Antibody-secreting Cells in the Outcome of Trypanosoma cruzi Infection

克氏锥虫感染结果中的抗体分泌细胞

• 批准号: 10614041
• 负责人: ADRIANA GRUPPI
• 金额: $ 13.33万
• 依托单位: NATIONAL RESEARCH COUNCIL OF ARGENTINA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614041
• 关键词: Acute; Adenosine; Adjuvant; Affect; Affinity; Anatomy; Antibodies; Antibody Affinity; Antibody Formation; Antibody-mediated protection; Antigen Presentation; Antigen-Presenting Cells; Antigens; Appearance; Autoantibodies; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Bacterial Infections; Biological Assay; Bone Marrow; CD8-Positive T-Lymphocytes; CD80 gene; CD86 gene; COVID-19; Cells; Chagas Disease; Characteristics; Chimera organism; Chronic; Clinic; Clinical; Coculture Techniques; Comprehension; Cues; Cytometry; Data; Detection; Development; Disease; Disease Outcome; Disease Progression; Enzyme-Linked Immunosorbent Assay; Evaluation; Exhibits; Experimental Models; Flow Cytometry; Frequencies; Functional disorder; Generations; Helper-Inducer T-Lymphocyte; Heterogeneity; Humoral Immunities; IL17 gene; IgG1; IgG2; Image; Immune; Immune response; Immunity; Immunofluorescence Immunologic; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin M; Immunoglobulin Somatic Hypermutation; Immunoglobulin Switch Recombination; Immunoglobulin-Secreting Cells; Immunology; Immunosuppression; In Vitro; Infection; Inflammatory; Interleukin-6; Knowledge; Latin America; Link; Lymphocyte Activation; Lymphocytic choriomeningitis virus; Measures; Microbe; Modeling; Mus; Mutant Strains Mice; Nucleosides; Outcome; Parasite Control; Parasitemia; Parasites; Parasitic infection; Pathogenesis; Pathogenicity; Pathway interactions; Persons; Phase; Plasmablast; Plasmodium; Play; Population; Public Health; Publishing; Reaction; Regulation; Reporting; Role; Salmonella; Side; Signal Transduction; Source; Specificity; Structure of germinal center of lymph node; T cell response; T-Lymphocyte; TNF gene; Testing; Trypanosoma cruzi; Vaccines; Virus Diseases; adaptive immunity; antimicrobial; chronic infection; conditioning; cytokine; design; economic impact; experimental study; extracellular; immunoregulation; improved; in vivo; influenzavirus; innovation; migration; mortality; novel; novel therapeutics; pathogen; physically handicapped; programmed cell death ligand 1; response; single-cell RNA sequencing; therapeutic target

PROJECT SUMMARY/ABSTRACT Chagas disease, caused by the parasite Trypanosoma cruzi, affects 6 million people and has a major economic impact due to early mortality and physical disabilities. It is endemic in Latin America but has become a global public health concern following the migration of infected people. Disease progression that varies from symptomless to severe, has been linked to both parasite heterogeneity and host-related immunity. Parasite persistence as well as the intensity of the inflammatory immune response are determinants of the clinical manifestations of the disease. Understanding components of host immunity will be crucial to the comprehension of pathogenesis and will allow design of novel therapeutics. The acute phase of Chagas disease results in polyclonal B cell activation that may be related to the important early extrafollicular plasmablast (EF-PB) response that precedes germinal center (GC) reactions. In this direction, the source of polyreactive antibodies (Abs) was not clearly identified. We initially considered that this polyclonal B cell response would restrict anti-parasite responses. However, we observed that EF-PB produce parasite-specific Abs of different isotypes and that signals via BCR, in some way, condition PB generation which requires the participation of T follicular helper (Tfh) cells. Also, the EF-PB are the main source of IL-17 in T. cruzi infected mice and a fraction of them produce IL-6 and other cytokines and express molecules related to antigen presentation. Of note, IL-17 produced by B cells/PB was shown to be key to sustain CD8+T cell activity and survival. Finally, we determined that PB from T. cruzi infected mice express high levels of the ectoenzyme CD39, higher than T cells, which combined with CD73 hydrolyze exogenous ATP to adenosine which plays immunomodulatory functions. The absence of PB in early T. cruzi infection significantly increases the parasitemia, but on the other side, favors the earlier appearance of GC and increases the frequency of TNF+IFN+ T cells suggesting a controversial role of PB. Our findings are particularly timely given reports describing poor clinical outcomes in Covid19 associated with high PB responses. Altogether, the results support our hypothesis that early EF-PB from T. cruzi infected mice have parasite control capacity and can condition disease outcome. We are focused at further characterizing these EF-PB cell population/s to determine their heterogeneity as well as its contribution to protection or pathogenicity. Using different strategies such as single-cell RNAseq, analysis of somatic hypermutation, identification of antigen-specificity and affinity we will perform detailed characterizations of EF-PB in T. cruzi infected mice. By using genetically modified mice, co- culture experiments and mixed bone marrow chimeras we will be able to delineate the role of EF-PB and CD39 in conditioning humoral as well as cellular responses in experimental Chagas disease. The identification of the EF-PB characteristics and roles will be of great significance for the development of new strategies aiming at the therapeutic targeting of B cells in the clinic. For instance, this innovative approach could provide information required to develop an effective vaccine against T. cruzi.

