AUTHOR=Zhang Changjian , Chen Fangyan , Liu Xiaoyu , Han Xuelin , Hu Yingsong , Su Xueting , Chen Yong , Sun Yansong , Han Li 

TITLE=Gliotoxin Induces Cofilin Phosphorylation to Promote Actin Cytoskeleton Dynamics and Internalization of Aspergillus fumigatus Into Type II Human Pneumocyte Cells

JOURNAL=Frontiers in Microbiology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2019.01345

DOI=10.3389/fmicb.2019.01345

ISSN=1664-302X

ABSTRACT=<p><italic>Aspergillus fumigatus</italic> is able to internalize into lung epithelial cells to escape from immune attack for further dissemination. We previously reported that gliotoxin, a major mycotoxin of <italic>A. fumigatus</italic>, promotes this internalization; however, the mechanism remained unclear. Here, we report that gliotoxin is able to induce cofilin phosphorylation in A549 type II human pneumocytes. Either too high or too low a level of cofilin phosphorylation blocked the gliotoxin-induced actin cytoskeleton rearrangement and <italic>A. fumigatus</italic> internalization. LIM domain kinase 1 (LIMK1) and its upstream small GTPases (Cdc42 and RhoA, but not Rac1) predominantly mediated the gliotoxin-induced cofilin phosphorylation and <italic>A. fumigatus</italic> internalization. Simultaneously, gliotoxin significantly stimulated an increase in cAMP; however, adding an antagonist of PKA did not block gliotoxin-induced <italic>A. fumigatus</italic> internalization. <italic>In vivo</italic>, exogenous gliotoxin helped gliotoxin synthesis deficient strain <italic>gliPΔ</italic> invade into the lung tissue and the lung fungal burden increased markedly in immunosuppressed mice. In conclusion, these data revealed a novel role of gliotoxin in inducing cofilin phosphorylation mostly through the Cdc42/RhoA-LIMK1 signaling pathway to promote actin cytoskeleton rearrangement and internalization of <italic>A. fumigatus</italic> into type II human pneumocytes.</p>