Immature myeloid cells as targets for therapeutics to bacterial infection

描述（由申请人提供）：该提案将确定髓源性抑制细胞（MDSC）作为抗感染新治疗靶点的潜力。MDSC因其在癌症中明确的免疫抑制作用而受到最近的大量关注。MDSC在感染中的反应不像在癌症中那样好表征，但研究确实显示了与感染部位的MDSC浸润相关的一致的免疫抑制表型。在某些感染中，MDSC可能具有早期保护作用。MDSC具有分化为炎性单核细胞、巨噬细胞、髓样树突状细胞和中性粒细胞所必需的可塑性。因此，MDSC应答的双重性质（免疫抑制或保护）可能是由于这些细胞的形态学和生物标志物异质性，使得在感染期间的任何点的MDSC表型和功能的平衡可能决定结果。我们已经获得了初步的数据，证明了MDSC在感染细菌病原体沙门氏菌鼠伤寒血清型（S。鼠伤寒沙门氏菌）。此外，我们已经获得初步证据表明，虽然这些细胞可能具有与先天免疫作用一致的初始保护作用，但它们也对T细胞具有与抑制适应性免疫作用一致的有效抑制作用，这是S.鼠伤寒感染。该应用建立在MDSC可以在感染期间以时间方式被靶向的前提下，以在免疫应答的先天阶段期间利用它们的保护作用，并在免疫应答的适应性阶段期间降低它们的抑制活性。在具体目标1中，我们将描述MDSC在感染S.鼠伤寒这将涉及记录S。Typhimurium诱导的MDSC通过产生一氧化氮或谷胱甘肽酶-1抑制T细胞功能。在具体目标2中，我们将使用感染S的小鼠模型。鼠伤寒沙门氏菌感染的小鼠，以确定趋化因子受体CCR 2是否是MDSC移出骨髓所必需的，以及MDSC是否可以在外周扩增和成熟。鼠伤寒在具体目标3中，我们将特异性靶向MDSC扩增、激活和抑制活性，作为一种新的感染治疗方法，从先天性免疫应答过渡到适应性免疫应答。 公共卫生相关性：感染人类的微生物病原体已经进化出吸收或破坏免疫反应的能力，作为促进疾病的策略。需要靶向人类免疫应答而不是病原体的新的治疗策略来克服由于耐药微生物病原体引起的人类疾病增加的问题。本申请将测试以下假设：许多病原体吸收免疫细胞以抑制保护性应答，并且吸收的免疫抑制细胞可以作为广谱治疗方法特异性靶向以阻断感染性疾病。

DESCRIPTION (provided by applicant): This proposal will determine the potential for myeloid-derived suppressor cells (MDSC) as novel therapeutic targets against infection. MDSC have received a significant amount of recent attention for their well-defined immunosuppressive role in cancer. The response of MDSC in infection is not as well characterized as in cancer, but studies do show a consistent immunosuppressive phenotype associated with MDSC infiltration at sites of infection. In some infections, MDSC may have an early protective role. MDSC have the plasticity necessary to differentiate into inflammatory monocytes, macrophages, myeloid dendritic cells and neutrophils. Thus, the dual nature of the MDSC response (immunosuppressive or protective) may be due to the morphologic and biomarker heterogeneity of these cells, such that the balance of MDSC phenotypes and functions at any point during infection may determine the outcome. We have obtained preliminary data demonstrating a large response of MDSC in mice infected with the bacterial pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium). In addition, we have obtained preliminary evidence to suggest that while these cells may have an initial protective effect consistent with a role in innate immunity, they also have a potent inhibitory effect on T cells consistent with a role in suppression of adaptive immunity, which is a hallmark of S. Typhimurium infection. This application is built on the premise that MDSC can be targeted during infection in a temporal manner to capitalize on their protective role during the innate phase of the immune response and decrease their suppressive activity during the adaptive phase of the immune response. In Specific Aim 1, we will characterize the response and role of MDSC in mice infected with S. Typhimurium. This will involve documenting whether S. Typhimurium-induced MDSC suppress T cell function through production of nitric oxide or arginase-1. In Specific Aim 2, we will use a mouse model of infection with S. Typhimurium to determine if chemokine receptor CCR2 is required for emigration of MDSC out of bone marrow, and if MDSC can expand and mature in the periphery of mice infected with S. Typhimurium. In Specific Aim 3, we will specifically target MDSC expansion, activation and suppressive activity at the transition from innate to adaptive immune response as a novel therapeutic approach to infection. PUBLIC HEALTH RELEVANCE: Microbial pathogens that infect humans have evolved the ability to co-opt or subvert the immune response as a strategy to promote disease. New therapeutic strategies that target the human immune response rather than the pathogen are needed to overcome the problem of increased human disease due to drug resistant microbial pathogens. This application will test the hypothesis that many pathogens co-opt immune cells to suppress protective responses, and that the co-opted immunosuppressive cells can be specifically targeted as a broad- spectrum therapeutic approach to block infectious diseases.