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Lymphocytic Choriomeningitis

Introduction:  Lymphocytic choriomeningitis is a viral disease of mice that poses a zoonotic risk to humans.  The lymphocytic choriomeningitis virus (LCMV) is an arenavirus (single-stranded RNA virus).  Arenaviruses derive their name from their characteristic morphology which includes the unique feature of host ribosomes within the virion (arena=sand).  There are several strains of the virus; three that exhibit differences in mouse  pathogenicity are WE, Armstrong, and Traub.

  Wild mice are the resident host for LCMV, and laboratory mice and Syrian hamsters can be naturally infected.

Transmission:  LCMV can be shed in saliva, urine, and milk; chronically infected mice can shed the virus for a very long time.  Most commonly, the virus is  transmitted transplacentally, although bite wound and aerosol spread can occur.

Histo
Mouse

  When mice are infected in utero they are born without virus-specific cytotoxic T lymphcytes and are  considered immunotolerant,subclinical carriers.  Perinatal exposure to the virus results in persistent infection.  Experimental inoculation of immuno-competent adults results in fatal disease characterized by hepatitis and encephalitis; natural infection is generally cleared after an exaggerated immune  response by adult mice.

Pathology:  There are two forms of the infection in mice: persistent form and acute form.  The persistent form of the disease is acquired perinatally, results in lifelong viremia and shedding, and animals are  asymptomatic due to immune tolerance.  These  animals appear normal until approximately 7-10 months of age, at which time they develop immune complex-induced glomerulonephritis and die.  The acute or non-tolerant form of the disease arises from infection of immunocompetent adults and results in viremia without viral shedding.  In these animals, the disease is caused by T lymphocyte-mediated immune injury in response to the virus; immunosuppressive therapy halts the disease.  A similar pathogenesis has been described for Syrian hamsters.

  Many tissues can have non-suppurative inflammation in severe infections.  Both cytolytic and proliferative lesions can be seen and the type is determined by the strain of the mouse affected.  Lesions in the liver can include necrosis, accompanied by nodule infiltrates of lymphoid and Kupffer cells, and activated sinusoidal endothelium.  In lymphoid organs, cytolysis, cell  proliferation, and fibrinoid necrosis can be seen.  In later stages of the disease, the lesions observed are due to inflammation associated with immune complex deposition.  The most severely affected tissues are renal glomeruli and choroid plexus, but immune complex deposition can also occur in blood vessel walls, synovial membranes, and skin.  It is interesting that the lymphoid tissues in these animals are so severely affected, yet the immune system is still sufficiently strong to mount a response vigorous enough to kill the animal.

Clinical signs:  The clinical signs seen in LCMV infection vary with the strain of the virus involved.  The most virulent strain in mice and humans is WE.  In the cerebral form, convulsions, photophobia, and weakness characterize the disease.

  In rats, viral inoculation causes retinitis, auditory and visual impairments, and cerebellar hypoplasia.

Diagnosis:  Commercially available enzyme-linked immunosorbent assays (ELISA) and immuno-fluorescence assays (IFA) can be used to diagnose LCMV.  Adult mice infected with LCMV will exhibit sero-conversion after exposure but carrier mice may develop poor humoral immune response or consume antibody through immune complexes, which can lead to a false-negative result.  Therefore, using an adult contact sentinel becomes useful to detect the presence of LCMV by seroconversion.

  In mice that develop neurologic signs, lymphocytic choriomeningitis must be differentiated from mouse hepatitis virus, mouse encephalomyelitis virus, bacterial meningoencephalomyelitis, and other causes of neurologic disease such as toxicities, neoplasia, or trauma.  Presentations of early onset must be  differentiated from other causes of early mortality such as ectromelia virus, mouse hepatitis virus, and Tyzzer’s disease (Clostridium piliforme).

Control:  Control of LCMV infection includes barrier maintenance in holding facilities, parasite control, and obtaining mice from clean sources.  It is imperative to ensure that the animal feed has not been contaminated by wild rodents.  In the case that LCMV infection is diagnosed, all animals exposed should be tested and those positive should be eliminated.  The facilities should be decontaminated with appropriate  disinfectant.

