Abstract
We previously identified Alcaligenes spp. as a commensal bacterium that resides in lymphoid tissues, including Peyer’s patches. We found that Alcaligenes-derived lipopolysaccharide acted as a weak agonist of Toll-like receptor four due to the unique structure of lipid A, which lies in the core of lipopolysaccharide. This feature allowed the use of chemically synthesized Alcaligenes lipid A as a safe synthetic vaccine adjuvant that induces Th17 polarization to enhance systemic IgG and respiratory IgA responses to T-cell–dependent antigens (e.g., ovalbumin and pneumococcal surface protein A) without excessive inflammation. Here, we examined the adjuvant activity of Alcaligenes lipid A on a Haemophilus influenzae B conjugate vaccine that contains capsular polysaccharide polyribosyl ribitol phosphate (PRP), a T-cell–independent antigen, conjugated with the T-cell–dependent tetanus toxoid (TT) antigen (i.e., PRP-TT). When mice were subcutaneously immunized with PRP alone or mixed with TT, Alcaligenes lipid A did not affect PRP-specific IgG production. In contrast, PRP-specific serum IgG responses were enhanced when mice were immunized with PRP-TT, but these responses were impaired in similarly immunized T-cell—deficient nude mice. Furthermore, TT-specific—but not PRP-specific—T-cell activation occurred in mice immunized with PRP-TT together with Alcaligenes lipid A. In addition, coculture with Alcaligenes lipid A promoted significant proliferation of and enhanced antibody production by B cells. Together, these findings suggest that Alcaligenes lipid A exerts an adjuvant activity on thymus-independent Hib polysaccharide antigen in the presence of a T-cell–dependent conjugate carrier antigen.
Highlights
Host immunity includes both innate and adaptive phases for the induction of antigen-specific immune responses
Mice immunized with Haemophilus B conjugate vaccine in the presence of Alcaligenes lipid A had higher levels of PRPspecific serum IgG than did mice immunized with Haemophilus B conjugate vaccine alone at different antigen doses of 0.01 and 1 μg of polyribosyl ribitol phosphate (PRP) (Figures 1A; Supplementary Figure S1)
These results show that Alcaligenes lipid A can enhance the production of IgG against PRP, a TI antigen, when PRP is conjugated to tetanus toxoid (TT)
Summary
Host immunity includes both innate and adaptive phases for the induction of antigen-specific immune responses. Vaccines must use the host immune sequence of innate and adaptive phases for effectively promote the induction of an antigen-specific defense especially during the adaptive immune response (Messina et al, 2019). DCs can recognize microbial components (e.g., lipopolysaccharide [LPS]) through pattern-recognition receptors such as Toll-like receptors (Lipscomb and Masten, 2002), which induce the secretion of immune enhancing cytokines and promote antigen processing and presentation for the initiation and enhancement of antigenspecific immune responses (Lee and Iwasaki, 2007). We previously showed that the commensal bacterium Alcaligenes resides within Peyer’s patches, a well characterized mucosa-associated lymphoid tissue for the initiation of antigen-specific immune responses in the intestine (Obata et al, 2010; Kunisawa and Kiyono, 2012). Compared with non-symbiotic Escherichia coli, symbiotic Alcaligenes have low inflammatory activity, which is explained at least partly by the unique features of its LPS (Fung et al, 2016; Shibata et al, 2018; Hosomi et al, 2020)
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