A role for macrophage migration inhibitory factor in protective immunity against Aspergillus fumigatus |
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Authors: | Stojanovic Ivana Mirkov Ivana Kataranovski Milena Glamoclija Jasmina Stosic-Grujicic Stanislava |
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Affiliation: | a Department of Immunology, Institute for Biological Research “Sinisa Stankovic”, University of Belgrade, Belgrade, Serbia b Department of Ecology, Institute for Biological Research “Sinisa Stankovic”, University of Belgrade, Belgrade, Serbia c Department of Physiology and Biochemistry, Faculty of Biology, University of Belgrade, Belgrade, Serbia d Department of Plant Physiology (Mycology Lab.), Institute for Biological Research “Sinisa Stankovic”, University of Belgrade, Belgrade, Serbia |
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Abstract: | Inflammation plays an important role in protective immunity against fungi, including the opportunistic pathogen, Aspergillus fumigatus. The balance between pro-inflammatory and anti-inflammatory cytokines is a key determinant of infection outcome. Since macrophage migration inhibitory factor (MIF) is an upstream regulator of many cytokines, we analyzed herein the role of endogenous MIF in the host control of hematogenously disseminated aspergillosis using MIF−/− mice. As revealed by their mortality rate, MIF−/− mice were more susceptible to disseminated infection than WT mice. Moreover, pharmacologic inhibition of MIF with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester, (ISO-1) increased the susceptibility of WT mice to lethal infection. The higher tissue fungal burden early in sublethal infection indicated increased susceptibility of MIF−/− mice to sublethal infection as well. Substantial down-regulation of innate and acquired antifungal responses, characterized by decreased production of IL-1β, IL-6, TNF-α, IFN-γ and IL-17 in the spleen was noted in sublethally infected MIF−/− mice. In contrast, IL-4 was higher in MIF−/− than in WT mice. Taken together, our findings show that MIF contributes to host resistance against progressive invasive A. fumigatus infection by controlling downstream pro-inflammatory versus anti-inflammatory cytokine production thus determining the outcome of infection. |
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Keywords: | A. fumigatus, Aspergillus fumigatus cDNA, complementary DNA CFU, colony forming units ELISA, enzyme-linked immunosorbent assay FCS, fetal calf serum H& E, hematoxylin and eosin IFN-γ, interferon-γ IL, interleukin i.p., intraperitoneal ISO-1, (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester i.v., intravenous mAb, monoclonal antibody MBL, mannose-binding lectin MIF, macrophage migration inhibitory factor mRNA, messenger RNA PCR, polymerase chain reaction PBL, peripheral blood leukocytes p.i., postinfection SEM, standard error of mean Th, T helper TLR, Toll-like receptors TNF-α, tumor necrosis factor α WT, wild-type |
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