Interferon regulatory factor modulation underlies the bystander suppression of malaria antigen-driven IL-12 and IFN-γ in filaria-malaria co-infection.
In areas where polyparasitism is highly prevalent, the impact of multiple parasites on the host response is underestimated. In particular, the presence of helminth infection coincident with malaria profoundly alters the production of malaria-specific IFN-γ, IL-12p70, CXCL9, CXCL10 and CXCL11, cytokines/chemokines known to be critical in mediating malaria-specific immunity. In order to elucidate the mechanisms underlying the suppression of malaria-specific cytokines/chemokines, we assessed the expression of malaria-specific IL-12Rβ1, IL-12Rβ2 and interferon regulatory factor (IRF)-1 in blood obtained from 18 filaria-infected (Fil(+)) and 17 filaria-uninfected (Fil(-)) individuals in a filaria-malaria co-endemic region of Mali. We found that Fil(+) individuals had significantly lower RNA expression of IRF-1 but not IL-12Rβ1 or IL-12Rβ2 in response to malaria antigen stimulation. We also measured the frequency of IL-12-producing DCs from these subjects and found that Fil(+) subjects had lower frequencies of IL-12(+) mDCs after malaria antigen stimulation than did the Fil(-) subjects. Modeling these data in vitro, we found that mDCs pre-exposed to live microfilariae not only produced significantly lower levels of CXCL-9, CXCL-10, IL-12p35, IL-12p40, IL-12p19 and CXCL-11 following stimulation with malaria antigen but also markedly downregulated the expression of IRF-1, IRF-2 and IRF-3 compared with microfilaria-unexposed mDCs. siRNA-inhibition of irf-1 in mDCs downregulated the production of IL-12p70 through repression of IL-12p35. Our data demonstrate that the modulation of IRFs seen in filarial (and presumably other tissue-invasive helminths) infection underlies the suppression of malaria-specific cytokines/chemokines that play a crucial role in immunity to malaria.
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. metenous@niaid.nih.gov
Simon
S
Metenou
Michael
M
Kovacs
Benoit
B
Dembele
Yaya I
YI
Coulibaly
Amy D
AD
Klion
Thomas B
TB
Nutman
D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D017178:Brugia malayi / Q000276:immunology*; D054357:Chemokine CXCL10 / Q000276:immunology; D054371:Chemokine CXCL11 / Q000276:immunology; D054370:Chemokine CXCL9 / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D015536:Down-Regulation; D005368:Filariasis / Q000276:immunology* / Q000469:parasitology; D005434:Flow Cytometry; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology*; D018664:Interleukin-12 / Q000276:immunology*; D016778:Malaria, Falciparum / Q000276:immunology* / Q000469:parasitology; D008302:Mali; D010963:Plasmodium falciparum / Q000276:immunology*; D012313:RNA / Q000737:chemistry / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
D000953:Antigens, Protozoan; C114753:CXCL10 protein, human; C515202:CXCL11 protein, human; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D050856:Interferon Regulatory Factor-1; D034741:RNA, Small Interfering; D018664:Interleukin-12; D012313:RNA; D007371:Interferon-gamma