项目摘要/摘要 由克氏锥虫寄生虫引起的恰加斯病影响着600万人，并对经济产生重大影响 由于早期死亡和身体残疾。它在拉丁美洲流行，但已成为全球公共卫生 受感染者迁徙后的关切。疾病的进展从无症状到严重，有 与寄生虫的异质性和宿主相关免疫有关。寄生虫的持久性以及 炎性免疫反应是该病临床表现的决定因素。理解 宿主免疫成分将是理解发病机制的关键，并将允许设计新的 治疗学。 Chagas病急性期导致多克隆B细胞激活，这可能与重要的早期 毛囊外浆母细胞(EF-PB)反应先于生发中心(GC)反应。在这个方向上， 多反应抗体(Abs)的来源尚不清楚。我们最初认为这个多克隆B细胞 回应将限制抗寄生虫的反应。然而，我们观察到EF-PB产生寄生虫特异性抗体 不同的同工型和通过BCR的信号在某种程度上限制了需要参与的PB的产生 T滤泡辅助者(TFH)细胞。此外，在感染弓形虫的小鼠中，EF-PB是IL-17的主要来源，还有一部分 其中一些细胞产生IL-6和其他细胞因子，并表达与抗原呈递相关的分子。值得注意的是，IL-17 由B细胞/外周血产生的T细胞是维持CD8+T细胞活性和存活的关键。最后，我们决定 克氏锥虫感染小鼠的外周血细胞表达高水平的胞外酶CD39，高于T细胞 与CD73一起将外源ATP水解为腺苷，腺苷起免疫调节作用。PB的缺失 在早期感染克氏毛滴虫显著增加寄生虫血症，但另一方面，有利于更早出现 并增加肿瘤坏死因子+干扰素+T细胞的频率，这表明PB的作用存在争议。我们的发现是 特别及时，因为报告描述了Covid19中与高PB反应相关的糟糕的临床结果。 总之，这些结果支持了我们的假设，即感染弓形虫小鼠的早期EF-PB对寄生虫有控制作用。 能力和条件疾病的结果。我们专注于进一步表征这些EF-PB细胞群/S 以确定它们的异质性及其对保护或致病性的贡献。使用不同的策略 如单细胞RNAseq、体细胞超突变分析、抗原特异性和亲和力鉴定等 将在感染毛滴虫的小鼠身上进行EF-PB的详细特征研究。通过使用转基因小鼠，联合 培养实验和混合骨髓嵌合体，我们将能够描述EF-PB和CD39在 实验性恰加斯病的体液和细胞反应的条件化。EF-PB的鉴定 其特点和作用将对制定新的战略目标具有重要意义 B细胞的临床靶向治疗。例如，这种创新的方法可以提供信息 需要开发一种有效的克氏锥虫疫苗。

项目成果

Eosinophil adherence to infective larvae of Trichinella spiralis: quantification and modulation.

嗜酸性粒细胞粘附于旋毛虫感染性幼虫：定量和调节。

• 发表时间: 1985
• 期刊: Immunology
• 影响因子: 6.4
• 作者: Pincus,SH;Cammarata,P
• 通讯作者: Cammarata,P

B cells from Patients with Rheumatoid Arthritis Show Conserved CD39-Mediated Regulatory Function and increased CD39 Expression After Positive Response to Therapy.

来自类风湿关节炎患者的B细胞表现出保守的CD39介导的调节功能，在对治疗阳性后的CD39表达增加。

• DOI: 10.1016/j.jmb.2020.10.021
• 发表时间: 2021-01-08
• 期刊: JOURNAL OF MOLECULAR BIOLOGY
• 影响因子: 5.6
• 作者: Zacca, E. R.;Amezcua Vesely, M. C.;Ferrero, P., V;Acosta, C. D., V;Ponce, N. E.;Bossio, S. N.;Mussano, E.;Onetti, L.;Cadile, I;Acosta Rodriguez, E., V;Montes, C. L.;Gruppi, A.
• 通讯作者: Gruppi, A.