CCL20 Displays Antimicrobial Activity Against Cryptosporidium parvum, but Its Expression Is Reduced During Infection in the Intestine of Neonatal Mice.

CCL20 is a chemokine with antimicrobial activity. We investigated its expression and role during neonatal cryptosporidiosis, a worldwide protozoan enteric disease leading to severe diarrhea. Surprisingly, during infection by Cryptosporidium parvum, CCL20 production by the intestine of neonatal mice is reduced by a mechanism independent both of the enteric flora and of interferon γ, a key cytokine for the resolution of this infection. However, oral administration of recombinant CCL20 to neonatal mice significantly reduced the parasite load by a mechanism that was independent of immune cell recruitment and occurred instead by direct cytolytic activity on free stages of the parasite. MiR21 functionally targets CCL20 and is upregulated during the infection, thus contributing to the downregulation of the chemokine. Our findings demonstrate for the first time the direct antiparasitic activity of CCL20 against an enteric protozoan and its downregulation during C. parvum infection, which is detrimental to parasite clearance.

[1]  Lifang Zhao,et al.  Transcriptional regulation of CCL20 expression. , 2014, Microbes and infection.

[2]  William Guesdon,et al.  The gut flora is required for the control of intestinal infection by poly(I:C) administration in neonates , 2014, Gut microbes.

[3]  Yaoyu Feng,et al.  Non-coding RNAs in epithelial immunity to Cryptosporidium infection , 2014, Parasitology.

[4]  William Guesdon,et al.  Poly(I:C)-induced protection of neonatal mice against intestinal Cryptosporidium parvum infection requires an additional TLR5 signal provided by the gut flora. , 2014, The Journal of infectious diseases.

[5]  F. Shanahan,et al.  Identification of TLR10 as a Key Mediator of the Inflammatory Response to Listeria monocytogenes in Intestinal Epithelial Cells and Macrophages , 2013, The Journal of Immunology.

[6]  S. Rabot,et al.  Intestinal CD103+ Dendritic Cells Are Key Players in the Innate Immune Control of Cryptosporidium parvum Infection in Neonatal Mice , 2013, PLoS pathogens.

[7]  B. Striepen.  Parasitic infections: Time to tackle cryptosporidiosis , 2013, Nature.

[8]  M. Glanemann,et al.  miR-21 and its target gene CCL20 are both highly overexpressed in the microenvironment of colorectal tumors: significance of their regulation. , 2013, Oncology reports.

[9]  A. B. Lyons,et al.  CC Chemokine Ligand 20 and Its Cognate Receptor CCR6 in Mucosal T Cell Immunology and Inflammatory Bowel Disease: Odd Couple or Axis of Evil? , 2013, Front. Immunol..

[10]  A. Egesten,et al.  Human Chemokines as Antimicrobial Peptides with Direct Parasiticidal Effect on Leishmania mexicana In Vitro , 2013, PloS one.

[11]  W. Karpus,et al.  TLR1-induced chemokine production is critical for mucosal immunity against Yersinia enterocolitica , 2013, Mucosal Immunology.

[12]  P. Murphy,et al.  Antimicrobial Chemokines , 2012, Front. Immun..

[13]  Deborah A Schaefer,et al.  Antibody fusions reduce onset of experimental Cryptosporidium parvum infection in calves , 2012, Veterinary Parasitology.

[14]  P. Ghadjar,et al.  miR-21 functionally interacts with the 3'UTR of chemokine CCL20 and down-regulates CCL20 expression in miR-21 transfected colorectal cancer cells. , 2012, Cancer letters.

[15]  Deborah A Schaefer,et al.  Phospholipases and Cationic Peptides Inhibit Cryptosporidium parvum Sporozoite Infectivity by Parasiticidal and Non-Parasiticidal Mechanisms , 2012, The Journal of parasitology.

[16]  M. Gangidine,et al.  Proinflammatory Chemokines in the Intestinal Lumen Contribute to Intestinal Dysfunction During Endotoxemia , 2012, Shock.

[17]  Deborah A Schaefer,et al.  Antibodies Fused to Innate Immune Molecules Reduce Initiation of Cryptosporidium parvum Infection in Mice , 2010, Antimicrobial Agents and Chemotherapy.

[18]  A. Fanning,et al.  Modulation of pathogen-induced CCL20 secretion from HT-29 human intestinal epithelial cells by commensal bacteria , 2009, BMC Immunology.

[19]  Jun Liu,et al.  MicroRNA-98 and let-7 Confer Cholangiocyte Expression of Cytokine-Inducible Src Homology 2-Containing Protein in Response to Microbial Challenge12 , 2009, The Journal of Immunology.

[20]  M. Dwinell,et al.  CCR6 Regulation of the Actin Cytoskeleton Orchestrates Human Beta Defensin-2- and CCL20-mediated Restitution of Colonic Epithelial Cells* , 2009, Journal of Biological Chemistry.

