AUTHOR=Soliman Sameh S. M. , El-Labbad Eman M. , Abu-Qiyas Ameera , Fayed Bahgat , Hamoda Alshaimaa M. , Al-Rawi Ahmed M. , Dakalbab Salam , El-Shorbagi Abdel-Nasser A. , Hamad Mawieh , Ibrahim Ashraf S. , Mohammad Mohammad G. 

TITLE=Novel Secreted Peptides From Rhizopus arrhizus var. delemar With Immunomodulatory Effects That Enhance Fungal Pathogenesis

JOURNAL=Frontiers in Microbiology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2022.863133

DOI=10.3389/fmicb.2022.863133

ISSN=1664-302X

ABSTRACT=Secreted fungal peptides are known to influence the interactions between the pathogen ‎and host innate immunity. The aim of this study is to screen and evaluate secreted peptides from ‎the fungus Rhizopus delemar for their immunomodulatory activity. By using mass spectrometry ‎and immuno-informatics analysis, we identified three secreted peptides CesT (S16), Colicin ‎‎(S17) and Ca2+/calmodulin-dependent protein kinase/ligand (CAMK/CAMKL) (S27). Culturing ‎peripheral blood-derived monocytic macrophages (PBMMs) in the presence of S16 or S17 caused ‎cell clumping, while culturing them with S27 resulted in the formation of spindle-shape cells. ‎S27-treated PBMM showed cell cycle arrest at G0 phase and exhibited alternatively ‎activatedmacrophage phenotype with pronounced reduction in scavenger receptors CD163 and ‎CD206. Homology prediction indicated that IL-4/IL-13 is the immunomodulatory target of S27. ‎Confirming this prediction, S27 initiated macrophages activation through phosphorylation of ‎STAT-6, and STAT-6 inhibition reversed the activity of S27 and reduced the formation of ‎spindle-shaped PBMMs. Lastly, S27 treatment of PBMMs was associated with an influence on ‎the expression of iron regulatory genes (e.g. hepcidin, ferroportin, transferrin receptor 1 and ‎ferritin) in a pattern that is consistent with increased cellular iron release, a condition known to ‎enhance Rhizopus infection. Collectively, R. delemar secretes peptides with immunomodulatory ‎activities that support fungal pathogenesis, while targeting IL-4/IL-13R, STAT-6 axis is a ‎potential therapeutic approach to enhance their PBMM-mediated fungal phagocytosis. This ‎represents a potential new approach to overcome lethal mucormycosis.‎