Oral and intraperitoneal administration of phosphorothioate oligodeoxynucleotides leads to control of Cryptosporidium parvum infection in neonatal mice.
BACKGROUND
Neonates are particularly vulnerable to infections, in part because of the incomplete development of their immune system. Recent advances in immunostimulatory treatments based on conserved microbial components led us to assess the potential of oligodeoxynucleotides (ODNs) for decreasing the sensitivity of neonates to Cryptosporidium parvum infection.


METHODS
Neonate mice were treated orally or intraperitoneally (ip) with CpG ODNs or non-CpG ODNs 24 h before C. parvum infection, and parasite load and cytokine up-regulation were evaluated.


RESULTS
CpG ODN 1668 and non-CpG ODN 1668 administered orally, as well as CpG ODN 1668 administered ip, induced an 80%-95% decrease in intestinal parasite load 6 days after infection. Intraperitoneal and oral pretreatment with CpG ODN 1668 led to a strong initial up-regulation of cytokines and CD69 messenger RNA in the intestine and a decrease in parasite load by a Toll-like receptor 9 (TLR9)-dependent mechanism. By contrast, oral administration of non-CpG ODN 1668 decreased parasite load by a TLR9-independent mechanism.


CONCLUSIONS
The control of neonatal C. parvum infection by ip or oral administration of ODNs is feasible by 2 different mechanisms: (1) the well-known interaction involving CpG/TLR9, leading to the production of cytokines and lymphocyte activation, and (2) a new unknown mechanism that is independent of TLR9 and effective orally.
Barrier
Mathieu
M
Laboratoire Contrôle et Immunologie des Maladies Entériques du Nouveau-né, UR1282 Infectiologie Animale et Santé Publique, Institut National de la Recherche Agronomique de Tours, Nouzilly, France.
Lacroix-Lamandé
Sonia
S
Mancassola
Roselyne
R
Auray
Gaël
G
Bernardet
Nelly
N
Chaussé
Anne-Marie
AM
Uematsu
Satoshi
S
Akira
Shizuo
S
Laurent
Fabrice
F
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn; D003457:Cryptosporidiosis / Q000188:drug therapy; D016785:Cryptosporidium parvum / Q000187:drug effects* / Q000472:pathogenicity; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D021261:Parasitic Sensitivity Tests; D016133:Polymerase Chain Reaction; D016053:RNA, Protozoan / Q000032:analysis; D013047:Specific Pathogen-Free Organisms
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D016053:RNA, Protozoan