An Early Intestinal Mucosal Source of Gamma Interferon Is Associated with Resistance to and Control ofCryptosporidium parvumInfection in Mice

Abstract

Resistance to and control of Cryptosporidium parvum infection in mice in the absence of adaptive immunity appears to be gamma interferon (IFN-␥) dependent. Using an IFN-␥-neutralizing antibody in a murine model, we demonstrated increased susceptibility to infection within 24 h. We correlated this early resistance and control with increased mucosal expression of IFN-␥ and demonstrate that CD8 ؉ T-cell receptor ␣␤ intestinal intraepithelial lymphocytes express and secrete this cytokine shortly after infection. The rapid kinetics of IFN-␥ expression and secretion by naive CD8 ؉ T cells in response to a protozoan pathogen have not previously been demonstrated.Cryptosporidium parvum is an enteric, intracellular, zoonotic parasite that causes significant morbidity, particularly among people suffering from AIDS and children in developing countries. With the exception of highly active antiretroviral therapy, there remains no effective therapy for AIDS-related cryptosporidiosis. Our understanding of the immune response to C. parvum is not complete. From studies of human and animal cryptosporidiosis, it is apparent that adaptive immunity, in the form of CD4 ϩ T cells and the cytokine gamma interferon (IFN-␥), is important for resistance to and clearance of the infection (24). However, there is convincing evidence from studies of C. parvum infection in scid mice of an IFN-␥-dependent innate resistance to infection with this parasite (7). The mechanism of this innate immune response as well as the source of IFN-␥ in this setting, however, remains undefined. Since C. parvum infects primarily the gastrointestinal epithelium, we hypothesized that immune cells within the mucosa contribute to this innate IFN-␥-dependent immunity.The purpose of this study was to demonstrate the presence of and characterize the IFN-␥-dependent innate immune response to C. parvum infection in mice. We hypothesized that intraepithelial lymphocytes (iIEL) are mediators of this IFN-␥-dependent innate immunity. Using a neutralizing anti-IFN-␥ antibody, we show increased susceptibility to C. parvum infection in C57BL/6 wild-type mice within 24 h after infection. We also demonstrate increased IFN-␥ expression within the terminal ileum in mice 24 h after infection with C. parvum and identify the specific cellular compartments that contribute to this early cytokine expression.Early resistance to C. parvum infection is IFN-␥ dependent.

Intestinal Immune Response to HumanCryptosporidiumsp. Infection

“…In murine models, IFN-␥ is a critical mediator of the innate and acquired immune responses controlling cryptosporidiosis (10,52,66,87). Similarly, severe Cryptosporidium-associated diarrhea has been described for HIV-negative individuals with IFN-␥ deficiency (28).…”

CD4+T Cells Are Not Essential for Control of Early AcuteCryptosporidium parvumInfection in Neonatal Mice

“…Ultimate control of infection in adult mice and humans is dependent on CD4 ϩ T cells (2,27), and IFN-␥ expression by these cells could be a key factor in host defense, although in humans, this cytokine might be more important during secondary infection (12,14,36). In one report, CD8 ϩ T cells in juvenile mice were reported to be involved in very early innate immunity (17), and antigen-specific human CD8 ϩ T cells cytotoxic to C. parvuminfected cells have been developed in vitro (25), but numerous other studies suggest that there is no major role for CD8 ϩ T cells in establishing immunity (2,30). An investigation with ␥␦ ϩ T cell-deficient mice suggested that ␥␦ ϩ cells had a partial protective effect against infection in neonatal mice but not adult mice (35).…”

MyD88-Dependent Pathways Mediate Resistance toCryptosporidium parvumInfection in Mice

“…Furthermore, SCID mice develop a delayed-onset chronic infection, whereas IFN-␥ Ϫ/Ϫ mice carrying the scid mutation succumb to acute infection, indicating the importance of this cytokine in the activation of innate immune responses to cryptosporidiosis in mice (18). We have recently shown that IFN-␥ is produced by intestinal CD8 ϩ intraepithelial lymphocytes as early as 24 h after C. parvum infection in mice (25).…”