Aspergillus fumigatus is the most frequent cause of invasive mold infections worldwide. Platelets contribute to inflammation and promote thrombosis, characteristically seen in aspergillosis, and might be involved both in antifungal defense and in the histopathological process. In the experiments reported here, in vitro activation of platelets by conidia, swollen conidia, and hyphae from A. fumigatus was assessed by flow cytometry and enzyme immunoassays. THP-1 monocytes and human monocytes with and without platelets were cultured with hyphae from A. fumigatus, and the release of interleukin-8 (IL-8) was measured by enzyme immunoassays. A. fumigatus potently induced the expression of CD62-p and CD63 and the release of CD40 ligand, RANTES, and Dickkopf homolog 1 in platelets, with particularly enhancing effects of hyphae compared with conidia. The hypha-mediated activation of platelets further enhanced the release of IL-8 both in THP-1 monocytes and in human adherent monocytes. In conclusion, we have found that A. fumigatus is a potent inducer of platelet-mediated inflammation, potentially promoting protective as well as harmful responses during aspergillosis.Aspergillosis is the most common mold infection worldwide, and Aspergillus fumigatus accounts for more than 90% of the cases (6). In contrast to most human pathogens, which are encountered infrequently, A. fumigatus spores are inhaled on a daily basis, and occasionally, exposure to large numbers of conidia can occur. The first-line host defense against Aspergillus infection is based on innate immunity mediated by monocytes/macrophages and neutrophils (11,12,17,18). The adaptive immune system responds to a pathogen only after it has been recognized by the innate immune system (11). While inadequate immune responses may predispose to invasive disease, overly robust responses can result in immune-mediated inflammatory tissue damage. Thus, imbalanced immune responses to A. fumigatus may result in a spectrum of human disease states ranging from allergic bronchopulmonary aspergillosis to invasive aspergillosis in the immunocompromised host (9). Despite better diagnostic tools and therapeutic advances, the infection is difficult to diagnose and treat, and the outcome of invasive aspergillosis is often fatal.Several lines of evidence support a role for platelets in inflammation (10). Platelet-mediated inflammation has been demonstrated during various acute and chronic infections, and it has been suggested that platelets contribute to antimicrobial defenses (5, 8). Very little is known about the role of platelets in defense against Aspergillus infection. In this connection, it is interesting that important risk groups for invasive aspergillosis, e.g., patients with chemotherapy-induced neutropenia and recipients of hematopoietic stem cell transplants (6, 13), very often have concurrent thrombocytopenia in addition to neutropenia. Furthermore, it has been reported that liver transplant recipients with thrombocytopenia have a considerably higher incidence of fungal infe...

Toll-like receptors (TLRs) are involved in the host defense against Aspergillus fumigatus infections, and some TLRs may even be exploited by the mould to escape immune mechanisms. We have previously shown that conidia from A. fumigatus increase expression of TLR5 in human monocytes. When further investigating a possible role of TLR5 in A. fumigatus infections, we observed a decrease in conidial viability after culturing with TLR5-knockdown THP-1 monocytes. Secondly, our experiments showed an increase in conidial viability when THP-1 monocytes, together with flagellin, are cultured with conidia. Thirdly, we found that treatment of THP-1 monocytes with a monoclonal antibody against TLR5 resulted in increased conidial viability after culturing. Experiments with a HEK-293 cell line only expressing TLR5 did not indicate that conidia directly interact with TLR5. Further studies of the intracellular molecular mechanisms activated concomitant with activation of TLR5 that have an enhancing effect on the viability of conidia may shed new light on the defense against conidia in monocytic cells, and possibly also on the function of the TLR5 system.

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The objective of these studies was to investigate genes of importance in the pathogenesis of Aspergillus infections. To do so, we employed microarray methodology to explore gene expression in human monocytes infected with Aspergillus conidia as compared with unstimulated monocytes and those stimulated with lipopolysaccharide (LPS) signaling through TOLL-like receptor 4 (TLR4). We found 997 (P