Cell-Mediated Immunity toToxoplasma gondiiDevelops Primarily by Local Th1 Host Immune Responses in the Absence of Parasite Replication

Abstract

A single inoculation of mice with the live, attenuated Toxoplasma gondii uracil auxotroph strain cps1-1 induces long-lasting immunity against lethal challenge with hypervirulent strain RH. The mechanism for this robust immunity in the absence of parasite replication has not been addressed. The mechanism of long-lasting immunity, the importance of route of immunization, cellular recruitment to the site of infection, and local and systemic inflammation were evaluated. Our results show that infection with cps1-1 elicits long-lasting CD8+ T cell- mediated immunity. We show that immunization with cps1-1-infected dendritic cells elicits long-lasting immunity. Intraperitoneal infection with cps1-1 induced a rapid influx of GR1+ neutrophils and two stages of GR1+CD68+ inflammatory monocyte infiltration into the site of inoculation. CD19+ B cells and CD3+ T cells steadily increase for 8 days after infection. CD8+ T cells were rapidly recruited to the site of infection and increased faster than CD4+ T cells. Surprisingly, cps1-1 infection induced high systemic levels of bioactive IL-12p70 and a very low level and transient systemic IFN-γ. Furthermore, we show significant levels of these inflammatory cytokines were locally produced at the site of cps1-1 inoculation. These findings offer new insight into immunological mechanisms and local host responses to a non-replicating type I parasite infection associated with development of long-lasting immunity to Toxoplasma gondii.

Nonreplicating, Cyst-Defective Type II Toxoplasma gondii Vaccine Strains Stimulate Protective Immunity against Acute and Chronic Infection

“…Type I uracil auxotroph vaccines were previously described to stimulate potent T cell-mediated immunity to virulent type I challenge infection (15,18,19,(21)(22)(23)(24). While the type I CPS uracil auxotroph vaccine also protected vaccinated mice from virulent type II challenge infection and reduced chronic infection (cyst burdens) by ϳ98%, vaccinated mice were incompletely protected from chronic infection (33).…”

“…Immunity elicited by vaccination with CPS requires production of interleukin-12 (IL-12) (24,25), IFN-␥ (15,19), and CD8 ϩ T cell populations (25,26), which possess cytolytic activity in vitro and in vivo (22). Previous studies have implicated a key role for active T. gondii invasion of host cells in mechanisms that promote T cell immunity to Toxoplasma (27)(28)(29).…”

“…Disruption of the orotidine 5=-monophosphate decarboxylase gene (OMPDC) in the virulent type I RH ⌬ku80 strain (17) also produced a nonreplicating uracil auxotroph mutant that elicited protective immunity to virulent acute infection (18). The extreme attenuation and avirulence of type I T. gondii uracil auxotrophs are exemplified by survival of severely immune-deficient IFN-␥ Ϫ/Ϫ knockout mice (15,18,19) and interleukin-2 receptor ␥ knockout (NOD/SCID/IL-2R␥ Ϫ/Ϫ ) mice (20) that were infected with high-dose challenges of CPS.…”

“…Disruption of the orotidine 5=-monophosphate decarboxylase gene (OMPDC) in the virulent type I RH ⌬ku80 strain (17) also produced a nonreplicating uracil auxotroph mutant that elicited protective immunity to virulent acute infection (18). The extreme attenuation and avirulence of type I T. gondii uracil auxotrophs are exemplified by survival of severely immune-deficient IFN-␥ Ϫ/Ϫ knockout mice (15, 18, 19) and interleukin-2 receptor ␥ knockout (NOD/SCID/IL-2R␥ Ϫ/Ϫ ) mice (20) that were infected with high-dose challenges of CPS.Vaccination with CPS elicits a lifelong CD8 ϩ T cell-dependent immunity against infection with type I strains (15,18,19,21,22 ϩ T cell responses and highly effective protective immunity to Toxoplasma (21).Previously, vaccination with CPS was shown to protect mice against a virulent acute infection after challenge with a type I or type II strain of T. gondii. However, this CPS vaccination did not completely prevent the development of cysts and chronic infection in mice that were challenged with a type II strain (33).…”

“…Vaccination with CPS elicits a lifelong CD8 ϩ T cell-dependent immunity against infection with type I strains (15,18,19,21,22 ϩ T cell responses and highly effective protective immunity to Toxoplasma (21).…”