Type II enterotoxins as mucosal immunomodulators

作为粘膜免疫调节剂的 II 型肠毒素

• 批准号: 7845035
• 负责人: Terry D. Connell
• 金额: $ 33.93万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-15 至 2011-09-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7845035
• 关键词: ADP ribosylation; Ablation; Address; Adjuvant; Adjuvanticity; Affect; Affinity; Antibodies; Antigen-Presenting Cells; Antigens; Apoptosis; Award; Binding; Biochemistry; Blood Circulation; Catalytic Domain; Cell physiology; Cell surface; Cells; Cholera Toxin; Collection; Communities; Cyclic AMP; Data; Dendritic Cells; Endoplasmic Reticulum; Engineering; Enterotoxins; Equilibrium; Escherichia coli; Event; Exhibits; Flow Cytometry; Gangliosides; Genetic; Genitourinary system; Goals; Grant; Immune; Immune response; Immunization; Immunocompetent; Immunology; Immunomodulators; Investigation; Ligands; Lymphocyte; Lymphocyte Subset; Lymphoid Cell; Measures; Modeling; Molecular; Monitor; Mouse Strains; Mucosal Immune Responses; Mucous Membrane; Mus; Nature; Oral; Pattern; Pilot Projects; Population; Process; Production; Recombinants; Research Personnel; Role; Sentinel; Signal Transduction; Site; Stomach; Streptococcus mutans; Structure; Surface; T-Lymphocyte; Testing; Transgenic Mice; Vaccines; Vagina; base; cellular imaging; cytokine; holotoxins; immunoregulation; interdisciplinary collaboration; mouse model; mucosal site; mutant; oral pathogen; pathogen; polypeptide; programs; receptor; receptor binding; research study; response; trafficking; uptake

DESCRIPTION (provided by applicant): There is an urgent need to develop new means for potentiating protective immune responses against pathogens that infect the oral, gastric and urogenital mucosae. The objective of this proposal is to evaluate the mucosal adjuvant activities of LT-IIa and LT-IIb, two Escherichia coli Type II enterotoxins. LT-IIa and LT-IIb induce distinctive patterns of enhanced immune responses which are profoundly different from those induced by cholera toxin (CT). Whereas CT commonly induces a predominant Th2-type response based on antibody isotype and cytokine patterns, mice administered with Type II enterotoxins as adjuvants exhibit a more balanced Th1/Th2 response. We have also demonstrated that LT-IIa, LT-IIb, and CT interact with different populations of lymphocytes and induce in those populations distinctive cellular responses (apoptosis, cytokine production, proliferation, etc.). Collectively, these data provide strong evidence that LT-IIa and LT-IIb (and CT) utilize different cellular and molecular mechanisms for immunomodulation. Our hypothesis is that the distinctive adjuvant activities of LT-IIa and LT-IIb (and CT) are elicited by their binding affinity for different receptors on immunocompetent cells which are required to trigger specific signal transduction events. To test this hypothesis, the adjuvant activities of the LT-IIa and LT-IIb, and a collection of mutant enterotoxins with altered receptor-binding activities, will be analyzed in a mucosal mouse model using Agl/II of the oral pathogen Streptococcus mutans as a model antigen. Other LT-IIa and LT-IIb mutants will be engineered to establish the importance of ADP- ribosylation and cellular trafficking in immunomodulation. Prior investigations have revealed a receptor on lymphocytes which is likely the trigger for the adjuvant activities of LT-IIb. Ablation and blocking experiments using relevant lymphocytes will be used to characterize the receptor. The affect of the enterotoxins on the cellular and molecular responses of dendritic cells, the major sentinel antigen- presenting cells of the mucosa, will be investigated as a further means to correlate the adjuvant activities of LT-IIa and LT-IIb with particular lymphocytes. Efficacy of the mutant enterotoxins as protective mucosal adjuvants will also be determined using an established S. mutans murine colonization model. The fundamental information obtained herein will be essential for establishing the potential of Type II enterotoxins, or their non-toxic mutants, as mucosal adjuvants for subsequent vaccine use.

