Cryptosporidium parvumInfection Rapidly Induces a Protective Innate Immune Response Involving Type I Interferon

Abstract

Type II interferon (IFN), IFN-gamma, is important in innate immunity to the intestinal protozoan parasite Cryptosporidium species, which infects epithelial cells (enterocytes). This investigation is, to our knowledge, the first to characterize the role of type I IFN in innate immunity to this parasite. Pretreatment of human or murine enterocyte cell lines with IFN-alpha/beta inhibited parasite development, and we identified that a key mechanism of cytokine action was to prevent parasite invasion of enterocytes. IFN-alpha/beta was rapidly expressed by infected murine enterocytes and also by bone marrow-derived dendritic cells that were exposed to live parasites. Treatment of neonatal severe combined immunodeficiency mice with anti-IFN-alpha/beta neutralizing antibodies before infection increased oocyst reproduction, as measured at the peak of infection, and parasite numbers in gut epithelium were also increased 2 days after infection. The latter observation correlated with strong intestinal expression of both IFN-alpha and IFN-beta messenger RNA within 24 h after infection. Treatment with anti-IFN-alpha/beta, however, did not reduce early expression of IFN-gamma. These findings identify a novel early innate host response against Cryptosporidium parvum involving IFN-alpha/beta.

MicroRNA-221 controls expression of intercellular adhesion molecule-1 in epithelial cells in response to Cryptosporidium parvum infection

“…The invasion of intestinal and biliary epithelial cells by C. parvum in vitro activates epithelial cells, resulting in the production and secretion of various cytokines and chemokines and anti-microbial peptides (e.g., β-defensins and cathelicidins) that can kill C. parvum or inhibit parasite growth (Chen et al, 2005; Ehigiator et al 2005; Barakat et al, 2009). MyD88-deficient mice and IFN-γ- or TNF-α-deficient mice are more sensitive to C. parvum infection (Lacroix et al, 2001; Rogers et al, 2006), and acquired resistance to cryptosporidial infection is dependent upon T-cells (McDonald et al, 2000; Deng et al, 2004).…”

The gut flora is required for the control of intestinal infection by poly(I:C) administration in neonates

“…23 The development of C. parvum infection in intestinal epithelial cells is effectively controlled by both type I and type II IFNs. 32,33 We observed that the injection of poly(I:C) into infected IFN-αRand IFN-γ-deficient neonatal mice did not reduce the parasite load in the intestines. 23 Unlike type I IFNs, IFN-γ affects the invasion of enterocytes by C. parvum by decreasing the amount of cellular Fe 2+ available.…”

“…23 Unlike type I IFNs, IFN-γ affects the invasion of enterocytes by C. parvum by decreasing the amount of cellular Fe 2+ available. 32,33 These different mechanisms of protection mediated by IFNs suggest synergy between these molecules in the control of parasite development. Type I and II IFNs bind to IFN-αR1-R2 and IFN-γR1-R2, respectively, but both induce the formation of Stat1-Stat1 homodimers, which are translocated to the nucleus, where they bind GAS (an IFN-γ-activated site) elements, thereby inducing gene transcription.…”

Systemic and Mucosal Immune Responses to Cryptosporidium—Vaccine Development

“…Dendritic cells migrate toward areas of C. parvum infection in an IFN- γ-dependent manner (38), but until recently, their role in clearance of the parasite was unclear. In vitro studies found that bone marrow-derived dendritic cells challenged with C. parvum sporozoites or antigens secreted a number of cytokines, including type I IFN, TNF-α, IL-6, IL-1β, IL-12, and IL-18 (36,56,59). More recent studies have elucidated the importance of dendritic cells in vivo .…”