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
Affiliations
Shengli Ding
College of Plant Sciences & Key Laboratory of Zoonosis Research, Ministry of Education, Jilin University, Changchun, Jilin 130062, China; Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX 77807, USA; Department of Plant Pathology, College of Plant Protection, Henan Agricultural University, Zhengzhou, Henan 450002, China
Jing Yang
Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX 77807, USA
Xuehuan Feng
Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX 77807, USA
Aseem Pandey
Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX 77807, USA; Department of Veterinary Pathobiology, Texas A&M University, College Station, TX 77843, USA
Rola Barhoumi
Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843-4458, USA
Dongmei Zhang
Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX 77807, USA
Samantha L. Bell
Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX 77807, USA
Yue Liu
College of Plant Sciences & Key Laboratory of Zoonosis Research, Ministry of Education, Jilin University, Changchun, Jilin 130062, China
Luciana Fachini da Costa
Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX 77807, USA; Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, College Station, TX 77843, USA
Allison Rice-Ficht
Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, College Station, TX 77843, USA
Robert O. Watson
Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX 77807, USA
Kristin L. Patrick
Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX 77807, USA
Qing-Ming Qin
College of Plant Sciences & Key Laboratory of Zoonosis Research, Ministry of Education, Jilin University, Changchun, Jilin 130062, China; Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX 77807, USA; Corresponding author
Thomas A. Ficht
Department of Veterinary Pathobiology, Texas A&M University, College Station, TX 77843, USA; Corresponding author
Paul de Figueiredo
Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX 77807, USA; Department of Veterinary Pathobiology, Texas A&M University, College Station, TX 77843, USA; Corresponding author
Summary: 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.
