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Type I IFNs Play a Role in Early Resistance, but Subsequent Susceptibility, to the African Trypanosomes¹

Rebecca Lopez^*, Karen P. Demick, John M. Mansfield and Donna M. Paulnock^2,*

^* Department of Medical Microbiology and Immunology and Department of Bacteriology, University of Wisconsin Medical School, Madison, WI 53706

Macrophages express a spectrum of proinflammatory and regulatory mediators during African trypanosomiasis. Microarray analyses revealed similar profiles of induced genes in macrophages stimulated with the trypanosome soluble variant surface glycoprotein in vitro and in macrophages taken from infected mice. Genes associated with the acute phase response and with type I IFN responses were prominent components of the macrophage activation profiles expressed within 72 h in vitro and in vivo. Thus, induction of proinflammatory gene expression is a characteristic of early trypanosome infection that is driven primarily by soluble variant surface glycoprotein exposure, and it may be that IFN-/β plays a central role in regulation of early resistance to trypanosomes. To test this hypothesis, we assessed parameters of infection in mouse strains with genetic alterations in the IFN-/β response pathway. We found that Ifnar1^–/– mice, which lack the receptor for type I IFNs, exhibited delayed control of parasite burden during the first week of infection and died earlier than did wild-type controls. However, infection of Ubp43^–/– mice, which are hyperresponsive to type I IFNs, did not exhibit enhanced resistance to trypanosomes. Instead, these animals also failed to control parasite burden and were more susceptible than wild-type animals. Additionally, the Ubp43^–/– mice exhibited a significant defect in IFN- production, which is definitively linked to host resistance in trypanosomiasis. These results show that type I IFNs play a role in early control of parasites in infected mice but may contribute to down-regulation of IFN- production and subsequent loss of host resistance later in infection.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by funds from U.S. Public Health Service Grants AI048242 and AI051421 (to D.M.P.) and AI22441 and AI073346 (to J.M.M.), as well as by a predoctoral fellowship to R.L. from the Ford Foundation.

² Address correspondence and reprint requests to Dr. Donna M. Paulnock, Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, 1550 Linden Drive, Microbial Sciences Building, Madison, WI 53706. E-mail address: paulnock{at}wisc.edu

³ Abbreviations used in this paper: VSG, variant surface glycoprotein; GIP, glycosylinositolphosphate; IRF, IFN regulatory factor; mfVSG, GPI-anchored membrane form of the VSG molecule; ODN, oligodeoxynucleotide; PBSG, PBS containing 1 mM EDTA and 1% glucose; PEC, peritoneal cells; SPC, spleen cells; sVSG, soluble VSG; TRAF, TNFR-associated factor; wt, wild type.

⁴ The online version of this article contains supplemental material.