Selective Effects of Interleukin (IL)–15 on Antifungal Activity and IL‐8 Release by Polymorphonuclear Leukocytes in Response to Hyphae of<i>Aspergillus</i>Species

Winn, Richard M.; Gil-Lamaignere, Cristina; Roilides, Emmanuel; Simitsopoulou, Maria; Lyman, Caron A.; Maloukou, Avgi; Walsh, Thomas J.

doi:10.1086/377099

Cited by 45 publications

(37 citation statements)

References 32 publications

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“…Richardson et al found that CXCL8/IL-8 enhanced the phagocytosis of conidia by polymorphonuclear neutrophils (38). Winn et al also demonstrated that IL-15-stimulated polymorphonuclear leukocytes exhibit enhanced release of CXCL8/IL-8 in response to the hyphae of A. fumigatus (49). This current study further contributes to our understanding of IL-8 in the phagocytic response of HMCs to conidia of A. fumigatus.…”

Section: Vol 74 2006 Functional Genomics Of Monocytes Against Aspersupporting

confidence: 64%

Functional Genomics of Innate Host Defense Molecules in Normal Human Monocytes in Response toAspergillus fumigatus

et al. 2006

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Aspergillus fumigatus induces the release of innate immune-related molecules from phagocytic cells early in the course of infection. Little is known, however, about the complex expression profiles of the multiple genes involved in this response. We therefore investigated the kinetics of early gene expression in human monocytes (HMCs) infected with conidia of A. fumigatus using DNA microarray analysis. Total RNA from HMCs at 0, 2, 4, and 6 h was extracted, linearly amplified, hybridized onto Affymetrix HG133 Plus 2.0 gene chips, and analyzed with an Affymetrix scanner. Changes in gene expression were calculated as a ratio of those expressed by infected versus control HMCs. Aspergillus fumigatus induced differential regulation of expression in 1,827 genes (P < 0.05). Genes encoding cytokines and chemokines involved in host defense against A. fumigatus, including interleukin-1␤ (IL-1␤), IL-8, CXCL2, CCL4, CCL3, and CCL20, as well as the opsonin long pentraxin 3, were up-regulated during the first 2 to 6 h, coinciding with an increase in phagocytosis. Simultaneously, genes encoding CD14, ficolin1, and MARCO were down-regulated, and genes encoding IL-10 and matrix metalloproteinase 1 were up-regulated. Up-regulation of the genes encoding heat shock proteins 40 and 110 and connexins 26 and 30 may point to novel molecules whose role in the pathogenesis of aspergillosis has not been previously reported. Verification of the transcriptional profiling was obtained for selected genes by reverse transcription-PCR and enzyme immunoassay. Thus, A. fumigatus conidia induced a coordinated expression of genes important in host defense and immunomodulation.Invasive aspergillosis is an important cause of morbidity and mortality among immunocompromised patients. Risk factors for developing aspergillosis include aplastic anemia (46), hematopoietic stem cell transplantation (32), solid organ transplantation (44), and phagocytic deficiencies, such as chronic granulomatous disease and human immunodeficiency virus infection (40,43). Aspergillus fumigatus is the species most commonly identified as the cause of invasive aspergillosis.Monocytes/macrophages play a pivotal role in normal host defense against A. fumigatus. The innate host response against this pathogen is mediated by release of immune-related molecules from phagocytic cells. However, little is known about the complex expression kinetic profiles of the multiple genes mediating the initial immune response to A. fumigatus. Thus, we hypothesized that conidia of A. fumigatus would induce reciprocal changes in expression of genes encoding products related to innate immunity that may provide insight into early host-parasite interaction.In this study, we used microarray analysis to elucidate the initial kinetics of the transcriptional response of genes encoding innate host defense molecules in normal human monocytes after in vitro stimulation/infection with A. fumigatus conidia. We report herein the changes in expression of genes whose products are involved in the initial innate immun...

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Section: Vol 74 2006 Functional Genomics Of Monocytes Against Aspersupporting

confidence: 64%

Functional Genomics of Innate Host Defense Molecules in Normal Human Monocytes in Response toAspergillus fumigatus

et al. 2006

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“…However, sustained injury for one hour or longer eventually leads to cell death [20]. In general, PMN are very efficient in carrying out such hyphal damage in vitro without need for additional stimulation, and it is extremely hard to further enhance their basal function with target opsonization [20] or cytokines [21,22]. However, we observed that supernatants from infected oral epithelial cells enhanced the basal hyphal inhibitory activity of neutrophils, by two-to three-fold at lower E:T ratios, consistent with prior reports using recombinant human cytokines (Fig.…”

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confidence: 99%

Candida albicans-infected oral epithelial cells augment the anti-fungal activity of human neutrophilsin vitro

