The aim of this study was the analysis of the cytokine response in BALB/c mice infected with the highly virulent RH or the weakly virulent Beverley strains of Toxoplasma gondii. Analysis of cytokine messages showed increased expression of IL12, IFN-γ and TNF-α, but not IL4 mRNAs in spleen cells after infection with the T. gondii strains RH and Beverley. High levels of circulating IL12 and IFN-γ were detected in the serum of mice infected with strain RH, although TNF-α levels remained low. In contrast, the same cytokines were detected at only low levels in the serum of mice infected with the Beverley strain. Administration of antibody against IL12 or IFN-γ significantly delayed time to death of mice infected with strain RH compared to controls. T-Cell-deficient as well as normal mice were equally infected by strain RH, suggesting that T lymphocytes do not contribute to the response. Depletion of natural killer cells from the splenocyte population abolished the in vitro production of IFN-γ. Together, our data suggest that the virulent strain RH induces in BALB/c mice a type 1 cytokine pattern with T-cell-independent overproduction of IL12 and IFN-γ that may be involved in the pathogenesis of this micro-organism.
AfonsoL. C. C,
SchartonT. M,
VieiraL. Q,
WysockaM,
TrinchieriG,
ScottP.1994; The adjuvant effect of interleukin-12 in a vaccine against Leishmania major . Science 263:235–237[CrossRef]
AraujoM. I,
BlissS. K,
SuzukiY,
AlcarazA,
DenkersE. Y,
PearceE. J.2001; Interleukin-12 promotes pathologic liver changes and death in mice coinfected with Schistosoma mansoni and Toxoplasma gondii . Infect immun 69:1454–1462[CrossRef]
BurkeJ. M,
RobertsC. W,
HunterC. A,
MurrayM,
AlexanderJ.1994; Temporal differences in the expression of mRNA for IL-10 and IFN-γ in the brains and spleens of C57BL/10 mice infected with Toxoplasma gondii . Parasite Immunol 16:305–314[CrossRef]
CoutelierJ.-P,
van der LogtJ. T. M,
HeessenF. W. A,
WarnierG,
Van SnickJ.1986a; Rheumatoid factor production in 129/sv mice: involvement of an intestinal infectious agent. J Immunol 137:337–340
CoutelierJ.-P,
Van RoostE,
LambotteP,
Van SnickJ.1986b; The murine antibody response to lactate dehydrogenase-elevating virus. J Gen Virol 67:1099–1108[CrossRef]
EhlersS,
KutschS,
EhlersE. M,
BeniniJ,
PfefferK.2000; Lethal granuloma disintegration in mycobacteria-infected TNFRp55-/- mice is dependent on T cells and IL-12. J Immunol 165:483–492[CrossRef]
FiorentinoB. F,
BondM. W,
MosmannT. R.1989; Two types of mouse T helper cell.IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med 170:2081–2095[CrossRef]
GajewskiT. F,
FitchF. W.1988; Anti-proliferative effect of IFN-γ in immune regulation.I. IFN-γ inhibits the proliferation of Th2 but not Th1 murine helper T lymphocyte clones. J Immunol 140:4245–4252
GazzinelliR. T,
HakimF. T,
HienyS,
ShearerG. M,
SherA.1991; Synergistic role of CD4+ and CD8+ T lymphocytes in IFN-γ production and protective immunity induced by an attenuated Toxoplasma gondii vaccine. J Immunol 146:286–292
GazzinelliR. T,
XuY,
HienyS,
CheeverA,
SherA.1992; Simultaneous depletion of CD4+ and CD8+ T lymphocytes is required to reactivate chronic infection with Toxoplasma gondii . J Immunol 149:175–180
GazzinelliR. T,
HienyS,
WynnT,
WolfS,
SherA.1993a; Interleukin-12 is required for the T-cell-independent induction of interferon-γ by an intracellular parasite and induces resistance in T-cell-deficient hosts. Proc Natl Acad Sci U S A 90:6115–6119[CrossRef]
GazzinelliR. T,
EltoumI,
WynnT. A,
SherA.1993b; Acute cerebral toxoplasmosis is induced by in vivo neutralization of TNF-α and correlates with the down-regulated expression of inducible nitric oxide synthase and other markers of macrophage activation. J Immunol 151:3672–3681
GazzinelliR. T,
WysockaM,
HienyS,
Scharton-KerstenT,
CheeverA,
KuhnR,
MullerW,
TrinchieriG,
SherA.1996; In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-γ and TNF-α. J Immunol 157:798–805
HeinzelF. P,
RerkoR. M,
LingP,
HakimiJ,
SchoenhautD. S.1994; Interleukin-12 is produced in vivo during endotoxemia and stimulates synthesis of gamma interferon. Infect Immun 62:4244–4249
HeremansH,
