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Infection and Immunity, December 2007, p. 5806-5818, Vol. 75, No. 12
0019-9567/07/$08.00+0     doi:10.1128/IAI.01005-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Macrophage-Mediated but Gamma Interferon-Independent Innate Immune Responses Control the Primary Wave of Plasmodium yoelii Parasitemia{triangledown}

Kevin N. Couper,1 Daniel G. Blount,1 Julius C. R. Hafalla,1 Nico van Rooijen,2 J. Brian de Souza,1,3 and Eleanor M. Riley1*

Immunology Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom,1 Department of Molecular Cell Biology, Vrije Universiteit, Amsterdam, The Netherlands,2 Department of Immunology and Molecular Pathology, University College London Medical School, 46 Cleveland Street, London W1T 4JF, United Kingdom3

Received 23 July 2007/ Returned for modification 11 September 2007/ Accepted 29 September 2007

In most models of blood-stage malaria infection, proinflammatory immune responses are required for control of infection and elimination of parasites. We hypothesized therefore that the fulminant infections caused in mice by the lethal strain of Plasmodium yoelii (17XL) might be due to failure to activate a sufficient inflammatory response. Here we have compared the adaptive CD4+ T-cell and innate immune response to P. yoelii 17XL with that induced by the self-resolving, nonlethal strain of P. yoelii, 17X(NL). During the first 7 to 9 days of infection, splenic effector CD4+ T-cell responses were similar in mice with lethal and nonlethal infections with similar levels of activation in vivo and equivalent proliferation in vitro following mitogenic stimulation. Nonspecific T-cell hyporesponsiveness was observed at similar levels during both infections and was due, in part, to suppression mediated by CD11b+ cells. Importantly, however, RAG–/– mice were able to control the initial growth phase of nonlethal P. yoelii infection as effectively as wild-type mice, indicating that T cells and/or B cells play little, if any, role in control of the primary peak of parasitemia. Somewhat unexpectedly, we could find no clear role for either NK cells or gamma interferon (IFN-{gamma}) in controlling primary P. yoelii infection. In contrast, depletion of monocytes/macrophages exacerbated parasite growth and anemia during both lethal and nonlethal acute P. yoelii infections, indicating that there is an IFN-{gamma}-, NK cell-, and T-cell-independent pathway for induction of effector macrophages during acute malaria infection.

* Corresponding author. Mailing address: Immunology Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom. Phone: (44) 207 927 2706. Fax: (44) 207 927 2807. E-mail: eleanor.riley{at}lshtm.ac.uk

{triangledown} Published ahead of print on 8 October 2007.

Editor: W. A. Petri, Jr.

Infection and Immunity, December 2007, p. 5806-5818, Vol. 75, No. 12
0019-9567/07/$08.00+0     doi:10.1128/IAI.01005-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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