Neuronal Nitric Oxide Synthase Is Necessary for Elimination of Giardia lamblia Infections in Mice

Abstract

NO produced by inducible NO synthase (NOS2) is important for the control of numerous infections. In vitro, NO inhibits replication and differentiation of the intestinal protozoan parasite Giardia lamblia. However, the role of NO against this parasite has not been tested in vivo. IL-6-deficient mice fail to control Giardia infections, and these mice have reduced levels of NOS2 mRNA in the small intestine after infection compared with wild-type mice. However, NOS2 gene-targeted mice and wild-type mice treated with the NOS2 inhibitor N-iminoethyl-l-lysine eliminated parasites as well as control mice. In contrast, neuronal NOS (NOS1)-deficient mice and wild-type mice treated with the nonspecific NOS inhibitor NG-nitro-l-arginine methyl ester and the NOS1-specific inhibitor 7-nitroindazole all had delayed parasite clearance. Finally, Giardia infection increased gastrointestinal motility in wild-type mice, but not in SCID mice. Furthermore, treatment of wild-type mice with NG-nitro-l-arginine methyl ester or loperamide prevented both the increased motility and the elimination of parasites. Together, these data show that NOS1, but not NOS2, is necessary for clearance of Giardia infection. They also suggest that increased gastrointestinal motility contributes to elimination of the parasite and may also contribute to parasite-induced diarrhea. Importantly, this is the first example of NOS1 being involved in the elimination of an infection.

Role of apolipoprotein E4 in protecting children against early childhood diarrhea outcomes and implications for later development

“…One may involve the oxidative stress balance during parasitic infection, possibly involving arginine transport. Since the arginine selective cationic transporter is upregulated in APOE4 knock-in mice in neuroglia, increased arginine uptake by enterocytes could provide critical generation of NO during enteric infection caused by Giardia lamblia [86,50], which we and others have found to be correlated with cognitive deficits following diarrhea [49,87], thus enhancing host defenses against enteric infections and diarrhea. Those potential mechanisms are topics of our ongoing studies.…”

“…Therefore, we raised the hypothesis that the cholesterol bioavailability might be shifted from the parasite, which cannot synthesize cholesterol per se, to the developing brain. Additionally, since apoE4 knock-in mice have increased activity of the arginine cationic transporter in glial cells, we postulate whether a similar transport within enterocytes may enhance intestinal immune defenses against infection, by elevating NO levels [50].…”

Selective neutrality analysis of 17 STRs in Mediterranean populations

“…70,71 A recent study has reported the first example of NOS1 being involved in the elimination of an infection in mice. 72 The NOS1 (CA)n repeat localized in the 3¢ untranslated region of exon 29 and the existence of allelic mRNA sequence variation have been reported. 73 An association has also been demonstrated between asthma and this dinucleotide repeat polymorphism 74,75 confirming a functional role of this short tandem repeat.…”

The effects of nitric oxide on the immune response during giardiasis

“…The authors also suggested that increased gastrointestinal motility contributes to the parasite elimination and this is the fi rst example of NOS1 being involved in the elimination of an infection. 48 In fact, the intestinal hypermotility is an important host mechanism of defense against Giardia. This defense appears to depend on the development of a normal adaptive immune response against the parasite, as it did not occur in mice lacking T and B-cells, although it is possible, in principle, that T or B-cells contribute to hypermotility independent of their role in adaptive antigiardial immunity.…”

“…They lack the conventional respiratory oxidases, as well as the systems (catalase, superoxide dismutase, glutathione reductase) responsible for the scavenging of radical oxygen species (ROS). 73 Data from Li et al 48 involving human infection with G. lamblia, indicate that signals mediated by enzymes nitric oxide synthases (NOS1 but not NOS2) play a key role in eliminating this infection.…”