Acute cerebral toxoplasmosis is induced by in vivo neutralization of TNF-alpha and correlates with the down-regulated expression of inducible nitric oxide synthase and other markers of macrophage activation.
C57BL/6 mice infected with the ME-49 strain of Toxoplasma gondii develop a progressive encephalitis culminating in 100% mortality between 12 and 15 wk after intraperitoneal inoculation of the parasite. Moreover, when injected at 4 wk after infection with anti-IFN-gamma mAb, progression of toxoplasmic encephalitis is markedly accelerated, resulting in death of the animals by 9 to 12 days posttreatment. In this study, we investigated the expression of mRNAs encoding cytokines as well as lymphocyte and macrophage markers during the development of toxoplasmic encephalitis. High levels of lymphocyte CD4 and CD8 surface Ag transcript were detected in the brains of mice throughout the infection. In addition from 2 to 4 wk we found elevations of Th1 (IFN-gamma and IL-2) but not of Th2 (IL-4 and IL-5) cytokine mRNAs. The elevation in Th1 cytokines was accompanied by increases in the expression of monokine (IL-1, IL-6, IL-10, granulocyte macrophage-colony stimulating factor [GM-CSF], and TNF-alpha) mRNAs, as well as markers expressed by activated macrophages (major histocompatibility class II [Ia], inducible nitric oxide synthase [iNOS] and macrophage activation gene 1 [Mag-1]). Interestingly, after 8 wk of infection with T. gondii we observed a dramatic decrease of Th1 cytokine and most monokine (IL-1, IL-6, GM-CSF, and TNF-alpha) as well as Mag-1 and iNOS mRNA levels. This down-regulation was associated with enhanced necrosis and neutrophilic infiltrates in the brain accompanied by increased expression of genes expressed specifically by the tachyzoite stage of T. gondii (T. gondii surface antigen 1 [SAG-1] and T. gondii surface antigen 2 [SAG-2]). Similarly, in mice chronically infected with T. gondii and treated with anti-IFN-gamma mAb the resulting pathology was associated with decreased expression of TNF-alpha and iNOS and increased expression of SAG-1 and SAG-2. Moreover, treatment with anti-TNF-alpha mAb also resulted in enhanced pathology, which correlated with low levels of iNOS mRNA and high levels of tachyzoite-specific mRNAs. Together these results suggest that reactivation of T. gondii results from a down-regulation of IFN-gamma and TNF-alpha expression leading to decreased macrophage or microglial cell activation, release of parasite growth, and subsequent tissue damage.
Gazzinelli
R T
RT
Immunology and Cell Biology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Eltoum
I
I
Wynn
T A
TA
Sher
A
A
D000208:Acute Disease; D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis*; D000818:Animals; D001483:Base Sequence; D016207:Cytokines / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000502:physiology; D008262:Macrophage Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D019001:Nitric Oxide Synthase; D016781:Toxoplasmosis, Cerebral / Q000209:etiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases