Cryptosporidium infection in an adult mouse model. Independent roles for IFN-gamma and CD4+ T lymphocytes in protective immunity.
Cryptosporidium is a protozoan parasite that can cause chronic life-threatening diarrhea in immunocompromised persons. Host immune responses are poorly understood, an impediment to development of effective therapy. In mice, normal adult BALB/c animals resist infection whereas chronic symptomatic cryptosporidiosis develops in adult nude mice and in neonatally infected BALB/c mice treated with anti-CD4 mAb. To define further the immune defects that allow mice to be infected with Cryptosporidium, adult BALB/c mice were treated with cytolytic anti-CD4 or anti-CD8 or with neutralizing anti-IFN-gamma or anti-IL-2 mAb. Chronic infection, manifested by continuous shedding of sparse but statistically significant numbers of oocysts, occurred with anti-CD4 +/- anti-CD8 mAb treatment although anti-CD8 mAb treatment alone did not allow infection. Treatment with anti-IFN-gamma mAb greatly enhanced oocyst shedding but infection was self-limited. Treatment with a combination of anti-CD4 and anti-IFN-gamma mAb permitted both chronic infection and shedding of large numbers of oocysts. Furthermore mice treated initially with anti-CD4 mAb showed a substantial increase in oocyst shedding when later treated with anti-IFN-gamma mAb; and mice treated initially with both mAbs showed a decline in oocyst shedding when anti-IFN-gamma mAb was stopped. Anti-IFN-gamma mAb treatment of congenitally athymic adult BALB/c mice led to an approximately a 75-fold increase in oocyst shedding. Treatment of adult BALB/c mice with anti-IL-2 mAb did not permit Cryptosporidium infection. These results suggest that redundant immunologic mechanisms limit Cryptosporidium infection such that both CD4+ cells and IFN-gamma are required to prevent initiation of infection whereas either alone can limit the extent (IFN-gamma) or duration (CD4+ T cells) of infection. They also suggest that production of IFN-gamma by a non-T cell contributes to host immunity.
Department of Preventive Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814.
B L
BL
Ungar
T C
TC
Kao
J A
JA
Burris
F D
FD
Finkelman
D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology; D015704:CD4 Antigens / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016827:CD8 Antigens; D003457:Cryptosporidiosis / Q000276:immunology*; D004195:Disease Models, Animal; D005243:Feces / Q000382:microbiology; D007082:Ileum / Q000473:pathology; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000276:immunology*; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D013997:Time Factors
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D015704:CD4 Antigens; D016827:CD8 Antigens; D007371:Interferon-gamma