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Departments of
*Pathology and
Medicine, Albert Einstein College of Medicine, Bronx, NY 10461
The apicomplexan parasite Toxoplasma gondii expands during acute infection via a cycle of invasion, intracellular replication, and lytic egress. Physiological regulation has not yet been demonstrated for either invasion or egress. We now report that, in contrast to cell culture systems, in which egress occurs only after five or more parasite divisions (2–3 days), intracellular residence is strikingly abbreviated in inflammatory cells in vivo, and early egress (after zero to two divisions) is the dominant parasite fate in acutely infected mice. Adoptive transfer experiments demonstrate rapid, reciprocal, kinetically uniform parasite transfer between donor and recipient compartments, with a t1/2 of 
3 h. Inflammatory macrophages are major participants in this cycle of lytic egress and reinfection, which drives rapid macrophage turnover. Inflammatory triggering cells, principally macrophages, elicit egress in infected target macrophages, a process we term externally triggered egress (ETE). The mechanism of ETE does not require reactive oxygen or nitrogen species, the mitochondrial permeability transition pore, or a variety of signal transduction mediators, but is dependent on intracellular calcium and is highly sensitive to SB203580, an inhibitor of p38 MAPK as well as a related parasite-encoded kinase. SB203580 both inhibited the initiation of ETE and altered the progression of egress. Parasites recently completing a cycle of egress and reinfection were preferentially restricted in vivo, supporting a model in which ETE may favor host defense by a process of haven disruption. ETE represents a novel example of interaction between a parasite infectious cycle and host microenvironment.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by funds from National Institutes of Health Grants AI-55358 (to A.O.) and AI-39454 (to L.M.W.), and by the Flow Cytometry Core of the Center for AIDS Research (AI-51519).
2 Address correspondence and reprint requests to Dr. Amos Orlofsky, Albert Einstein College of Medicine, Golding 704, 1300 Morris Park Avenue, Bronx, NY 10461. E-mail address: orlofsky{at}aecom.yu.edu
3 Abbreviations used in this paper: ETE, externally triggered egress; DAP, donor cell-associated parasite; ECFP, enhanced cyan fluorescent protein; L-NIL, N-iminoethyl-L-lysine; moi, multiplicity of infection; NDAP, non-donor cell-associated parasite; PEM, peritoneal exudate macrophage; PPADS, pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate; WT-RH, wild-type RH strain; YFP, yellow fluorescent protein.
4 The online version of this article contains supplemental material.
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