Immune responses of the host

Arenaviruses are generally carried by rodents with little ill-effect to the carrier; however, transmission from rodents to primates can cause severe encephalitis, hepatitis or hemorrhagic syndrome. Thus, rodent and humans can have drastically different immunologic and pathologic responses to infection. We will describe the classical studies of cell-mediated immunopathology in the LCMV/murine model with the caveat that it does not apply to arenavirus disease in primates.

LCMV was first isolated in the early 1930s from a man who died of encephalitis in St Louis, Missouri. It was never entirely clear whether the virus came from the deceased person or from the laboratory mice used for passage, because similar stocks of LCMV were isolated from mice in other laboratories around the same time. Electron microscopy and serological studies confirmed the familial relatedness of the various laboratory isolates and some new viruses from outbreaks in Africa (Lassa virus) and South America (Machupo and Junin).

Ever since the 1960s, LCMV was used to study virus-induced cell-mediated immunity. There are two types of murine infection: an acute infection that correlates with vigorous cell-mediated immunity (as measured by CTL assay) or a persistent infection that correlates with little cell-mediated immunity (Figure 2). The immune response to the acute infection either kills the mouse by engendering meningitis, or subsides and leaves the mouse LCMV-immune. Adoptive transfer of splenocytes from an LCMV-immune mouse can clear infection in a persistently infected mouse. Clearance is mediated by CDS" and not

Figure 1 The arenaviruses are noncyto-pathic and bud from the host cell. They have a granular appearance from which the name (L. arena, sandy) is derived. (Reproduced by permission from M Buchmeier, La Jolla, CA.)

CD4+ splenocytes, as shown by antibody depletion of lymphocyte subsets. In contrast to their beneficial effects in clearing virus infection, the CD8 ! cells mediate pathology (choriomeningitis) when injected intracerebrally. Thus the LCMV/murine model offered a paradigm for the positive and negative effects of CTL-mediated immunity. Even though LCMV has an acid-sensitive envelope, it has recently been shown to infect the gastric mucosa at very low doses; thus expanding its usefulness to studies of mucosal immunity.

LCMV-specific cell-mediated immunity was defined by studies with transgenic mice, synthetic peptides, and recombinant vaccinia expression vectors. BALB/c (H-2d) mice make a CTL response primarily to epitopes on the viral envelope, GP, whereas C3H (H-2b) mice respond primarily to epitopes on the NP. Synthetic peptides were used to define the most important residues for these CTL epitopes. Transgenic mice lacking CD8+ expression (either by CD8 gene knockout or by knockout of (3,-microglobulin) have greatly reduced CTL responses, resulting in virus persistence. Intracerebrally infected mice lacking CD8+ lymphocytes die later than normal mice, thus the CD8-mediated immunopathology is reduced but not entirely eliminated. Knockout mice lacking perforin are also unable to clear infections, indicating that virus clearance is dependent on the perforin-mediated destruction of virus-infected cells. Mice lacking CD4+ cells or B cells are able to clear virus-infected cells initially, but virus reappears and the mice then succumb to acute infection.

LCMV infection induces inflammatory intermediates such as interferon y (IFNy) and tumor necrosis factor a (TNFa), both of which influence the host's immune response to other pathogens. IFNy stimulates the proliferation of natural killer (NK) cells that serve to eliminate certain pathogen-infected cells and some tumors. TNFa produced in the liver as a result of LCMV infection can clear hepatitis B virus infection, even in perforin-negative mice, probably by

(Poor CTL response) (Vigorous CTL response) may kill mouse

Adoptive transfer of LCMV-immune mouse splenocytes

Persistent infection is cleared!

Figure 2 In the murine/LCMV model, acute and persistent infections are correlated with vigorous and poor virus-specific CTL responses, respectively. Acute infection generally requires an adult immunocompetent mouse, whereas persistent infection generally occurs in a neonatal or immunosuppressed mouse, or in an adult mouse given an immunosuppressive variant of LCMV. Vigorous CTL response can mediate lethal immunopathology, but adoptive transfer of CTL can also mediate virus clearance.

Adoptive transfer of LCMV-immune mouse splenocytes

Persistent infection is cleared!

inducing an RNase that destroys the hepatitis viral nucleic acid.

Junin, Machupo and Lassa viruses can cause hemorrhagic fever in primates, the severity of which is directly proportional to virus titer. Arenavirus disease in primates is not alleviated by immunosuppressive cyclophosphamide. The Junin and Machupo diseases are primarily treated with convalescent serum, whereas Lassa disease is primarily treated with ribavirin, since antisera are only effective early in the disease.

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