Interactions between fungal hyaluronic acid and host CD44 promote internalization by recruiting host autophagy proteins to forming phagosomes

Shengli Ding; Jing Yang; Xuehuan Feng; Aseem Pandey; Rola Barhoumi; Dongmei Zhang; Samantha L Bell; Yue Liu; Luciana Fachini da Costa; Allison Rice-Ficht; Robert O Watson; Kristin L Patrick; Qing-Ming Qin; Thomas A Ficht; Paul de Figueiredo

doi:10.1016/j.isci.2021.102192

Interactions between fungal hyaluronic acid and host CD44 promote internalization by recruiting host autophagy proteins to forming phagosomes

iScience. 2021 Feb 12;24(3):102192. doi: 10.1016/j.isci.2021.102192. eCollection 2021 Mar 19.

Authors

Shengli Ding^{1

2

3}, Jing Yang², Xuehuan Feng², Aseem Pandey^{2

4}, Rola Barhoumi⁵, Dongmei Zhang², Samantha L Bell², Yue Liu¹, Luciana Fachini da Costa^{2

6}, Allison Rice-Ficht⁶, Robert O Watson², Kristin L Patrick², Qing-Ming Qin^{1

2}, Thomas A Ficht⁴, Paul de Figueiredo^{2

4}

Affiliations

¹ College of Plant Sciences & Key Laboratory of Zoonosis Research, Ministry of Education, Jilin University, Changchun, Jilin 130062, China.
² Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX 77807, USA.
³ Department of Plant Pathology, College of Plant Protection, Henan Agricultural University, Zhengzhou, Henan 450002, China.
⁴ Department of Veterinary Pathobiology, Texas A&M University, College Station, TX 77843, USA.
⁵ Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843-4458, USA.
⁶ Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, College Station, TX 77843, USA.

Abstract

Phagocytosis and autophagy play critical roles in immune defense. The human fungal pathogen Cryptococcus neoformans (Cn) subverts host autophagy-initiation complex (AIC)-related proteins, to promote its phagocytosis and intracellular parasitism of host cells. The mechanisms by which the pathogen engages host AIC-related proteins remain obscure. Here, we show that the recruitment of host AIC proteins to forming phagosomes is dependent upon the activity of CD44, a host cell surface receptor that engages fungal hyaluronic acid (HA). This interaction elevates intracellular Ca²⁺ concentrations and activates CaMKKβ and its downstream target AMPKα, which results in activation of ULK1 and the recruitment of AIC components. Moreover, we demonstrate that HA-coated beads efficiently recruit AIC components to phagosomes and CD44 interacts with AIC components. Taken together, these findings show that fungal HA plays a critical role in directing the internalization and productive intracellular membrane trafficking of a fungal pathogen of global importance.

Keywords: Immunology; Mycology.