Abstract
The mannose-sensitive hemagglutination pilus strain of Pseudomonas aeruginosa (PA-MSHA) has been shown to trigger naïve immune responses through the activation of monocytes, macrophages, natural killer cells (NK cells) and antigen presenting cells (APCs). Based on the hypothesis that PA-MSHA activates natural immunity through the Toll-like receptor (TLR) pathway, we scanned several critical TLR pathway molecules in mouse splenocytes using high-throughput real-time QRT-PCR and co-stimulatory molecule in bone marrow-derived dendritic cells (BMDCs) following in vitro stimulation by PA-MSHA. PA-MSHA enabled activation of the TLR pathway mediated by NF-κB and JNK signaling in splenocytes, and the co-stimulatory molecule CD86 was up-regulated in BMDCs. We then assessed the adjuvant effect of PA-MSHA for HIV-1 DNA vaccines. In comparison to DNA inoculation alone, co-inoculation with low dosage of PA-MSHA enhanced specific immunoreactivity against HIV-1 Env in both cellular and humoral responses, and promoted antibody avidity maturation. However, high doses of adjuvant resulted in an immunosuppressive effect; a two- or three-inoculation regimen yielded low antibody responses and the two-inoculation regimen exhibited only a slight cellular immunity response. To our knowledge, this is the first report demonstrating the utility of PA-MSHA as an adjuvant to a DNA vaccine. Further research is needed to investigate the exact mechanisms through which PA-MSHA achieves its adjuvant effects on innate immune responses, especially on dendritic cells.
Highlights
Despite decades of global research efforts, an efficacious HIV vaccine has remained elusive far
To directly assess the role of PA-MSHA during Toll-like receptor (TLR) activation, mouse splenocytes were stimulated with PA-MSHA in vitro and differential expression of the TLR pathway molecules were measured at several time-points by real-time qRT-PCR
We assessed the ability of PA-MSHA to activate innate immune responses in murine splenocytes and bone marrow-derived dendritic cells (BMDCs), as well as its in vivo adjuvant effects in enhancing cellular and humoral immune responses to HIV-1 Env peptides following co-administration with a DNA vaccine
Summary
Despite decades of global research efforts, an efficacious HIV vaccine has remained elusive far. Poor delivery efficiency has impaired their practical use; despite considerable efforts to improve delivery, DNA vaccination results in only minute levels of antigens in the body for inducing the immune system. A number of adjuvant strategies have been designed to improve plasmid DNA immunogenicity, including directly stimulating the immune system as well as enhancing plasmid DNA expression. DNA vaccine adjuvants are an active field of research and have generated a broad range of candidate molecules. CpG oligodeoxynucleotide (CpG-ODN), a successful adjuvant, has been shown in several clinical trials [1,2,3] and pilot studies [4,5,6,7] to effectively enhance specific cellular and humoral immune responses. Other materials such as bacterial toxins [8], saponins [9], lipopolysaccharide derivatives [10], lipopeptides and cytokines have demonstrated adjuvant effects
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