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Infection and Immunity, June 2008, p. 2352-2361, Vol. 76, No. 6
0019-9567/08/$08.00+0     doi:10.1128/IAI.01780-06
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Upregulation of Cytokines Is Detected in the Placentas of Cattle Infected with Neospora caninum and Is More Marked Early in Gestation When Fetal Death Is Observed

Veterinary Parasitology, Liverpool School of Tropical Medicine/Faculty of Veterinary Science, University of Liverpool, Pembroke Place, Liverpool L3 5QA, United Kingdom,¹ Department of Veterinary Pathology, Faculty of Veterinary Science, University of Liverpool, P.O. Box 147, Liverpool L69 7ZJ, United Kingdom,² Department of Veterinary Clinical Science, Veterinary Teaching Hospital, Leahurst, Neston CH64 7TE, United Kingdom,³ Institute for Animal Health, Compton, Berkshire RG20 7NN, United Kingdom⁴

Received 8 November 2006/ Returned for modification 30 December 2006/ Accepted 12 February 2008

The protozoan parasite Neospora caninum causes fetal death after experimental infection of pregnant cattle in early gestation, but the fetus survives a similar infection in late gestation. An increase in Th1-type cytokines in the placenta in response to the presence of the parasite has been implicated as a contributory factor to fetal death due to immune-mediated pathological alterations. We measured, using real-time reverse transcription-PCR and enzyme-linked immunosorbent assay, the levels of cytokines in the placentas of cattle experimentally infected with N. caninum in early and late gestation. After infection in early gestation, fetal death occurred, and the levels of mRNA of both Th1 and Th2 cytokines, including interleukin-2 (IL-2), gamma interferon (IFN-), IL-12p40, tumor necrosis factor alpha (TNF-), IL-18, IL-10, and IL-4, were significantly (P < 0.01) increased by up to 1,000-fold. There was extensive placental necrosis and a corresponding infiltration of CD4⁺ T cells and macrophages. IFN- protein expression was also highly increased, and a modest increase in transforming growth factor β was detected. A much smaller increase in the same cytokines and IFN- protein expression, with minimal placental necrosis and inflammatory infiltration, occurred after N. caninum infection in late gestation when the fetuses survived. Comparison of cytokine mRNA levels in separated maternal and fetal placental tissue that showed maternal tissue was the major source of all cytokine mRNA except for IL-10 and TNF-, which were similar in both maternal and fetal tissues. These results suggest that the magnitude of the cytokine response correlates with but is not necessarily the cause of fetal death and demonstrate that a polarized Th1 response was not evident in the placentas of N. caninum-infected cattle.

Published ahead of print on 24 March 2008.

Editor: J. F. Urban, Jr.