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*
Institut für Neuropathologie, Universitätskliniken Bonn, Bonn, Germany;
Department CNS, F. Hoffmann-La Roche, Basel, Switzerland; and
Institut für Medizinische Mikrobiologie und Hygiene, Universität Heidelberg, Fakultät für Klinische Medizin, Mannheim, Germany
TNF-
exerts its biologic activity through two distinct
receptors, TNF receptor type 1 (TNFR1, p55) and TNF receptor type 2
(TNFR2, p75). To analyze their function in toxoplasmosis, we orally
infected mice genetically deficient for TNFR1
(TNFR10/0), TNFR2 (TNFR20/0), or both TNF
receptors (TNFR1/20/0), as well as wild-type (wt) mice with
a low-virulent strain of Toxoplasma gondii.
TNFR1/20/0 and TNFR10/0 mice succumbed to
toxoplasmosis within 17 and 27 days, respectively, whereas
TNFR20/0 and wt mice were equally resistant to acute
toxoplasmosis. Histopathology attributed death of
TNFR1/20/0 and TNFR10/0 mice to a fulminant
necrotizing encephalitis. In addition, pneumonia contributed to the
fatal outcome. The poor prognosis of TNFR1/20/0 and
TNFR10/0 mice was reflected by a significantly increased
parasitic load in the brain and lung as compared with
TNFR20/0 and wt mice. Immunohistochemistry demonstrated a
remarkable reduction of inducible nitric oxide synthase protein in
brain and lung of TNFR1/20/0 and TNFR10/0 as
compared with TNFR20/0 and wt mice. Reverse-transcribed PCR
showed that in contrast to TNFR20/0 and wt mice,
TNFR10/0 mice were unable to up-regulate inducible nitric
oxide synthase mRNA transcripts in the course of infection, whereas
intracerebral levels of IFN-
, TNF-, and IL-1ß mRNA transcripts,
recruitment of immune cells to the brain, and the amount of apoptotic
cells in inflammatory foci did not differ significantly among the
various experimental groups. These results illustrate that in
Toxoplasma encephalitis, TNF--mediated immune responses
are of crucial importance and that signaling through TNFR1, but not
TNFR2, provides the stimulus required for the induction of protective
nitric oxide.
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