Infections with filamentous fungi are common to all animals, but attention is rising especially due to the increasing incidence and high mortality rates observed in immunocompromised human individuals. Here, Aspergillus fumigatus and other members of its genus are the leading causative agents. Attributes like their saprophytic life-style in various ecological niches coupled with nutritional flexibility and a broad host range have fostered the hypothesis that environmental predators could have been the actual target for some of their virulence determinants. In this mini review, we have merged the recent findings focused on the potential dual-use of fungal defense strategies against innate immune cells and soil amoebae as natural phagocytes. Well-established virulence attributes like the melanized surface of fungal conidia or their capacity to produce toxic secondary metabolites have also been found to be protective against the model amoeba Dictyostelium discoideum. Some of the recent advances during interaction studies with human cells have further promoted the adaptation of other amoeba infection models, including the wide-spread generalist Acanthamoeba castellanii, or less prominent representatives like Vermamoeba vermiformis. We further highlight prospects and limits of these natural phagocyte models with regard to the infection biology of filamentous fungi and in comparison to the phagocytes of the innate immune system.

Establishment of multicellularity represents a major transition in eukaryote evolution. A subgroup of Amoebozoa, the dictyosteliids, has evolved a relatively simple aggregative multicellular stage resulting in a fruiting body supported by a stalk. Protosteloid amoeba, which are scattered throughout the amoebozoan tree, differ by producing only one or few single stalked spores. Thus, one obvious difference in the developmental cycle of protosteliids and dictyosteliids seems to be the establishment of multicellularity. To separate spore development from multicellular interactions, we compared the genome and transcriptome of a Protostelium species (Protostelium aurantium var. fungivorum) with those of social and solitary members of the Amoebozoa. During fruiting body formation nearly 4,000 genes, corresponding to specific pathways required for differentiation processes, are upregulated. A comparison with genes involved in the development of dictyosteliids revealed conservation of >500 genes, but most of them are also present in Acanthamoeba castellanii for which fruiting bodies have not been documented. Moreover, expression regulation of those genes differs between P. aurantium and Dictyostelium discoideum. Within Amoebozoa differentiation to fruiting bodies is common, but our current genome analysis suggests that protosteliids and dictyosteliids used different routes to achieve this. Most remarkable is both the large repertoire and diversity between species in genes that mediate environmental sensing and signal processing. This likely reflects an immense adaptability of the single cell stage to varying environmental conditions. We surmise that this signaling repertoire provided sufficient building blocks to accommodate the relatively simple demands for cell–cell communication in the early multicellular forms.

Summary Size and diverse morphologies pose a primary challenge for phagocytes such as innate immune cells and predatory amoebae when encountering fungal prey. Although filamentous fungi can escape phagocytic killing by pure physical constraints, unicellular spores and yeasts can mask molecular surface patterns or arrest phagocytic processing. Here, we show that the fungivorous amoeba Protostelium aurantium was able to adjust its killing and feeding mechanisms to these different cell shapes. Yeast‐like fungi from the major fungal groups of basidiomycetes and ascomycetes were readily internalized by phagocytosis, except for the human pathogen Candida albicans whose mannoprotein coat was essential to escape recognition by the amoeba. Dormant spores of the filamentous fungus Aspergillus fumigatus also remained unrecognized, but swelling and the onset of germination induced internalization and intracellular killing by the amoeba. Mature hyphae of A. fumigatus were mostly attacked from the hyphal tip and killed by an actin‐mediated invasion of fungal filaments. Our results demonstrate that predatory pressure imposed by amoebae in natural environments selects for distinct survival strategies in yeast and filamentous fungi but commonly targets the fungal cell wall as a crucial molecular pattern associated to prey and pathogens.