An immunostimulatory oligodeoxynucleotide containing a cytidine-guanosine motif protects senescence-accelerated mice from lethal influenza virus by augmenting the T helper type 1 response

Abstract

The SAM-P1 strain of senescence-accelerated model mice shows an impaired T helper type 1 (Th1) immune response upon infection with influenza virus, which results in high susceptibility to the virus. Treatment of spleen cells from SAM-P1 mice with an immunostimulatory oligodeoxynucleotide containing a cytidine-guanosine motif (CpG ODN) in vitro increased the ratio of the titre of IFN-c to that of IL-4. Administration of CpG ODN to SAM-P1 mice generated satisfactory virus-specific cytotoxic T-lymphocyte responses and natural killer cell activation and the virus-specific immunoglobulin (Ig) isotype switched from IgG1 to IgG2a. Virus growth in the lungs of CpG ODN-treated SAM-P1 mice was cleared quickly and mice survived the lethal influenza virus infection. It could be inferred that a possible mechanism of CpG ODN for normalization of senescence-associated dysregulation of the Th1/Th2 balance involves the upregulated expression of CD154 and CD40 molecules on immune-competent cells. These results suggest that CpG ODN could contribute to the development of a protective strategy against infectious diseases, especially among immunocompromised elderly persons, by stimulating Th1 immune responses.

CpG Oligodeoxynucleotides Protect Newborn Mice from a Lethal Challenge with the Neurotropic Tacaribe Arenavirus

“…In addition, recent studies show that systemic administration of CpG ODN improved recovery of mice infected with the Friend leukemia virus and senescent mice infected with the influenza virus (12,44). Protection in all cases was linked to induction of a Th1 response.…”

Activation of Toll-like receptor 9 and production of epitope specific antibody by liposome-encapsulated CpG-DNA

“…Several investigators have shown that the CpG-DNA has an outstanding immunostimulatory activity for inducing a strong Th1 immune response, resulting in induction of Th1 cytokines such as IL-12, IFN-α and IFN-γ (3)(4)(5). The enhanced Th1 responses contribute to the protection of the host from infectious agents (6). CpG-DNA also improves antigenpresenting cell activity through upregulation of major histocompatibility (MHC) class II molecules and costimulatory molecules (CD40, CD80, and CD86) (7)(8)(9).…”

Prophylactic Administration of Bacterially Derived Immunomodulators Improves the Outcome of Influenza Virus Infection in a Murine Model

“…CpG treatment results in potent Th1 cytokine expression (IFNs and interleukin-12 ), activation of dendritic cells (DCs), NK cells, and B cells, and induction of Th1 cells and a Th1 antibody profile (30,35,83). CpG has been extensively studied in animal models of systemic and pulmonary infectious diseases caused by influenza virus (15,82) and other bacterial, fungal, and parasitic pathogens (3,9,15,17,25,34,51,77). Bacterially derived ADP-ribosylating enterotoxins, including CT from Vibrio cholerae and LT from E. coli, are robust systemic and mucosal adjuvants.…”

“…The first strategy has been demonstrated in animal models by administering host proteins/glycoproteins that function in immune defense, such as the pattern recognition receptor (PRR) mindin (28), milk-derived glycoproteins (61), and virally delivered interferon (IFN) cytokines (27). Immunomodifiers of microbial origin have also been used to enhance host response to infection, including the binding subunit of cholera toxin (CT-B) (49), Th1-promoting Toll-like receptor (TLR) agonists CpG oligodeoxynucleotides (ODN) (15,82), poly(I:C) (81), 3 M-011 (23), and synthetic lipid A analogs (11). Immunomodulators used in the second strategy, with the aim to prevent detrimental inflammation, have been associated with improved infection outcomes and include enterotoxin mutant LT(S63K) (80) and anti-inflammatory COX-2 inhibitors (84).…”