A protective role for interleukin 18 in interferon γ-mediated innate immunity to Cryptosporidium parvum that is independent of natural killer cells.

Innate immunity against some intracellular parasitic protozoa involves interleukin 18 (IL-18)-mediated interferon γ (IFN-γ) production by natural killer (NK) cells, but the role of IL-18 in innate resistance to Cryptosporidium infection is unknown. Adult Rag2(-/-)γc(-/-) mice that lack NK cells, T cells, and B cells demonstrated resistance to Cryptosporidium parvum infection that was IFN-γ dependent. Treatment with anti-IL-18-neutralizing antibodies resulted in loss of resistance correlating with reduced intestinal IFN-γ expression. Intestinal mature IL-18 expression increased in vivo during infection and also in the intestinal epithelial cell line CMT-93 following combined IFN-γ treatment/infection. Peritoneal macrophages produced IFN-γ when stimulated with IL-18 combined with interleukin 12, and the latter was expressed in vivo during infection. Macrophage depletion in infected mice caused a rapid growth of infection with no increase in IFN-γ expression. These findings provide evidence of an NK cell-independent, IFN-γ-mediated innate immune pathway against C. parvum in which IL-18 and macrophages play prominent parts.

[1]  S. Tzipori,et al.  Cryptosporidiosis in rhesus macaques challenged during acute and chronic phases of SIV infection. , 2011, AIDS research and human retroviruses.

[2]  J. D. Di Santo,et al.  CD4+ T Cells Are Not Essential for Control of Early Acute Cryptosporidium parvum Infection in Neonatal Mice , 2011, Infection and Immunity.

[3]  G. Macfarlane,et al.  Induction of cytokine formation by human intestinal bacteria in gut epithelial cell lines , 2011, Journal of applied microbiology.

[4]  M. Kastan,et al.  The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. , 2010, Immunity.

[5]  U. Schleicher,et al.  IL-18, but not IL-15, contributes to the IL-12-dependent induction of NK-cell effector functions by Leishmania infantum in vivo , 2010, European journal of immunology.

[6]  G. Foster,et al.  Cryptosporidium parvum infection rapidly induces a protective innate immune response involving type I interferon. , 2009, The Journal of infectious diseases.

[7]  M. Bajaj‐Elliott,et al.  Dysregulation of interferon‐γ‐mediated signalling pathway in intestinal epithelial cells by Cryptosporidium parvum infection , 2009, Cellular microbiology.

[8]  J. D. Di Santo,et al.  Roles for NK Cells and an NK Cell-Independent Source of Intestinal Gamma Interferon for Innate Immunity to Cryptosporidium parvum Infection , 2009, Infection and Immunity.

[9]  C. Tremblay,et al.  Role of interleukin-18 in the development and pathogenesis of AIDS. , 2009, AIDS reviews.

[10]  I. Förster,et al.  Dynamics of gut mucosal and systemic Th1/Th2 cytokine responses in interferon-gamma and interleukin-12p40 knock out mice during primary and challenge Cryptosporidium parvum infection. , 2009, Immunobiology.

[11]  B. Clotet,et al.  Secretion of interferon‐γ by human macrophages demonstrated at the single‐cell level after costimulation with interleukin (IL)‐12 plus IL‐18 , 2009, Immunology.

[12]  O. Maeda,et al.  Helicobacter pylori infection upregulates interleukin-18 production from gastric epithelial cells , 2008, European journal of gastroenterology & hepatology.

[13]  Makiko Kobayashi,et al.  Cooperative Role of Macrophages and Neutrophils in Host Antiprotozoan Resistance in Mice Acutely Infected with Cryptosporidium parvum , 2008, Infection and Immunity.

[14]  F. Petry,et al.  Humoral immune response in IL‐12 and IFN‐γ deficient mice after infection with Cryptosporidium parvum , 2008, Parasite immunology.

[15]  M. Russo,et al.  Role of Endogenous IFN-γ in Macrophage Programming Induced by IL-12 and IL-18 , 2007 .

[16]  J. Mead,et al.  Cryptosporidium parvum: the contribution of Th1-inducing pathways to the resolution of infection in mice. , 2007, Experimental parasitology.

[17]  M. Bajaj‐Elliott,et al.  A potential role for interleukin‐18 in inhibition of the development of Cryptosporidium parvum , 2006, Clinical and experimental immunology.