Human implications:  LCMV poses a serious zoonotic concern and human infection is characterized by fever, myalgia, sore throat, photophobia, nausea, and  vomiting.  It can range from mild disease (fever and respiratory symptoms) to severe illness (meningitis and meningoencephalitis).  In humans, the incubation period for LCMV is approximately 6 to 13 days.  An influenza-like prodromal stage develops and, after a brief recovery, central nervous system (CNS) signs may appear.  Additionally, CNS signs may appear  without a prodromal stage.  When meningitis or  meningoencephalitis develops, the course of the disease can be lethal.

  In utero hamster-induced human infections have led to the development of hydrocephalus, uveitis, and chorioretinitis.  Also, these children were noted to have mental retardation and reduced visual acuity.

 Differential diagnoses for the disease in humans include herpes encephalitis, mononucleosis, menin-gitis, and influenza.  Ninety percent of human  outbreaks have been associated with pet trade.  Of these, ninety percent are associated with hamsters.

  Humans become infected with LCMV through direct contact or contact with infected food.  In laboratory settings, human infections arise more commonly from handling materials such as cell lines, monoclonal antibodies, and transplantable tumors containing the virus rather than from direct handling of viral cultures.

  Diagnosis of LCMV infection in humans is based on virus isolation from blood or cerebrospinal fluid in conjunction with IFA assay.

  In humans, ribavirin has been used to treat infections with beneficial outcome when administered early in the disease.  Still, because of the low incidence of the  disease, there is no sufficient evidence of treatment success.

Impact on research:  LCMV infection in mice has a variety of effects on research, especially immunologic research.  LCMV infection induces development of severe cellular and humoral immune suppression,  enhances natural killer (NK) cell activity, interferon  production, macrophage function, and virus-specific cytotoxic T-cell proliferation.  It also increases endo-thelial adhesion molecules in the serum, alters cytokine gene expression, and delays skin allograft and tumor rejection.  Additionally, LCMV infection increases susceptibility to infection with various agents such as ectromelia virus, inhibits tumorigenic potential of polyoma virus, inactivates experimental hepatitis B infection, and alters behavior and cognitive functions in mice.

  LCMV has been identified in transplantable tumors, cell cultures, strains of organisms that are passed on to laboratory mice, and monoclonal antibodies.  As mentioned above, this poses a serious zoonotic risk.

-by Dr. Jose Vilches, Class of 2007
-edited by Dr. Pam Mouser, ADDL Graduate Student

References:

Books

  1. Davis JK: 2006.  Notes from Purdue University SVM course VPB 540– Use and Care of Laboratory Animals. Spring, 2006

  2. Fox JG et al.:2002.  Laboratory Animal Medicine, 2nd ed. Academic Press.

  3. Hrapkiewicz K, L Medine, and DD Holmes: 2003  Clinical laboratory animal medicine: an introduc tion. 2nd ed. Iowa State University Press.

  4. Krauss H et al: 2003.  Zoonoses: infectious  diseases transmissible from animal to humans. 3rd ed. ASM Press.

  5. Murphy FA et al: 1999.  Veterinary Virology. 3rd ed. Academic Press

  6. Sirois M: 2005.  Laboratory Animal Medicine: Principles and Procedures.  Elsevier Mosby.

  7. Suckow MA, SH Weisbroth and CL Franklin: 2006.  The laboratory rat.  Elsevier


 Scientific journals:

  1. Barton LL, CJ Peters and TG Ksiazek: 1995. Lymphocytic choriomeningitis virus: an unrecognized teratogenic pathogen.  Emerging Infectious Diseases 1(4): 152-153.

  2. Lehmann-Grube F and J Lohler: 1981.  Immunopathologic alterations of lymphatic tissues of mice infected with lymphocytic choriomeningitis virus. II.  Pathogenic mechanism.  Laboratory  Investigation 44(3): 205-213.

  3. Lohler J and F Lehmann-Grube.  Immuno-pathologic alterations of lymphatic tissues of mice infected with lymphocytic choriomeningitis virus. I. Histologic findings. Laboratory Investigation 44(3): 193-204.

  4. Nicklas W et al: 1999.  Implications of infectious agents on results of animal experiments.  Laboratory Animals 33 (Supplement):39-87.

  5.  Parker JC et al: 1976.  Lymphocytic chorio-meningitis virus infection in fetal, newborn, and adult Syrian hamsters (Mesocricetus auratus)  Infection and Immunity 13(3): 967-981.

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