The goal of this proposal is to determine the effectiveness of pneumococcal vaccines influenced by the common human STING (stimulator of interferon genes) variant R71H-G230A-R293Q (HAQ). Pneumococcal diseases kill more people than all other vaccine-preventable diseases combined. Pneumovax 23 and Prevnar 13 are polysaccharide vaccines providing serotype-specific protection. Since its approval in 1983, Pneumovax 23 results in only ~57% of overall disease reduction. Recently, Dr. Bruce Beutler?s group showed that polysaccharide Ag generates a cyclic dinucleotide (CDN) called 2?5?-3?5?-cyclic GMP-AMP (2?3?-cGAMP) in B cells leading to the activation of STING-Type I IFN pathway. STING is a receptor for CDN. STING-/- mice have decreased Ab production to Pneumovax 23. Our own data showed that STING-/- mice also have decreased Ab production to Prevnar 13. We previously identified a human STING variant HAQ that is common in non-Africans. ~3% of Caucasians and ~16% of East Asians are HAQ/HAQ. In fact, R232(wt)/HAQ, not the R232(wt)/R232(wt), is the most common STING genotype in East Asians. Examining B cells derived from human HAQ/HAQ individuals, we found that HAQ B cells have dramatically decreased STING expression. We hypothesize that Pneumovax 23 and Prevnar 13 vaccine effectiveness is influenced by HAQ STING variant. To test this hypothesis and uncover the in vivo mechanism, we generated the HAQ, AQ and Q293 STING knock-in mice.
In Aim 1, we will determine (a) the impact of HAQ STING on the effectiveness of Pneumovax 23 and Prevnar13 vaccines in vivo (Aim 1.1); (b) the in vivo mechanism by which HAQ STING influences Pneumovax 23 and Prevnar13 effectiveness (Aim 1.2). Pneumovax 23 and Prevnar 13 do not elicit strong mucosal immunity. A mucosal pneumococcal vaccine consists of a common protein Ag and a potent mucosal adjuvant can provide serotype-independent mucosal protection. Recently, a synthetic CDN, RpRp-c-di-AMPss, was reported to activate all human STING variants in HEK293T cells. Our preliminary data demonstrated that RpRp-c-di-AMPss has mucosal vaccine adjuvant activity eliciting strong Ab production and balanced Th1/Th2/Th17 response that depends on STING.
In Aim 2, we will determine (a) the impact of HAQ STING on the mucosal adjuvant activity of RpRp-c-di-AMPss in vivo (Aim 2.1); (b) the in vivo mechanism by which HAQ STING influences RpRp-c-di-AMPss mucosal adjuvant activity (Aim 2.2). We will evaluate RpRp-c-di-AMPss adjuvanted pneumococcal surface protein A (PspA) vaccine induced humoral, cellular immune responses, and the protective immunity against S. pneumoniae infection in our knock-in mice. Achieving these Aims will pave the way for the development of STING-targeting precision medicine in humans.
STING (Stimulator of interferon genes) mediates the vaccine activity of Pneumovax 23 and Prevnar13. This study aims to determine the impact of the common human HAQ STING variant on pneumococcal vaccines effectiveness. The knowledge obtained will pave the way for a precise vaccine strategy for the public.
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| Ruiz-Moreno, Juan Sebastian; Hamann, Lutz; Jin, Lei et al. (2018) The cGAS/STING Pathway Detects Streptococcus pneumoniae but Appears Dispensable for Antipneumococcal Defense in Mice and Humans. Infect Immun 86: |
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| Patel, Seema; Blaauboer, Steven M; Tucker, Heidi R et al. (2017) The Common R71H-G230A-R293Q Human TMEM173 Is a Null Allele. J Immunol 198:776-787 |
