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Date of Award

9-1979

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Medical Sciences

Supervisor

William E. Rawls

Abstract

Pichinde virus, a member of the arenaviridiae, causes a fatal disease when injected intraperitoneally into the inbred MHA strain of hamsters, but not in other strains. The fatal infection is associated with an inability to limit virus replication, and death appears to be a consequence of the virus-induced cytopathic effect within the reticuloen-dothelial system. The purpose of the current studies was to determine whether susceptibility to the lethal Pichinde virus infection was genetically acquired, and to obtain an understanding of the basis for this susceptibility.

Studies on survival and the ability to limit viremia following Pichinde virus infection in F₁ and back-cross progeny gave the results expected if a single autosomal dominant gene or linked genes were responsible for each of these phenotypes.

Initial Studies on the basis for the susceptibility of MHA hamsters to fatal Pichinde virus infections were designed to test the hypothesis that this strain was unable to mount a cell-mediated immune response against the virus. However, MHA hamsters were able to limit Pichinde virus replication and they survived the infection when the virus was inoculated by the footpad route. Furthermore, footpad-immunized MHA hamsters survived a normally lethal intraperitoneal challenge of Pichinde virus. These observations suggested that susceptible MHA hamsters were able to produce a protective immune response when the virus was given by this route.

Since cells of the reticuloendothelial system appeared to be a major target for Pichinde virus replications in vivo, a search for a target cell difference within the spleens of susceptible and resistant hamsters were undertaken. No difference in the ability of various spleen cell fractions from susceptible or resistant hamsters to support Pichinde virus growth in vitro could be demonstrated. However, the spleens of MHA hamsters which had been infected with Pichinde virus in vivo contained 10-fold more virus-producing cells at three days after infection than did spleens of resistant hamsters. The majority of the virus-producing cells in MHA hamster spleens were associated with the non-adherent fraction which sedimented at a rate typical of lymphocytes. In contrast, spleen cells from the resistant LSH strain of hamsters appeared to be deficient in this population. These observations support the hypothesis that the susceptible strain of hamsters had a spleen target cells for Pichinde virus replication which the resistant strain lacked.

Interestingly, the putative target cell was observed to co-purify with a cell population which mediated in vitro cytotoxicity against syngenetic or allogeneic tumour target cells. The cytotoxic effector cell was shown to be a non-adherent, non-phagocytic, small- to medium-sized cell which lacked detectable surface immunoglobulin. The cytotoxic activity was labile at 37°C, but was not abrogated by pretreatment with amonium chloride. Thus, this hamster effector cells resembled the natural killer (NK) lymphocyte which has been described in several species. Susceptible MHA hamsters exhibited high levels of endogenous NK activity, and this cytotoxicity was further augmented by Pichinde virus infection. In contrast, the resistant LSH strain showed lower levels of endogenous cytotoxicity, and Pichinde virus infection did not induce the same magnitude of increase in activity. These results support the hypothesis that susceptible MHA hamsters have an additional splenic target cell for Pichinde virus replication which the resistant strain lacks, and are consistant with the possibility that his target cells is in fact the NK cell.

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