Nitric oxide production by human intestinal epithelial cells and competition for arginine as potential determinants of host defense against the lumen-dwelling pathogen Giardia lamblia.
Giardia lamblia infection of the human small intestine is a common protozoan cause of diarrheal disease worldwide. Although infection is luminal and generally self-limiting, and secretory Abs are thought to be important in host defense, other defense mechanisms probably affect the duration of infection and the severity of symptoms. Because intestinal epithelial cells produce NO, and its stable end products, nitrite and nitrate, are detectable mainly on the apical side, we tested the hypothesis that NO production may constitute a host defense against G. lamblia. Several NO donors, but not their control compounds, inhibited giardial growth without affecting viability, suggesting that NO is cytostatic rather than cytotoxic for G. lamblia. NO donors also inhibited giardial differentiation induced by modeling crucial environmental factors, i. e., encystation induced by bile and alkaline pH, and excystation in response to gastric pH followed by alkaline pH and protease. Despite the potent antigiardial activity of NO, G. lamblia is not simply a passive target for host-produced NO, but has strategies to evade this potential host defense. Thus, in models of human intestinal epithelium, G. lamblia inhibited epithelial NO production by consuming arginine, the crucial substrate used by epithelial NO synthase to form NO. These studies define NO and arginine as central components in a novel cross-talk between a luminal pathogen and host intestinal epithelium.
Eckmann
L
L
Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA. leckmann@ucsd.edu
Laurent
F
F
Langford
T D
TD
Hetsko
M L
ML
Smith
J R
JR
Kagnoff
M F
MF
Gillin
F D
FD
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D001120:Arginine / Q000378:metabolism*; D001667:Binding, Competitive; D018938:Caco-2 Cells / Q000201:enzymology / Q000378:metabolism / Q000469:parasitology; D002450:Cell Communication / Q000276:immunology; D016764:Cell Polarity / Q000276:immunology; D016829:Giardia lamblia / Q000187:drug effects / Q000254:growth & development / Q000276:immunology / Q000472:pathogenicity*; D005873:Giardiasis / Q000276:immunology / Q000469:parasitology / Q000517:prevention & control*; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000502:physiology*; D019073:HT29 Cells / Q000201:enzymology / Q000378:metabolism / Q000469:parasitology; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology / Q000378:metabolism* / Q000469:parasitology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D009603:Nitroso Compounds / Q000494:pharmacology; D026422:S-Nitrosoglutathione
D000981:Antiprotozoal Agents; D006131:Growth Inhibitors; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D001120:Arginine; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D005978:Glutathione