CpG oligodeoxynucleotides protect newborn mice from a lethal challenge with the neurotropic Tacaribe arenavirus.
The innate immune system is key to limiting the early spread of most pathogens and directing the development of Ag-specific immunity. Recently, a number of synthetic molecules that activate the innate immune system by stimulating TLRs have been identified. Among them, synthetic oligodeoxynucleotides (ODNs) containing unmethylated CpG motifs (CpG ODNs) were shown to activate TLR9-bearing B cells, macrophages, and dendritic cells to induce a strong proinflammatory milieu and a type 1-biased immune response that protects mice from a variety of parasitic, bacterial, and viral infections. Although the protective effect of CpG ODN in adult mice was well established, its effectiveness in neonates, which have lower numbers of dendritic, B, and T cells and tend to favor Th2 responses, was unclear. This study uses the New World arenavirus Tacaribe, a neurotropic pathogen that is lethal in newborn mice, to explore the effectiveness of TLR-mediated innate immune responses. Neonatal BALB/c mice treated with CpG ODN at the time of infection had reduced viral load (p < 0.01) and increased survival (52%, p < 0.001 i.p.; 36%, p < 0.05 intranasally). Protection was achieved in mice treated no later than 3 days postchallenge and appears to be mediated by an increase in Ag-specific Abs (IgG and IgM) and to require inducible NO synthase expression and NO production. To our knowledge, this is the first study assessing the mechanisms by which CpG ODN can protect mice from a neurotropic viral infection.
Division of Therapeutic Proteins, Office of Biotechnology Products, Center for Drug Evaluation and Research, Federal Drug Administration, Bethesda, MD 20892, USA.
João A
JA
Pedras-Vasconcelos
David
D
Goucher
Montserrat
M
Puig
Leonardo H
LH
Tonelli
Vivian
V
Wang
Shuichi
S
Ito
Daniela
D
Verthelyi
D000818:Animals; D000831:Animals, Newborn; D000914:Antibodies, Viral / Q000096:biosynthesis; D001117:Arenaviridae Infections / Q000276:immunology / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D006477:Arenaviruses, New World / Q000276:immunology / Q000302:isolation & purification / Q000472:pathogenicity*; D001483:Base Sequence; D002494:Central Nervous System Infections / Q000276:immunology / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D008590:Meningoencephalitis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D000914:Antibodies, Viral; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma