Aspergillus fumigatus Induces Innate Immune Responses in Alveolar Macrophages through the MAPK Pathway Independently of TLR2 and TLR4

Unité des Aspergillus, Institut National de la Santé et de la Recherche Médicale E336, Institut Pasteur, Paris, France.
The Journal of Immunology (Impact Factor: 4.92). 10/2006; 177(6):3994-4001. DOI: 10.4049/jimmunol.177.6.3994
Source: PubMed


Aspergillus fumigatus causes invasive aspergillosis in immunosuppressed patients. In the immunocompetent host, inhaled conidia are cleared by alveolar macrophages. The signaling pathways of the alveolar macrophage involved in the clearance of A. fumigatus are poorly understood. Therefore, we investigated the role of TLRs in the immune response against A. fumigatus and their contribution to the signaling events triggered in murine alveolar macrophages upon infection with A. fumigatus conidia. Specifically, we examined the MAPKs and NF-kappaB activation and cytokine signaling. Our investigations revealed that immunocompetent TLR2, TLR4, and MyD88 knockout mice were not more susceptible to invasive aspergillosis as compared with wild-type mice and that the in vitro phosphorylation of the MAPKs ERK and p38 was not affected in TLR2, TLR4, or MyD88 knockout mice following stimulation with conidia. In vivo experiments suggest that ERK was an essential MAPK in the defense against A. fumigatus, whereas the activation of NF-kappaB appeared to play only a secondary role. In conclusion, our findings demonstrate that TLR2/4 recognition and MyD88 signaling are dispensable for the clearance of A. fumigatus under immunocompetent situations. Furthermore, our data stress the important role of ERK activation in innate immunity to A. fumigatus.