[18]  C. Bogdan,et al.  Production of interferon-γ by myeloid cells – fact or fancy? , 2006 .

[19]  A. White,et al.  Interleukin-15 activates human natural killer cells to clear the intestinal protozoan cryptosporidium. , 2005, The Journal of infectious diseases.

[20]  S. McDonald,et al.  Protection against the early acute phase of Cryptosporidium parvum infection conferred by interleukin-4-induced expression of T helper 1 cytokines. , 2004, The Journal of infectious diseases.

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

[22]  A. Rothfuchs,et al.  Macrophages, CD4+ or CD8+ Cells Are Each Sufficient for Protection against Chlamydia pneumoniae Infection through their Ability to Secrete IFN-γ1 , 2004, The Journal of Immunology.

[23]  A. Meyerhans,et al.  Rapid increase of mucosal CD4 T cells followed by clearance of intestinal cryptosporidiosis in an AIDS patient receiving highly active antiretroviral therapy. , 2001, Gastroenterology.

[24]  C. Hunter,et al.  Interleukin-18 (IL-18) Enhances Innate IL-12-Mediated Resistance to Toxoplasma gondii , 2000, Infection and Immunity.

[25]  K. Chmura,et al.  Interferon-γ Is Required for Innate Immunity to Cryptosporidium parvum in Mice , 2000 .

[26]  F. Galeazzi,et al.  Inflammation-induced impairment of enteric nerve function in nematode-infected mice is macrophage dependent. , 2000, American journal of physiology. Gastrointestinal and liver physiology.

[27]  J. Mead,et al.  Susceptibility differences to Cryptosporidium parvum infection in two strains of gamma interferon knockout mice. , 1998, The Journal of parasitology.

[28]  W. Davis,et al.  IL-4 Protects Adult C57BL/6 Mice from Prolonged Cryptosporidium parvum Infection: Analysis of CD4+αβ+IFN-γ+ and CD4+αβ+IL-4+ Lymphocytes in Gut-Associated Lymphoid Tissue During Resolution of Infection , 1998, The Journal of Immunology.

[29]  R. Fayer,et al.  Cryptosporidium and Cryptosporidiosis , 1997 .

[30]  T. K. van den Berg,et al.  Apoptosis of macrophages induced by liposome-mediated intracellular delivery of clodronate and propamidine. , 1996, Journal of immunological methods.

[31]  F. Finkelman,et al.  IL-12 protects immunocompetent and immunodeficient neonatal mice against infection with Cryptosporidium parvum. , 1996, Journal of immunology.

[32]  N. Van Rooijen,et al.  Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications. , 1994, Journal of immunological methods.

[33]  E. A. Havell,et al.  Gamma interferon functions in resistance to Cryptosporidium parvum infection in severe combined immunodeficient mice , 1993, Infection and immunity.

[34]  B. Gazzard,et al.  Cryptosporidiosis in HIV-seropositive patients. , 1992, The Quarterly journal of medicine.

[35]  N. C. Reese,et al.  A comparison of endogenous development of three isolates of Cryptosporidium in suckling mice. , 1986, The Journal of protozoology.

[36]  M. Russo,et al.  Role of endogenous IFN-gamma in macrophage programming induced by IL-12 and IL-18. , 2006, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[37]  C. Bogdan,et al.  Production of interferon-gamma by myeloid cells--fact or fancy? , 2006, Trends in immunology.

[38]  U. Yrlid,et al.  The Innate Immune Response Differs in Primary and Secondary Salmonella Infection , 2002 .

[39]  K. Chmura,et al.  Interferon-gamma is required for innate immunity to Cryptosporidium parvum in mice. , 2000, The Journal of infectious diseases.

[40]  G. Bancroft,et al.  Host immune responses against Cryptosporidium. , 2000, Contributions to microbiology.

[41]  H. Okamura,et al.  Interleukin-18: a novel cytokine that augments both innate and acquired immunity. , 1998, Advances in immunology.

[42]  J. Gobert,et al.  Kinetics of mucosal ileal gamma-interferon response during cryptosporidiosis in immunocompetent neonatal mice , 1996, Parasitology Research.

[43]  Immune responses. , 1968, Nature.