Abstract
Effective and safe vaccine adjuvants are needed to appropriately augment mucosal vaccine effects. Our previous study demonstrated that lipopolysaccharide (LPS) from Peyer’s patch resident Alcaligenes stimulated dendritic cells to promote the production of mucosal immunity-enhancing cytokines (e.g., IL-6 and BAFF), thus enhancing antigen-specific immune responses (including IgA production and Th17 responses) without excessive inflammation. Here, we chemically synthesized Alcaligenes lipid A, the biologically active part of LPS, and examined its efficacy as a nasal vaccine adjuvant for the induction of protectively immunity against Streptococcus pneumoniae infection. Mice were nasally immunized with pneumococcal surface protein A (PspA) as a vaccine antigen for S. pneumoniae, together with Alcaligenes lipid A. Alcaligenes lipid A supported the generation of high levels of PspA-specific IgA and IgG responses through the augmentation of germinal center formation in the nasopharynx-associated lymphoid tissue and cervical lymph nodes (CLNs). Moreover, Alcaligenes lipid A promoted PspA-specific CD4+ Th17 responses in the CLNs and spleen. Furthermore, neutrophils were recruited to infection sites upon nasal infection and synchronized with the antigen-specific T and B cell responses, resulting in the protection against S. pneumoniae infection. Taken together, Alcaligenes lipid A could be applied to the prospective adjuvant to enhance nasal vaccine efficacy by means of augmenting both the innate and acquired arms of mucosal immunity against respiratory bacterial infection.
Highlights
Various pathogens cause infectious diseases by invading through the surface of the respiratory and gastrointestinal tracts [1]
Mice nasally-immunized with pneumococcal surface protein A (PspA) and Alcaligenes lipid A showed higher levels of PspA-specific IgA antibodies in the nasal wash and bronchoalveolar lavage fluid (BALF) than mice immunized with PspA alone (Figure 1A,B), demonstrating that co-administration of Alcaligenes lipid A supported the generation of elevated antigen specific-immune responses both in upper and lower respiratory tracts
Co-administered Alcaligenes lipid A supported the induction of elevated PspA-specific antibody responses in upper respiratory tracts, so we examined whether nasally-co-administered Alcaligenes lipid A contributed for the germinal center (GC) formation in the nasopharynx-associated lymphoid tissue (NALT), an important immunological event for initiation of antigen-specific immune responses in the nasopharynx cavity [20]
Summary
Various pathogens cause infectious diseases by invading through the surface of the respiratory and gastrointestinal tracts [1]. In the respiratory immune system, nasopharynx-associated lymphoid tissue (NALT) has been suggested to be one of target tissues for the delivery of nasal vaccine, since it is equipped with all of the necessary immune cells for the induction of antigen-specific immune responses. It is generally known that as like the injection-type vaccines, nasal vaccination requires a safe and effective mucosal adjuvant for the induction of protective immunity. Escherichia coli-derived LPS is known to induce excessive inflammation, Alcaligenes-derived LPS showed biologically negligible inflammatory responses [10] These findings suggested that Alcaligenes LPS could be an effective and safe adjuvant. As it is known that Th17 response is essential to prevent pneumococcal infection [16] and Alcaligenes LPS could induce antigen-specific Th17 responses [10], nasal vaccination of PspA with Alcaligenes lipid A is expected to efficiently induce protective immunity against S. pneumoniae infection. Our current study indicated that Alcaligenes lipid A could be an efficient adjuvant for the nasal vaccines against respiratory infection with S. pneumoniae
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