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,
*
Medical Service, Department of Veterans Affairs Medical Center, South Texas Veterans Health Care System, San Antonio, TX 78284;
Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78284;
Department of Microbiology, University of Texas Health Science Center, San Antonio, TX 78284; and
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT 59840
Active human visceral leishmaniasis (VL) is characterized by a
progressive increase in visceral parasite burden, cachexia, massive
splenomegaly, and hypergammaglobulinemia. In contrast, mice infected
with Leishmania donovani, the most commonly studied
model of VL, do not develop overt, progressive disease. Furthermore,
mice control Leishmania infection through the generation
of NO, an effector mechanism that does not have a clear role in human
macrophage antimicrobial function. Remarkably, infection of the Syrian
hamster (Mesocricetus auratus) with L.
donovani reproduced the clinicopathological features of human
VL, and investigation into the mechanisms of disease in the hamster
revealed striking differences from the murine model. Uncontrolled
parasite replication in the hamster liver, spleen, and bone marrow
occurred despite a strong Th1-like cytokine (IL-2, IFN-
, and
TNF/lymphotoxin) response in these organs, suggesting impairment of
macrophage effector function. Indeed, throughout the course of
infection, inducible NO synthase (iNOS, NOS2) mRNA or enzyme activity
in liver or spleen tissue was not detected. In contrast, NOS2 mRNA and
enzyme activity was readily detected in the spleens of infected mice.
The impaired hamster NOS2 expression could not be explained by an
absence of the NOS2 gene, overproduction of IL-4, defective
TNF/lymphotoxin production (a potent second signal for NOS2 induction),
or early dominant production of the deactivating cytokines IL-10 and
TGF-
. Thus, although a Th1-like cytokine response was prominent, the
major antileishmanial effector mechanism that is responsible for
control of infection in mice was absent throughout the course of
progressive VL in the hamster.
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