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Infect Immun, March 1998, p. 1208-1215, Vol. 66, No. 3
Max Planck Institute for
Immunobiology1 and
Department of
Pathology,
Received 23 September 1997/Returned for modification 24 November
1997/Accepted 19 December 1997
Trypanosoma cruzi, the causative agent of Chagas'
disease, induces an innate and adaptive host immune response during the acute phase of infection. These responses were analyzed by comparing mouse lines deficient for the gamma interferon (IFN-
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Copyright © 1998, American Society for Microbiology. All rights reserved.
Defective Nitric Oxide Effector Functions Lead to
Extreme Susceptibility of Trypanosoma cruzi-Infected Mice
Deficient in Gamma Interferon Receptor or Inducible Nitric Oxide
Synthase
) receptor (IFN-
R
/
) or deficient for inducible nitric oxide
synthase (iNOS
/
). Both lines were highly susceptible,
with similar and dramatically increased parasite burdens and severe
histopathology and were incapable of surviving even very low doses,
exhibiting similar mortality kinetics. This pathophysiological
correlation has a common cause, since both mutant mouse strains were
unable to respond to infection by producing nitric oxide (NO) with the
consequence that mutant macrophages had impaired trypanocidal
activities. These in vivo and subsequent in vitro studies further
demonstrated that an IFN-
-dependent pathway of iNOS induction is
crucial for efficient NO production and mandatory for resisting acute
infection with T. cruzi. Despite this defect, both mutant
mouse strains had a rather normal proinflammatory cytokine response
(interleukin-12 [IL-12], IFN-
, IL-6), with the exception of an
impaired tumor necrosis factor alpha and IL-1
response in
IFN-
R
/
mice, demonstrating that only the latter two
cytokines are dependent on IFN-
activation. Moreover, polarization
of T cells in type 1 and type 2 T-helper (Th1/Th2) and cytotoxic T
(Tc1/Tc2) cells as well as T. cruzi-specific antibody
responses were normal in IFN-
R
/
mice, demonstrating
that IFN-
is not necessary for the promotion of T-cell
differentiation and T. cruzi-specific antibody responses.
*
Corresponding author. Mailing address: Department of
Immunology, University of Cape Town, H53, H Floor, Old Main Building, Groote Schoor Hospital, Observatory, Cape Town 7925, South Africa. Phone: 27-21/406-6147. Fax: 27-21/448-6116. E-mail:
fbrombac{at}samiot.uct.act.za.
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