描述（由申请人提供）：迫切需要开发新手段来增强感染口服，胃和泌尿生殖器粘膜的病原体的保护性免疫反应。该提案的目的是评估LT-IIA和LT-IIB的粘膜佐剂活性，这是两个大肠杆菌II型肠毒素。 LT-IIA和LT-IIB引起了增强的免疫反应的独特模式，这些模式与霍乱毒素（CT）诱导的免疫反应截然不同。尽管CT通常诱导基于抗体同种型和细胞因子模式的主要Th2型反应，而用II型肠毒素给药的小鼠作为辅助剂表现出更平衡的Th1/Th2反应。我们还证明了LT-IIA，LT-IIB和CT与不同种群的淋巴细胞相互作用，并在这些种群中诱导独特的细胞反应（细胞凋亡，细胞因子产生，增殖等）。总的来说，这些数据提供了有力的证据，表明LT-IIA和LT-IIB（和CT）利用不同的细胞和分子机制进行免疫调节。我们的假设是，LT-IIA和LT-IIB（和CT）的独特辅助活性是由于其对免疫能力细胞上不同受体的结合亲和力引起的，这是触发特定信号转导事件所必需的。为了检验该假设，将使用口腔病原体病原体链球菌突变的AGL/II分析LT-IIA和LT-IIB的辅助活性，以及​​具有改变受体结合活性的突变体肠毒素，其集合具有改变受体结合活性。将设计其他LT-IIA和LT-IIB突变体，以确定ADP-核糖基化和细胞运输在免疫调节中的重要性。先前的研究表明，淋巴细胞的受体可能是LT-IIB辅助活性的触发因素。使用相关淋巴细胞的消融和阻断实验将用于表征受体。肠毒素对树突状细胞的细胞和分子反应，粘膜的主要前哨抗原细胞的影响将被研究，以作为将LT-IIA和LT-IIB辅助活性与特定淋巴细胞相关的进一步手段。突变体肠毒素作为保护性粘膜佐剂的功效也将使用已建立的S. mutans鼠定殖模型确定。本文获得的基本信息对于确定II型肠毒素或其无毒突变体的潜力至关重要，作为随后使用疫苗的粘膜佐剂。

项目成果

Mapping of a microbial protein domain involved in binding and activation of the TLR2/TLR1 heterodimer.

• DOI: 10.4049/jimmunol.0803737
• 发表时间: 2009-03-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Liang S;Hosur KB;Lu S;Nawar HF;Weber BR;Tapping RI;Connell TD;Hajishengallis G
• 通讯作者: Hajishengallis G

The Divergent CD8+ T Cell Adjuvant Properties of LT-IIb and LT-IIc, Two Type II Heat-Labile Enterotoxins, Are Conferred by Their Ganglioside-Binding B Subunits.

LT-IIb 和 LT-IIc（两种 II 型热不稳定肠毒素）的不同 CD8 T 细胞佐剂特性是由其神经节苷脂结合 B 亚基赋予的。

• DOI: 10.1371/journal.pone.0142942
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Hu,JohnC;Greene,ChristopherJ;King-Lyons,NatalieD;Connell,TerryD
• 通讯作者: Connell,TerryD

Type II heat-labile enterotoxins: structure, function, and immunomodulatory properties.

• DOI: 10.1016/j.vetimm.2012.09.034
• 发表时间: 2013-03-15
• 期刊: Veterinary immunology and immunopathology
• 影响因子: 1.8
• 作者: Hajishengallis G;Connell TD
• 通讯作者: Connell TD

LT-IIc, a new member of the type II heat-labile enterotoxin family, exhibits potent immunomodulatory properties that are different from those induced by LT-IIa or LT-IIb.

• DOI: 10.1016/j.vaccine.2010.11.020
• 发表时间: 2011-01-17
• 期刊: VACCINE
• 影响因子: 5.5
• 作者: Nawar, Hesham F.;Greene, Christopher J.;Lee, Chang Hoon;Mandell, Lorrie M.;Hajishengallis, George;Connell, Terry D.
• 通讯作者: Connell, Terry D.

Intradermal administration of the Type II heat-labile enterotoxins LT-IIb and LT-IIc of enterotoxigenic Escherichia coli enhances humoral and CD8+ T cell immunity to a co-administered antigen.

• DOI: 10.1371/journal.pone.0113978
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Hu JC;Mathias-Santos C;Greene CJ;King-Lyons ND;Rodrigues JF;Hajishengallis G;Ferreira LC;Connell TD
• 通讯作者: Connell TD