Acute toxoplasmosis leads to lethal overproduction of Th1 cytokines

Virulence in Toxoplasma gondii is strongly influenced by the genotype of th e parasite. Type I strains uniformly cause rapid death in mice regardless o f the host genotype or the challenge dose. In contrast, the outcome of infe ctions with type II strains is highly dependent on the challenge dose and t he genotype of the host. To understand the basis of acute virulence in toxo plasmosis, 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 vir ulence were reflected in only modestly different growth rates in vivo, and both strains disseminated widely to different tissues. The key difference i n the virulent RH strain was the ability to reach high tissue burdens rapid ly following a low dose challenge. Lethal infections caused by type I (RH) or type II (PTG) strain infections were accompanied by extremely elevated l evels of Th1 cytokines in the serum, including IFN-gamma, TNF-alpha, IL-12, and IL-18. Extensive liver damage and lymphoid degeneration accompanied th e 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-alpha or IFN-gamma. Nonlethal infe ctions with a low dose of type II PTG strain parasites were characterized b y 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 impor tant feature of acute toxoplasmosis.