Human platelet-mediated cytotoxicity against Toxoplasma gondii: role of thromboxane.

Abstract

Human platelets, in the absence of antibody, are cytotoxic to tachyzoites of Toxoplasma gondii as determined by vital staining, transmission electron microscopy, and the failure of Toxoplasma to survive and replicate in mice after in vitro interaction of the organisms with platelets. Platelet to T. gondii ratios as low as 1:3 were toxic to the organisms with direct cell-cell contact essential for platelet-mediated cytotoxicity. Adherence of platelets to T. gondii and disruption of surface membranes and cytoplasmic contents of the organisms were observed ultrastructurally. Reactive oxygen species were not implicated in the platelet-mediated toxicity. The interaction of T. gondii with platelets resulted in a marked increase in thromboxane B2 (TXB2) production compared with that by unstimulated platelets. The cyclooxygenase inhibitors acetylsalicylic acid and indomethacin inhibited platelet-mediated cytolytic activity as did the selective TXA2 synthetase inhibitor dazmegrel, indicating a role for thromboxane in the platelet-induced cytotoxicity. Further, toxoplasmacidal activity was retained in the TXA2 synthetase-containing microsomal fractions of platelets disrupted by freezing and thawing; cytolytic activity was absent in microsome-depleted platelet supernatant fractions. Both the TXA2-generating platelet microsome system and a stable TXA2 analogue induced damage to the cellular membranes of the Toxoplasma as noted by transmission electron microscopy. These findings suggest that platelets may play a role in the host defense against Toxoplasma and that release of thromboxane may be important in this cytolytic process.

Toxoplasma gondii alters eicosanoid release by human mononuclear phagocytes: role of leukotrienes in interferon gamma-induced antitoxoplasma activity.

“…3). T. gondii incubated in buffer alone for 90 min release PGE2 (73.4 pg per 106 organisms in 90 min as we have previously reported [21]) but do not generate mono-HETEs or 5-1ipoxygenase products.…”

“…We recently reported that human platelets are cytotoxic to T. gondii tachyzoites, and TX release is important in this platelet-mediated toxoplasmacidal activity (21). Surface membrane vesiculation and cytoplasmic lysis in the T. gondii are prominent ultrastructural features of TXA2-induced injury (21). It is possible that TX generation by freshly isolated monocytes may contribute to the previously demonstrated (2) cytotoxic effect of these cells against T. gondii.…”

“…Similarly, we found that the monocytes after interaction with T. gondii primarily release TXB2. We recently reported that human platelets are cytotoxic to T. gondii tachyzoites, and TX release is important in this platelet-mediated toxoplasmacidal activity (21). Surface membrane vesiculation and cytoplasmic lysis in the T. gondii are prominent ultrastructural features of TXA2-induced injury (21).…”

“…gondii. The T. gondii RH strain was maintained by intraperitoneal passage in BALB/c mice (21). After lavage with Ca2+/Mg~+-free PBS, the peritoneal fluid was filtered through a 3-#m polycarbonate filter (Nucleopore Corp., Pleasanton, CA) to remove leukocytes.…”

Mechanisms of innate resistance toToxoplasma gondiiinfection

“…Nevertheless, this e¡ector mechanism cannot be identi¢ed in mice (Schwartzman et al 1990). Similarly, human platelets, via thromboxane production, have been shown to lyse parasitized cells (Yong et al 1991), although again a similar mechanism has not been identi¢ed in mice. However, depleting both wild-type mice and iNOSde¢cient mice of granulocytes, which have also been shown to have toxoplasmacidal activity in vitro (Wilson & Remington 1979), by using the RB6-8C5 antibody, results in signi¢cantly more rapid death in both the intraperitoneal (Scharton-Kersten et al 1997) and peroral routes of infection (P. Sayles, personal communication).…”