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*
Department of Molecular Microbiology and
Division of Comparative Medicine, Washington University School of Medicine, St. Louis, MO 63110; and
Division of Infectious Diseases, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262
Virulence in Toxoplasma gondii is strongly
influenced by the genotype of the parasite. Type I strains uniformly
cause rapid death in mice regardless of the host genotype or the
challenge dose. In contrast, the outcome of infections with type II
strains is highly dependent on the challenge dose and the genotype of
the host. To understand the basis of acute virulence in toxoplasmosis,
we compared low and high doses of the RH strain (type I) and the
ME49/PTG strain (type II) of T. gondii in outbred mice.
Differences in virulence were reflected in only modestly different
growth rates in vivo, and both strains disseminated widely to different
tissues. The key difference in the virulent RH strain was the ability
to reach high tissue burdens rapidly following a low dose challenge.
Lethal infections caused by type I (RH) or type II (PTG) strain
infections were accompanied by extremely elevated levels of Th1
cytokines in the serum, including IFN-
, TNF-
, IL-12, and IL-18.
Extensive liver damage and lymphoid degeneration accompanied the
elevated levels of cytokines produced during lethal infection.
Increased time of survival following lethal infection with the RH
strain was provided by neutralization of IL-18, but not TNF- or
IFN-. Nonlethal infections with a low dose of type II PTG strain
parasites were characterized by a modest induction of Th1 cytokines
that led to control of infection and minimal damage to host tissues.
Our findings establish that overstimulation of immune responses that
are normally necessary for protection is an important feature of acute
toxoplasmosis.
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