Van DammeJ,
DillenC,
DijkmansR,
BilliauA.1990; Interferon gamma, a mediator of lethal lipopolysaccharide-induced Schwartzman-like shock reactions in mice. J Exp Med 171:1853–1869[CrossRef]
HisaedaH,
SakaiT,
IshikawaH,
MaekawaY,
YasutomoK,
GoodR. A,
HimenoK.1997; Heat shock protein 65 induced by γδ T cells prevents apoptosis of macrophages and contributes to host defense in mice infected with Toxoplasma gondii . J Immunol 159:2375–2381
Markine-GoriaynoffD,
van der LogtJ. T. M,
TruyensC,
NguyenT. D,
HeessenF. W. A,
BigaignonG,
CarlierY,
CoutelierJ.-P.2000; IFN-γ-independent IgG2a production in mice infected with viruses and parasites. Int Immunol 12:223–230[CrossRef]
Markine-GoriaynoffD,
NguyenT. D,
BigaignonG,
Van SnickJ,
CoutelierJ.-P.2001; Distinct requirements for IL-6 in polyclonal and specific Ig production induced by microorganisms. Int Immunol 13:1185–1192[CrossRef]
MonteyneP,
RenauldJ.-C,
Van BroeckJ,
DunneD. W,
BrombacherF,
CoutelierJ.-P.1997; IL-4 independent regulation of in vivo IL-9 expression. J Immunol 159:2616–2623
MosmannT. R,
CherwinskiH,
BondM. W,
GiedlinM. A,
CoffmanR. L.1986; Two types of murine helper T cell clone.I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136:2348–2357
NeyerL. E,
GrunigG,
FortM,
RemingtonJ. S,
RennickD,
HunterC. A.1997; Role of interleukin-10 in regulation of T-cell-dependent mechanisms of resistance to Toxoplasma gondii. Infect Immun 65:1675–1682
NguyenB. T,
StadtsbaederS.1983; Comparative effects of cotrimoxazole (trimethoprim-sulphamethoxazole), pyrimethamine-sulphadiazine and spiramycin during avirulent infection with Toxoplasma gondii (Beverley strain) in mice. Br J Pharmacol 79:923–928[CrossRef]
NguyenT. D,
De KeselM,
BigaignonG,
HoetP,
PazzagliaG,
LammensM,
DelméeM.1996; Detection of Toxoplasma gondii tachyzoites and bradyzoites in blood, urine, and brains of infected mice. Clin Diagn Lab Immunol 3:635–639
OzmenL,
PericinM,
HakimiJ,
ChizzoniteR. A,
WysockaM,
TrinchieriG,
GatelyM,
GarottaG.1994; Interleukin 12, interferon-γ, and tumour necrosis factor-α are the key cytokines of the generalized Schwartzman reaction. J Exp Med 180:907–915[CrossRef]
ScottP,
NatovitzP,
CoffmanR. L,
PearceE,
SherA.1988; Immunoregulation of cutaneous leishmaniasis.T cell lines that transfer protective immunity or exacerbation belong to different T helper subsets and respond to distinct parasite antigens. J Exp Med 168:1675–1684[CrossRef]
SuzukiY,
YangQ,
YangS,
NguyenN,
LimS,
LiesenfeldO,
KojimaT,
RemingtonJ. S.1996; IL-4 is protective against development of toxoplasmic encephalitis. J Immunol 157:2564–2569
SuzukiY,
SherA,
YapG,
ParkD,
NeyerL. E,
LiesenfeldO,
FortM,
KangH,
GufwoliE.2000; IL-10 is required for prevention of necrosis in the small intestine and mortality in both genetically resistant BALB/c and susceptible C57BL/6 mice following peroral infection with Toxoplasma gondii . J Immunol 164:5375–5382[CrossRef]
VillardO,
CandolfiE,
DespringreJ. L,
DerouinF,
MarcellinL,
VivilleS,
KienT.1995; Protective effect of low doses of an anti-IL-4 monoclonal antibody in a murine model of acute toxoplasmosis. Parasite Immunol 17:233–236[CrossRef]
WalkerW,
RobertsC. W,
FergusonD. J. P,
JebbariH,
AlexanderJ.1997; Innate immunity to Toxoplasma gondii is influenced by gender and is associated with differences in interleukin-12 and gamma interferon production. Infect Immun 65:1119–1121
WilleU,
VillegasE. N,
StriepenB,
RoosD. S,
HunterC. A.2001; Interleukin-10 does not contribute to the pathogenesis of a virulent strain of Toxoplasma gondii . Parasite Immunol 23:291–296[CrossRef]
WolfS. F,
TempleP. A,
KobayashiM.14 other authors1991; Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells. J Immunol 146:3074–3081
WysockaM,
KubinM,
VieiraL. Q,
OzmenL,
GarottaG,
ScottP,
TrinchieriG.1995; Interleukin-12 is required for interferon-γ production and lethality in lipopolysaccharide-induced shock in mice. Eur J Immunol 25:672–676[CrossRef]
YapG,
PesinM,
SherA.2000; Cutting edge: IL-12 is required for the maintenance of IFN-γ production in T cells mediating chronic resistance to the intracellular pathogen, Toxoplasma gondii . J Immunol 165:628–631[CrossRef]