title: Talaromyces marneffei Mp1p Is a Virulence Factor that Binds and Sequesters a Key Proinflammatory Lipid to Dampen Host Innate Immune Response.
abstract: Talaromyces (Penicillium) marneffei is one of the leading causes of systemic mycosis in immunosuppressed or AIDS patients in Southeast Asia. How this intracellular pathogen evades the host immune defense remains unclear. We provide evidence that T. marneffei depletes levels of a key proinflammatory lipid mediator arachidonic acid (AA) to evade the host innate immune defense. Mechanistically, an abundant secretory mannoprotein Mp1p, shown previously to be a virulence factor, does so by binding AA with high affinity via a long hydrophobic central cavity found in the LBD2 domain. This sequesters a critical proinflammatory signaling lipid, and we see evidence that AA, AA's downstream metabolites, and the cytokines interleukin-6 and tumor necrosis factor α are downregulated in T. marneffei-infected J774 macrophages. Given that Mp1p-LBD2 homologs are identified in other fungal pathogens, we expect that this novel class of fatty-acid-binding proteins sequestering key proinflammatory lipid mediators represents a general virulence mechanism of pathogenic fungi.
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong SAR, China; Department of Microbiology, The University of Hong Kong, Hong Kong SAR, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Kong-Hung
authors.initials: KH
authors.lastname: Sze
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China; Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen 518000, China.
authors.forename: Wai-Hei
authors.initials: WH
authors.lastname: Lam
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China; Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen 518000, China; Department of Biology, Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen 518055, China.
authors.forename: Hongmin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong SAR, China; Department of Microbiology, The University of Hong Kong, Hong Kong SAR, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Yi-Hong
authors.initials: YH
authors.lastname: Ke
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong SAR, China; Department of Microbiology, The University of Hong Kong, Hong Kong SAR, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Man-Kit
authors.initials: MK
authors.lastname: Tse
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong SAR, China; Department of Microbiology, The University of Hong Kong, Hong Kong SAR, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Patrick C Y
authors.initials: PCY
authors.lastname: Woo
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong SAR, China; Department of Microbiology, The University of Hong Kong, Hong Kong SAR, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Susanna K P
authors.initials: SKP
authors.lastname: Lau
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong SAR, China; Department of Microbiology, The University of Hong Kong, Hong Kong SAR, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Candy C Y
authors.initials: CCY
authors.lastname: Lau
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong SAR, China; Department of Microbiology, The University of Hong Kong, Hong Kong SAR, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Jian-Piao
authors.initials: JP
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Edward T K
authors.initials: ETK
authors.lastname: Tung
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong SAR, China; Department of Microbiology, The University of Hong Kong, Hong Kong SAR, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Raymond K C
authors.initials: RKC
authors.lastname: Lo
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong SAR, China; Department of Microbiology, The University of Hong Kong, Hong Kong SAR, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Simin
authors.initials: S
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong SAR, China; Department of Microbiology, The University of Hong Kong, Hong Kong SAR, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong SAR, China. Electronic address: rytkao@hku.hk.
authors.forename: Richard Y T
authors.initials: RYT
authors.lastname: Kao
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China; Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen 518000, China. Electronic address: qhao@hku.hk.
authors.forename: Quan
authors.initials: Q
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong SAR, China; Department of Microbiology, The University of Hong Kong, Hong Kong SAR, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong SAR, China. Electronic address: kyyuen@hku.hk.
authors.forename: Kwok-Yung
authors.initials: KY
authors.lastname: Yuen
mesh_terms: D000818:Animals; D000946:Antigens, Fungal / Q000276:immunology*; D016718:Arachidonic Acid / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D007113:Immunity, Innate / Q000276:immunology*; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D018836:Inflammation Mediators / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D008055:Lipids / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D051379:Mice; D032901:Talaromyces / Q000276:immunology*; D037521:Virulence Factors / Q000737:chemistry / Q000276:immunology* / Q000302:isolation & purification
chemical_list: D000946:Antigens, Fungal; D018836:Inflammation Mediators; D008055:Lipids; D037521:Virulence Factors; D016718:Arachidonic Acid
keywords: Mp1p-LBD2; NMR interaction titration; Penicillium marneffei; Talaromyces marneffei; arachidonic acid; co-immunoprecipitation; crystal structure; innate immune evasion; proinflammatory signaling lipid; virulence mechanism