Type I IFNs play a role in early resistance, but subsequent susceptibility, to the African trypanosomes.
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-alpha/beta 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-alpha/beta 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-gamma 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-gamma production and subsequent loss of host resistance later in infection.
Lopez
Rebecca
R
Department of Medical Microbiology and Immunology, University of Wisconsin Medical School, Madison, WI 53706, USA.
Demick
Karen P
KP
Mansfield
John M
JM
Paulnock
Donna M
DM
D000818:Animals; D002460:Cell Line; D004198:Disease Susceptibility / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D007113:Immunity, Innate; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000378:metabolism; D007370:Interferon Type I / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000276:immunology; D013997:Time Factors; D014347:Trypanosoma brucei gambiense / Q000276:immunology*; D014353:Trypanosomiasis, African / Q000276:immunology* / Q000469:parasitology; D014643:Variant Surface Glycoproteins, Trypanosoma / Q000502:physiology
D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D014643:Variant Surface Glycoproteins, Trypanosoma; D016899:Interferon-beta; D007371:Interferon-gamma
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