Date of Award

8-1982

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Medical Sciences

Supervisor

Dr. William E. Rawls

Abstract

The arenaviridae are a group of enveloped, negative-stranded RNA viruses. These viruses characteristically produce persistent infections in their natural host, which is how they are maintained in nature. Experimentally-induced arenavirus disease has been found to possess similar pathological features of human disease. In the inbred MHA strain of Syrian hamster, Pichinde virus causes a fatal infection when inoculated intraperitoneally. Investigation of the factors leading to a fatal Pichinde virus disease in Syrian hamsters revealed that susceptibility was genetically determined. Susceptibility of MHA hamsters to a lethal infection of the virus appeared to be related to the presence of a splenic target cell for Pichinde virus replication that was minimally expressed in resistant hamster strains. In addition, during studies on cell-mediated immune responses to Pichinde virus antigens, it was discovered that MHA hamsters survived infection when the virus was given in the footpad. However, unlike the resistant LSH and LVG strain hamsters, the MHA hamsters did not manifest a footpad swelling response.

The present studies were initiated to determine some characteristics and possible mechanism(s) underlying the lack of footpad swelling response to a primary inoculation of Pichinde virus in the MHA strain hamster. MHA unresponsiveness was not due to a lack of immune recognition of Pichinde virus antigens, since this strain was shown to produce complement-fixing antibodies to Pichinde virus. Furthermore, footpad-inoculated MHA hamsters were protected against a subsequent intraperitoneal challenge with Pichinde virus.

Experiments designed to elucidate the genetic basis for presence or absence of footpad swelling revealed that expression of footpad swelling to Pichinde virus was a dominant trait controlled by a single gene or closely linked genes. Furthermore, the lack of responsiveness in MHA hamsters appeared to be specific for Pichinde virus, since footpad swelling could be elicited in this strain by footpad injection of either vaccinia virus or vesicular stomatitis virus. Histological analysis of the virus-injected footpad showed that footpad swelling was associated with an influx of mononuclear cells at the site of injection. These observations suggested that MHA unresponsiveness could not have been caused by a general defect in effector mechanisms that mediate the footpad swelling response.

A search for Pichinde virus-induced suppressor activity was then undertaken. Treatment of MHA hamsters with cyclophosphamide, a drug known to augment delayed hypersenstivity responses by inhibiting suppressor cell activity resulted in a significant footpad swelling response following Pichinde virus injection. Furthermore, transfer of lymphoid cells but not serum from 5 day footpad-inoculated MHA hamsters could specifically suppress footpad swelling to Pichinde virus in the LSH recipient.

Aqother parameter of cell-mediated immunity studied was the generation of cytotoxic cells. Pichinde virus primed MHA and LSH hamsters were capable of generating cytotoxic cells, after restimulation in vitro with virus but the cytotoxicity lacked specificity. When spleen cells from 7 day footpad-inoculated MHA hamsters were added to spleen cells from LSH hamsters, the cytotoxic activity of the latter cells was significantly suppressed.

These results taken together suggested that the absence of footpad swelling in the MHA strain hamster was caused by the generation of a cell-associated suppressor mechanism that appeared to be induced specifically by Pichinde virus.

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