2005

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Oropharyngeal candidiasis (OPC) is the most common opportunistic infection in immunosuppressed patients. In OPC, Candida albicans persists intraepithelially triggering inflammatory events, without generally causing invasive infection. Since neutrophils play an important role in preventing invasive infection and since they establish contact with the microorganisms only within the epithelial cell layer, we examined the ability of Candida-infected oral epithelial cells to augment neutrophil-mediated hyphal damage in vitro. We found that challenge of neutrophils with hyphal organisms in the presence of C. albicans-infected oral epithelial cell supernatants resulted in a significantly greater suppression of hyphal cell metabolic activity compared to basal neutrophil anti-fungal function. Anti-hyphal activity in response to these supernatants was partly inhibited by neutralizing anti-IL-1alpha antibody and IL-1 receptor antagonist. Control supernatants from uninfected oral epithelial cells, as well as C. albicans conditioned-medium had a much less pronounced effect on neutrophil anti-fungal activity, which was not inhibited by these cytokine antagonists. We conclude that oral epithelial cells can act as activators of neutrophil anti-hyphal function, an effect that can be partly attributed to the generation of immunomodulatory cytokines during the interaction of oral mucosal cells with the pathogen.

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“…Of the genes that were upregulated, IL-8 (or its receptor) has been shown to play an important role in protection against some forms of candidiasis (2,17,18,42,43). IL-8 also plays an important role in neutrophil phagocytosis of Aspergillus fumigatus in vitro and protection against paracoccidioidomycosis (36,39,52). Similarly, the L-and E-selectin genes have also been shown to be important in immunity to systemic candidiasis (34).…”

Section: Discussionmentioning

confidence: 99%

Deletion of theSSK1Response Regulator Gene inCandida albicansContributes to Enhanced Killing by Human Polymorphonuclear Neutrophils

Calderone

Richert

et al. 2005

Infect Immun

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The isolation and partial functional characterization of the two-component response regulator SSK1 gene of Candida albicans was previously reported. Compared to wild-type (CAF2-1) and gene-reconstituted (SSK23) strains, the ssk1 null strain (SSK21) was avirulent in a murine model of hematogenously disseminated candidiasis and less able to adhere to human esophageal cells. More recent data indicate that SSK21 is sensitive to 4 to 8 mM H 2 O 2 in vitro than CAF2-1 and SSK23. Furthermore, microarray studies indicate that the regulation of two classes of genes, those encoding cell wall functions and stress adaptation, are altered in the ssk1 mutant. In the present study, the susceptibility of strains CAF2-1, SSK21, and SSK23 to killing by human polymorphonuclear neutrophils (PMNs) was assessed. Results are also described for a newly constructed ssk1 mutant (SSK24) in which the URA3 gene is integrated into its native locus. Our results indicate that killing of SSK21 and SSK24 was significantly greater than that of CAF2-1 and SSK23 (P < 0.01). In order to determine why Ssk1p at least partially protects the organism against the killing activity of human PMNs, we compared the signal transduction activity and the inflammatory response gene profiles of PMNs infected with either the wild type or the ssk1 mutant. Phosphorylation of the mitogen-activated protein kinases p42/44 and p38 from neutrophils infected with either CAF2-1 (wild type) or SSK21 (ssk1/ssk1) was similar, while expression and phosphorylation of the JNK mitogen-activated protein kinase was not observed following infection with either strain. On the other hand, we observed an upregulation of seven inflammatory response genes in PMNs infected with the SSK21 mutant only, while an increase in interleukin-10 expression was measured in PMNs infected with either strain. Downregulation of interleukin-2 was observed in PMNs infected with either strain. Verification of the transcriptional profiling was obtained by reverse transcription-PCR for three of the genes that were upregulated in neutrophils infected with the ssk1 mutant. Also, the sensitivity of strain SSK21 to human defensin-1, one of the nonoxidative, antimicrobial peptides of PMNs, was greater than that of CAF2-1, demonstrating that nonoxidative killing in PMNs may contribute to the increased susceptibility of the ssk1 mutant. Our results indicate that the Ssk1p response regulator protein may provide at least partial adaptive functions for the survival of C. albicans following its encounter with human neutrophils.

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Selective Effects of Interleukin (IL)–15 on Antifungal Activity and IL‐8 Release by Polymorphonuclear Leukocytes in Response to Hyphae ofAspergillusSpecies

Cited by 45 publications

References 32 publications

Functional Genomics of Innate Host Defense Molecules in Normal Human Monocytes in Response toAspergillus fumigatus

Functional Genomics of Innate Host Defense Molecules in Normal Human Monocytes in Response toAspergillus fumigatus

Candida albicans-infected oral epithelial cells augment the anti-fungal activity of human neutrophilsin vitro

Deletion of theSSK1Response Regulator Gene inCandida albicansContributes to Enhanced Killing by Human Polymorphonuclear Neutrophils

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