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Available from: Marc Dubourdeau, May 04, 2015
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    • "Inactivation of MAPKs has a negative effect on the normal functioning of host systems including immune responses. For instance, Dubourdeau et al. indicated that inactivation of MAPK/ERK correlates with a decrease in the activation of innate immunity against A. fumigatus in a mouse model [43]. "
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    ABSTRACT: Fungi are the second most abundant type of human pathogens. Invasive fungal pathogens are leadingcauses of life-threatening infections in clinical settings. Toxicity to the host and drug-resistance aretwo major deleterious issues associated with existing antifungal agents. Increasing a host's toleranceand/or immunity to fungal pathogens has potential to alleviate these problems. A host's tolerance maybe improved by modulating the immune system such that it responds more rapidly and robustly in allfacets, ranging from the recognition of pathogens to their clearance from the host. An understandingof biological processes and genes that are perturbed during attempted fungal exposure, colonization,and/or invasion will help guide the identification of endogenous immunomodulators and/or smallmolecules that activate host-immune responses such as specialized adjuvants. In this study, we present computational techniques and approaches using publicly availabletranscriptional data sets, to predict immunomodulators that may act against multiple fungalpathogens. Our study analyzed data sets derived from host cells exposed to five fungal pathogens,namely, Alternaria alternata, Aspergillus fumigatus, Candida albicans, Pneumocystis jirovecii, andStachybotrys chartarum. We observed statistically significant associations between host responsesto A. fumigatus and C. albicans. Our analysis identified biological processes that were consistentlyperturbed by these two pathogens. These processes contained both immune response-inducing genessuch as MALT1, SERPINE1, ICAM1, and IL8, and immune response-repressing genes such asDUSP8, DUSP6, and SPRED2. We hypothesize that these genes belong to a pool of commonimmunomodulators that can potentially be activated or suppressed (agonized or antagonized) in orderto render the host more tolerant to infections caused by A. fumigatus and C. albicans. Conclusions Our computational approaches and methodologies described here can now be applied to newlygenerated or expanded data sets for further elucidation of additional drug targets. Moreover,identified immunomodulators may be used to generate experimentally testable hypotheses thatcould help in the discovery of broad-spectrum immunotherapeutic interventions. All of ourresults are available at the following supplementary website: Host-oriented therapy, Broad-spectrum target, Immunomodulation.
    BMC Microbiology 10/2013; 13(1):224. DOI:10.1186/1471-2180-13-224 · 2.73 Impact Factor
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    • "The recognition of fungal PAMPs by either TLRs (Meier et al., 2003) or Dectin-1 (Gersuk et al., 2006) leads to uptake of the spores. Intracellularly other receptors like NOD-2, a member of the NLR family (nucleotide-binding domain, leucine-rich repeatcontaining protein) (Dubourdeau et al., 2006; Zhang et al., 2008) can ultimately initiate MyD88-dependent or -independent mitogenactivated protein kinase (MAPK) signaling pathways, leading to the synthesis of a variety of proinflammatory cytokines like TNF-␣ "
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    ABSTRACT: The saprophytic fungus Aspergillus fumigatus is a mold which is ubiquitously present in the environment. It produces large numbers of spores, called conidia that we constantly inhale with the breathing air. Healthy individuals normally do not suffer from true fungal infections with this pathogen. A normally robust resistance against Aspergillus is based on the presence of a very effective immunological defense system in the vertebrate body. Inhaled conidia are first encountered by lung-resident alveolar macrophages and then by neutrophil granulocytes. Both cell types are able to effectively ingest and destroy the fungus. Although some responses of the adaptive immune system develop, the key protection is mediated by innate immunity. The importance of phagocytes for defense against aspergillosis is also supported by large numbers of animal studies. Despite the production of aggressive chemicals that can extracellularly destroy fungal pathogens, the main effector mechanism of the innate immune system is phagocytosis. Very recently, the production of extracellular neutrophil extracellular traps (NETs) consisting of nuclear DNA has been added to the armamentarium that innate immune cells use against infection with Aspergillus. Phagocyte responses to Aspergillus are very broad, and a number of new observations have added to this complexity in recent years. To summarize established and newer findings, we will give an overview on current knowledge of the phagocyte system for the protection against Aspergillus.
    International journal of medical microbiology: IJMM 06/2011; 301(5):436-44. DOI:10.1016/j.ijmm.2011.04.012 · 3.61 Impact Factor
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    • "Previous studies have focused on the role of immune cells, primarily macrophages and neutrophils, in response to A. fumigatus exposure [26]–[29]. Whilst professional phagocytic cells are important in mediating fungal clearance, the airway epithelium is the first point of contact for fungal conidia within the lung and represents an important surface of interaction [30]. Indeed many A. fumigatus-mediated diseases such as ABPA, severe asthma with fungal sensitization (SAFS), aspergilloma, and invasive pulmonary aspergillosis are associated with the respiratory tract. "
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    ABSTRACT: Given the complex nature of the responses that can occur in host-pathogen interactions, dual transcriptomics offers a powerful method of elucidating these interactions during infection. The gene expression patterns of Aspergillus fumigatus conidia or host cells have been reported in a number of previous studies, but each focused on only one of the interacting organisms. In the present study, we profiled simultaneously the transcriptional response of both A. fumigatus and human airway epithelial cells (AECs). 16HBE14o- transformed bronchial epithelial cells were incubated with A. fumigatus conidia at 37°C for 6 hours, followed by genome-wide transcriptome analysis using human and fungal microarrays. Differentially expressed gene lists were generated from the microarrays, from which biologically relevant themes were identified. Human and fungal candidate genes were selected for validation, using RT-qPCR, in both 16HBE14o- cells and primary AECs co-cultured with conidia. We report that ontologies related to the innate immune response are activated by co-incubation with A. fumigatus condia, and interleukin-6 (IL-6) was confirmed to be up-regulated in primary AECs via RT-qPCR. Concomitantly, A. fumigatus was found to up-regulate fungal pathways involved in iron acquisition, vacuolar acidification, and formate dehydrogenase activity. To our knowledge, this is the first study to apply a dual organism transcriptomics approach to interactions of A. fumigatus conidia and human airway epithelial cells. The up-regulation of IL-6 by epithelia and simultaneous activation of several pathways by fungal conidia warrants further investigation as we seek to better understand this interaction in both health and disease. The cellular response of the airway epithelium to A. fumigatus is important to understand if we are to improve host-pathogen outcomes.
    PLoS ONE 05/2011; 6(5):e20527. DOI:10.1371/journal.pone.0020527 · 3.23 Impact Factor
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