title: Host-derived, pore-forming toxin-like protein and trefoil factor complex protects the host against microbial infection.
abstract: Aerolysins are virulence factors belonging to the bacterial β-pore-forming toxin superfamily. Surprisingly, numerous aerolysin-like proteins exist in vertebrates, but their biological functions are unknown. βγ-CAT, a complex of an aerolysin-like protein subunit (two βγ-crystallin domains followed by an aerolysin pore-forming domain) and two trefoil factor subunits, has been identified in frogs (Bombina maxima) skin secretions. Here, we report the rich expression of this protein, in the frog blood and immune-related tissues, and the induction of its presence in peritoneal lavage by bacterial challenge. This phenomena raises the possibility of its involvement in antimicrobial infection. When βγ-CAT was administrated in a peritoneal infection model, it greatly accelerated bacterial clearance and increased the survival rate of both frogs and mice. Meanwhile, accelerated Interleukin-1β release and enhanced local leukocyte recruitments were determined, which may partially explain the robust and effective antimicrobial responses observed. The release of interleukin-1β was potently triggered by βγ-CAT from the frog peritoneal cells and murine macrophages in vitro. βγ-CAT was rapidly endocytosed and translocated to lysosomes, where it formed high molecular mass SDS-stable oligomers (>170 kDa). Lysosomal destabilization and cathepsin B release were detected, which may explain the activation of caspase-1 inflammasome and subsequent interleukin-1β maturation and release. To our knowledge, these results provide the first functional evidence of the ability of a host-derived aerolysin-like protein to counter microbial infection by eliciting rapid and effective host innate immune responses. The findings will also largely help to elucidate the possible involvement and action mechanisms of aerolysin-like proteins and/or trefoil factors widely existing in vertebrates in the host defense against pathogens.
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms, The Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiang
authors.forename: Chao
authors.initials: C
authors.lastname: Yan
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Guo
authors.forename: Kaifeng
authors.initials: K
authors.lastname: Zhou
authors.forename: Sheng'an
authors.initials: S
authors.lastname: Li
authors.forename: Qian
authors.initials: Q
authors.lastname: Gao
authors.forename: Xuan
authors.initials: X
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Zhao
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Lee
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001001:Anura / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D001427:Bacterial Toxins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D020585:Comamonas; D004705:Endocytosis; D004927:Escherichia coli Infections / Q000276:immunology / Q000517:prevention & control; D016905:Gram-Negative Bacterial Infections / Q000276:immunology / Q000517:prevention & control; D054884:Host-Pathogen Interactions / Q000276:immunology*; D007113:Immunity, Innate; D058847:Inflammasomes / Q000276:immunology; D053583:Interleukin-1beta / Q000096:biosynthesis; D008247:Lysosomes / Q000276:immunology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D052899:Pore Forming Cytotoxic Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D012867:Skin / Q000276:immunology / Q000382:microbiology; D013203:Staphylococcal Infections / Q000276:immunology / Q000517:prevention & control; D000071164:Trefoil Factor-2
chemical_list: D001427:Bacterial Toxins; D058847:Inflammasomes; D053583:Interleukin-1beta; D010455:Peptides; D052899:Pore Forming Cytotoxic Proteins; D000071164:Trefoil Factor-2; C032676:aerolysin
keywords: infectious disease; innate immunity; interleukin-1beta
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