John E. Coe

The Hamster as a Model of Human Visceral Leishmaniasis: Progressive Disease and Impaired Generation of Nitric Oxide in the Face of a Prominent Th1-Like Cytokine Response

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-γ, 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-β. 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.

Hamster female protein, a sex-limited pentraxin, is a constituent of Syrian hamster amyloid.

Female protein (FP) is a pentraxin of Syrian hamster which is a homologue of two human pentraxins, C-reaction protein (CRP) and amyloid P component (AP). Functionally, FP has been shown to be similar to CRP, although FP has more homology at the amino terminus with AP. The present work investigated amyloid in the Syrian hamster to determine whether FP was involved in a manner analogous to AP. FP was found to be a constituent of Syrian hamster amyloid. This conclusion was based on the following results: (a) FP was consistently detected in amyloid deposits by fluorescent microscopy with specific antisera; (b) The amount of FP extractable from hamster livers directly correlated with the presence of amyloid; and (c) 125I-FP injected intravenously into amyloidotic hamsters rapidly left the intravascular compartment and was found subsequently in amyloid deposits. This unusual alteration of plasma metabolism and amyloid localization of 125I-FP was a characteristic finding in amyloidotic hamsters and was specific for 125I-FP. Therefore, as an amyloid component, FP appears to be functionally similar to human AP. However, FP synthesis is under sex steroid control and the unique sex-limited expression of this pentraxin was associated with an equally novel propensity for deposition of amyloid in female hamsters under normal or experimental conditions. Thus, a high serum level of FP, as found in normal females or diethylstilbestrol-treated males, was associated with enhanced amyloidosis. Although speculative at present, a primary role for serum FP in hamster amyloid deposition may be experimentally approachable by hormonal manipulation of FP synthesis.

Serological Evidence for an Inflammatory Response in Murine Scrapie

Transmissible spongiform encephalopathies (TSEs) are initiated by a novel kind of agent that produces characteristic degenerative changes in the brain without a detectable systemic inflammatory response or serological changes. A murine scrapie model was evaluated for changes in plasma concentration of serum amyloid P component (SAP), a protein that is up-regulated in infected and/or injured mice during the acute phase response (APR). C57BL10 and IRW mice inoculated with scrapie brain developed clinical scrapie 125-150 days later. At this time, concentration of plasma SAP increased in most of them. The SAP level increased > or =3-fold in >80% of the scrapie-affected C57BL10 mice and IRW male mice. A similar increase was found in <3% of respective nonscrapie control mice. The up-regulation of mouse SAP during clinical scrapie provides evidence for the activation of a systemic APR in TSE, a serological change that may be clinically useful.