A call to arms: Mustering secondary metabolites for success and survival of an opportunistic pathogen

Aspergillus fumigatus is a ubiquitous saprophytic mold able to grow on a diversity of material ranging from decayed organic matter in the environment to space station cupolas 1. Yet this fungus is equally adept as a serious opportunistic pathogen, causing pulmonary aspergillosis and the more deadly invasive aspergillosis (IA). There are an estimated 3,000,000 cases of pulmonary aspergillosis annually and more than 200,000 cases of IA each year reaching a mortality rate of up to 90% in the most susceptible populations 2. Difficulties in treating IA include delayed detection and increasing resistance to antifungal treatment. Like many opportunistic fungi, there is no one gene that makes A. fumigatus such a threatening pathogen. One unique feature of this pathogen is its arsenal of small molecules that impact disease development. Secondary metabolites are characterized as bioactive molecules of low molecular weight that are not required for growth of the organism but instead aid survival in harsh environments, resisting desiccation and UV stress and improving competition with other microbes. For A. fumigatus, these benefits extend to aiding growth not only in the environment but in the human body as well. Some secondary metabolites combat the host immune system by affecting immune cell function or by shielding the fungus against host attack, whereas others allow the fungus to acquire essential, scarce cofactors. The following synopsis of secondary metabolites produced by the opportunistic human pathogen A. fumigatus highlights how microbial metabolites, although undoubtedly evolved as environmental protectants, can impact infectious disease development (Fig 1). Although we delineate the roles of each metabolite by category for ease of discussion (e.g., “on the offensive,” “scavenging the battlefield,” “arms race”), the reader should note that each metabolite may have several biological roles for the fungus, in part illustrated in Fig 1. Open in a separate window Fig 1 Roles of Aspergillus fumigatus secondary metabolites. A list of the secondary metabolites produced by A. fumigatus, flanked by their proposed roles in the environment (right) and the host (left). Metabolites with a “?” indicate that the compound has not been examined in a niche. Bracketed numerals (e.g., 22) indicate the reference associated with the role of the metabolite. Nidulanin A is a proposed metabolite produced by A. fumigatus, whereas all other metabolites are characterized end-product metabolites from a biosynthetic gene cluster. ROS, reactive oxygen species; TNF-α, tumor necrosis factor alpha.