Date Published: April 26, 2019
Publisher: Public Library of Science
Author(s): Binita Nepal, Ryan Myers, Jessica M. Lohmar, Olivier Puel, Brett Thompson, Matthew Van Cura, Ana M. Calvo, Kap-Hoon Han.
The fungus Aspergillus fumigatus is a ubiquitous opportunistic human pathogen capable of causing a life-threatening disease called invasive aspergillosis, or IA, with an associated 40–90% mortality rate in immunocompromised patients. Of the approximately 250 species known in the genus Aspergillus, A. fumigatus is responsible for up to 90% of IA infections. This study focuses on examining the role of the putative polysaccharide synthase cpsA gene in A. fumigatus virulence. Additionally, we evaluated its role in cellular processes that influence invasion and colonization of host tissue. Importantly, our results support that cpsA is indispensable for virulence in A. fumigatus infection of non-neutropenic hosts. Our study revealed that cpsA affects growth and sporulation in this fungus. Absence of cpsA resulted in a drastic reduction in conidiation, and forced overexpression of cpsA produced partially fluffy colonies with low sporulation levels, suggesting that wild-type cpsA expression levels are required for proper conidiation in this fungus. This study also showed that cpsA is necessary for normal cell wall integrity and composition. Furthermore, both deletion and overexpression of cpsA resulted in a reduction in the ability of A. fumigatus to adhere to surfaces, and caused increased sensitivity to oxidative stress. Interestingly, metabolomics analysis indicated that cpsA affects A. fumigatus secondary metabolism. Forced overexpression of cpsA resulted in a statistically significant difference in the production of fumigaclavine A, fumigaclavine B, fumigaclavine C, verruculogen TR-2, and tryprostatin A.
Invasive Aspergillosis (IA) is a life-threatening mycosis in immunocompromised individuals. The fungus A. fumigatus is the most common cause of IA , resulting in high mortality rates between 40% and 90%. The deadliness of A. fumigatus is in large part due to the small size of its conidia (2 to 3 μm in diameter). These spores can easily reach the lung alveoli, establishing an infection that can become angioinvasive, colonizing other organs in the human body, including the liver, kidneys, and brain. In the case of immunocompetent individuals, conidia are efficiently eliminated through normal mucociliary clearance. In addition, epithelial cells or alveolar macrophages are able to eliminate conidia and initiate a proinflammatory response that recruits neutrophils (PMN type). These neutrophils destroy hyphae from germinated conidia that evade macrophages. The highest risk of developing IA is primarily a consequence of a dysfunction of these defenses. In the immunocompromised, such as patients with hematological malignancies, transplants, prolonged steroid treatments and cancer and HIV, the systemic nature of the infection can be fatal [2,3,4]. The risk of IA increases due to neutropenia (depletion of neutrophils) and corticosteroid-induced immunosupression [5,6,7,8,9].
In fungi, polysaccharides play a crucial role in structural integrity, and comprise more than 90% of the cell wall . Besides structural roles, fungal polysaccharides serve as an energy reserve in the form of intracellular inclusions . Polysaccharides also play a role in pathogenesis by influencing the host-pathogen interaction . cpsA, annotated as a putative polysaccharide synthase gene, was identified in a mutagenesis screening in the model fungus A. nidulans where it influenced several cellular processes including development and secondary metabolism [18,19]. Sequence analysis showed that cpsA homologs exist in other fungal species including the opportunistic human pathogen A. fumigatus.