tissue. Adapted from Peters3 with the permission of the publisher. The dagger symbol denotes death.
However, another pattern was suggested early on by observations of LCMV. A monkey was inoculated with brain tissue from a patient thought to have St. Louis encephalitis. One of the persons who conducted the autopsy on the monkey became fatally infected with LCMV, as did one of the persons performing the autopsy on that patient. In retrospect, these two fatal cases resembled a viral hemorrhagic fever syndrome typical of another arenavirus disease, Lassa fever from Africa. LCMV strains inoculated into macaques or marmosets result in a fatal infection with an apparently similar pathogenesis. The same pathogenetic process was seen again in three patients with lymphoma in whom chemotherapy had failed, after they were inoculated with a strain of LCMV in an attempt to induce tumor remission (see graph, bottom panel). These patients had sustained viremia; the virus was isolated from multiple organs, and they died two to six weeks later. As in the transplant recipients discussed by Fischer et al., the microscopic lesions in the three patients were not substantial, and inflammatory infiltrates were not prominent. Thus, the pathogenesis of these syndromes is dependent on sustained viremia and not on the T-cell immune response to virus in tissues, as are meningeal syndromes in mice and humans. Indeed, immunosuppression is not protective against these syndromes but, rather, predisposes humans to the hemorrhagic fever-like syndrome as it does in the experimental animal models of arenaviral hemorrhagic fevers.
LCMV has been administered to patients in the hope that it will cause tumor regression. It can infect transplanted cells and cause chronic infection, with LCMV antigens serving as transplantation antigens. Under proper experimental conditions, the T-cell response to these antigens can result in the regression of tumors, particularly lymphoid tumors. In the single survivor among the eight infected solid-organ recipients in the study by Fischer et al., immunosuppressive medications were tapered at the same time as treatment with ribavirin — an antiviral drug known to be effective against LCMV — was initiated. Presumably, the balance between the reduction of viral infection and the increase in the immune response permitted clearance of the virus without an immune attack on the patient's own organs or his transplanted kidney, as might occur with an experimental tumor or infected meninges.
What should be done about controlling LCMV in organ transplantation? The testing of potential donors by means of polymerase chain reaction or immunohistochemical analysis is theoretically possible but would be extremely expensive and, judging from these two donors, not necessarily effective. The determination of a history of ownership of a pet rodent is neither sensitive nor specific to LCMV infection. One obvious way to reduce the risk of human infection with LCMV is to have suppliers of pet rodents screen their colonies for the infection. Mice are known to carry silent, vertically transmitted LCMV infection. Hamsters and possibly other pet rodents, although not hosts in the wild, can sustain continuous transmission under breeding-colony conditions, with disastrous consequences.4 Wild mice can introduce LCMV into colonies of either hamsters or mice. Thus, regulations to ensure the absence of virus in rodent colonies would reduce the risk of LCMV infection posed to pet owners and decrease the risk of transmission from transplanted organs. Such screening seems justified, given the serious nature of LCMV disease and the particular risk to fetuses: LCMV infection in pregnant women is an increasingly recognized cause of hydrocephalus, mental retardation, and chorioretinitis in newborns.5
Dr. Peters reports having received consulting fees from Acambis, a vaccine manufacturer.
Source Information
Dr. Peters is a professor of tropical and emerging virology and director of biodefense at the Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston.
References
Lehmann-Grube F. Lymphocytic choriomeningitis virus. New York: Springer-Verlag, 1971.
Zinkernagel RM. Lymphocytic choriomeningitis virus and immunology. Curr Top Microbiol Immunol 2002;263:1-5.
Peters CJ. Arenavirus diseases. In: Porterfield JS, ed. Exotic viral infections. London: Chapman & Hall Medical, 1995:227-46.
Gregg MB. Recent outbreaks of lymphocytic choriomeningitis in the United States of America. Bull World Health Organ 1975;52:549-553.
Mets MB, Barton LL, Khan AS, Ksiazek TG. Lymphocytic choriomeningitis virus: an underdiagnosed cause of congenital chorioretinitis. Am J Ophthalmol 2000;130:209-215.(C.J. Peters, M.D.)