[21]  P. Sansonetti,et al.  Virulent Shigella flexneri subverts the host innate immune response through manipulation of antimicrobial peptide gene expression , 2008, The Journal of experimental medicine.

[22]  A. White,et al.  Cryptosporidium infection of human intestinal epithelial cells increases expression of osteoprotegerin: a novel mechanism for evasion of host defenses. , 2008, The Journal of infectious diseases.

[23]  Steven P. O'Hara,et al.  A Cellular Micro-RNA, let-7i, Regulates Toll-like Receptor 4 Expression and Contributes to Cholangiocyte Immune Responses against Cryptosporidium parvum Infection* , 2007, Journal of Biological Chemistry.

[24]  S. Lacroix-Lamandé,et al.  Involvement of intestinal epithelial cells in dendritic cell recruitment during C. parvum infection. , 2007, Microbes and infection.

[25]  C. Wira,et al.  Effect of oestradiol on PAMP‐mediated CCL20/MIP‐3α production by mouse uterine epithelial cells in culture , 2006, Immunology.

[26]  S. Akira,et al.  Oral and intraperitoneal administration of phosphorothioate oligodeoxynucleotides leads to control of Cryptosporidium parvum infection in neonatal mice. , 2006, The Journal of infectious diseases.

[27]  M. Bajaj‐Elliott,et al.  Differential Regulation of β-Defensin Gene Expression during Cryptosporidium parvum Infection , 2004, Infection and Immunity.

[28]  D. Hoover,et al.  Many chemokines including CCL20/MIP‐3α display antimicrobial activity , 2003 .

[29]  M. Zanetti,et al.  In vitro effect on Cryptosporidium parvum of short-term exposure to cathelicidin peptides. , 2003, The Journal of antimicrobial chemotherapy.

[30]  D. Hoover,et al.  Many chemokines including CCL20/MIP-3alpha display antimicrobial activity. , 2003, Journal of leukocyte biology.

[31]  D. Hoover,et al.  The Structure of Human Macrophage Inflammatory Protein-3α/CCL20 , 2002, The Journal of Biological Chemistry.

[32]  S. Lacroix-Lamandé,et al.  Role of Gamma Interferon in Chemokine Expression in the Ileum of Mice and in a Murine Intestinal Epithelial Cell Line after Cryptosporidium parvum Infection , 2002, Infection and Immunity.

[33]  D. Hoover,et al.  The structure of human macrophage inflammatory protein-3alpha /CCL20. Linking antimicrobial and CC chemokine receptor-6-binding activities with human beta-defensins. , 2002, The Journal of biological chemistry.

[34]  J. Sirard,et al.  Flagellin stimulation of intestinal epithelial cells triggers CCL20-mediated migration of dendritic cells , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[35]  O. Yoshie,et al.  Proinflammatory cytokines induce liver and activation-regulated chemokine/macrophage inflammatory protein-3α/CCL20 in mucosal epithelial cells through NF-κB , 2001 .

[36]  F. Laurent,et al.  Cryptosporidium parvum-Specific Mucosal Immune Response in C57BL/6 Neonatal and Gamma Interferon-Deficient Mice: Role of Tumor Necrosis Factor Alpha in Protection , 2001, Infection and Immunity.

[37]  R. Pollok,et al.  Interferon gamma induces enterocyte resistance against infection by the intracellular pathogen Cryptosporidium parvum. , 2001, Gastroenterology.

[38]  O. Yoshie,et al.  Proinflammatory cytokines induce liver and activation-regulated chemokine/macrophage inflammatory protein-3alpha/CCL20 in mucosal epithelial cells through NF-kappaB [correction of NK-kappaB]. , 2001, International immunology.

[39]  L Eckmann,et al.  Intestinal Epithelial Cell Apoptosis following Cryptosporidium parvum Infection , 2000, Infection and Immunity.

[40]  J. Perfettini,et al.  Caspase-dependent apoptosis during infection with Cryptosporidium parvum. , 1999, Microbes and infection.

[41]  N. Perreault,et al.  Primary cultures of fully differentiated and pure human intestinal epithelial cells. , 1998, Experimental cell research.

[42]  M. Kagnoff,et al.  Cryptosporidium parvum infection of human intestinal epithelial cells induces the polarized secretion of C-X-C chemokines , 1997, Infection and immunity.

[43]  S. Tzipori,et al.  Profiles of healing and nonhealing Cryptosporidium parvum infection in C57BL/6 mice with functional B and T lymphocytes: the extent of gamma interferon modulation determines the outcome of infection , 1997, Infection and immunity.

[44]  S. Kernéis,et al.  Transimmortalized mouse intestinal cells (m-ICc12) that maintain a crypt phenotype. , 1996, The American journal of physiology.