Protective versus deleterious immune responses that impact vaccine efficacy against Staphylococcus aureus bloodstream infection

金黄色葡萄球菌(SA)是一种主要的人类病原体，可引起危及生命的系统性感染。在……里面 事实上，金黄色葡萄球菌是医院内菌血症最常见的原因，患病率为26%。尽管 临床护理的改善，SA血流感染(BSI)继续构成重大挑战，因为 治疗失败率和死亡率。由耐甲氧西林金黄色葡萄球菌(MRSA)菌株引起的感染有 对抗生素的抗药性越来越强，导致治疗失败和患者预后不佳。如果主机- 定向治疗这种有效的金黄色葡萄球菌疫苗可以提供一种替代抗生素的方法，更好地了解 促进保护的免疫机制的研究是至关重要的。这一点尤其重要，因为所有的SA疫苗接种 在过去的二十年里，这些尝试在人体试验中都以失败告终。值得注意的是，在最近的一项试验中，针对金黄色葡萄球菌的疫苗 铁表面决定簇B(ISDB)对心胸手术后金黄色葡萄球菌感染有相反的效果 接种疫苗并感染金黄色葡萄球菌的患者多器官衰竭的发生率高出2倍， 死亡率是安慰剂对照组的5倍。虽然造成这一灾难性结果的原因尚不清楚，但 后研究表明，在缺乏或低水平的血清T细胞细胞因子(IL-2和IL-17)的时候 接种疫苗使他们容易出现治疗失败的情况。因此，迫切需要了解 导致这些有害结果的潜在免疫学机制。我们在小鼠身上的初步发现 用致死性照射的全细胞免疫小鼠所引发的有害免疫反应 疫苗或皮内暴露于SA，从而在SA BSI攻击时导致疾病恶化和死亡。 这种表型与CD4T细胞介导的干扰素γ依赖的免疫病理学有关，可能是一种 Th1/Th17应答失衡。这项提议的目标是检验压倒一切的假设 暴露于金黄色葡萄球菌抗原和毒力因子或皮肤金黄色葡萄球菌感染影响自然和疫苗诱导 在随后的SA BSI期间，CD4T细胞反应。为此，我们将使用小鼠来完全确定T细胞的特征 对两个疫苗平台的应答，并将评估对SA表面抗原或对 类毒素疫苗不同程度地调节CD4T细胞反应，从而诱导疫苗免疫 针对随后的金黄色葡萄球菌BSI，以及这些反应是否能受到不同疫苗佐剂的影响(目标1)。 利用WT小鼠和人HLA-DR4转基因小鼠以及几株WT和等基因突变的SA菌株 将研究毛孔形成毒素和超抗原如何调节CD4T细胞反应，从而影响自然 疫苗诱导抗金黄色葡萄球菌BSI免疫(目标2)。我们还将建立和使用一种新的非人类灵长类动物 金黄色葡萄球菌BSI模型及评价预暴露对疫苗免疫原性的影响，重点是CD4T 细胞反应和我们的多价类毒素疫苗的有效性(目标3)。这项提议的最终目标是 了解疫苗诱导的保护性免疫在互补的临床前模型中对SA BSI的免疫深化 我们对SA BSI免疫的了解有助于指导更有效的疫苗预防灾难性后果 在未来的临床试验中。

Staphylococcus aureus (SA) is a major human pathogen that can cause life threatening systemic infections. In fact, S. aureus is the most common cause of nosocomial bacteremia with a prevalence of 26%. Despite improvements in clinical care, SA bloodstream infection (BSI) continues to pose a major challenge due to high rate of treatment failure and mortality. Infections that are caused by methicillin-resistant SA (MRSA) strains are becoming increasingly resistant to antibiotics, leading to treatment failures and poor patient outcomes. If host- directed therapies such an effective SA vaccine can provide an alternative to antibiotics, a greater understanding of immune mechanisms that promote protection is essential. This is especially important since all SA vaccination attempts over the past two decades have failed in human trials. Notably, in a recent trial, a vaccine targeting SA iron surface determinant B (IsdB) against SA infections following cardiothoracic surgery had the opposite effect and patients who were vaccinated and suffered a SA infection had a 2-fold higher rate of multiorgan failure and a 5-fold higher mortality than placebo controls. While reasons for this catastrophic outcome are still unknown, a post-hoc study suggested that absent or low serum T cell cytokine levels (IL-2 and IL-17) at the time of vaccination predisposed them for treatment failure. There is therefore an urgent need to understand the underlying immunological mechanisms that lead to these deleterious outcomes. Our preliminary findings in mice recapitulate deleterious immune responses triggered by immunizing mice with a lethally irradiated whole cell vaccine or by intradermal exposure to SA that led to exacerbated disease and mortality upon SA BSI challenge. This phenotype was associated with a CD4 T cell mediated, IFNγ-dependent immunopathology and likely an imbalance of Th1/Th17 responses. The goal of this proposal is to test the overarching hypothesis that prior exposure to SA antigens and virulence factors or cutaneous SA infection impact natural- and vaccine-elicited CD4 T cell responses during a subsequent SA BSI. To this end, using mice we will fully characterize the T cell responses to two vaccine platforms and will evaluate how the initial response to SA surface antigens or to a toxoid vaccine differentially regulate the CD4 T cell response, and consequently the vaccine-elicited immunity against subsequent SA BSI and if these responses can be influenced by different vaccine adjuvants (Aim 1). Using WT mice and human HLA-DR4 transgenic mice as well as several WT and isogenic mutant SA strains we will investigate how pore forming toxins and superantigens modulate CD4 T cell responses that affect natural and vaccine induced immunity against SA BSI (Aim 2). We will also establish and use a novel nonhuman primate model of SA BSI and evaluate the impact of pre-exposure on vaccine immunogenicity, with a focus on CD4 T cell responses, and efficacy of our multivalent toxoid vaccine (Aim 3). The ultimate goal of this proposal is to understand protective vaccine-induced immunity against SA BSI in complementary pre-clinical models to deepen our understanding of immunity to SA BSI to help guide more effective vaccines to prevent disastrous outcomes in future clinical trials.