Adaptive immunity against Pneumocystis

针对肺孢子菌的适应性免疫

• 批准号: 8711554
• 负责人: Chad Steele
• 金额: $ 36.02万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8711554
• 关键词: Address; Antibody Formation; Attenuated; Automobile Driving; B-Lymphocytes; C57BL/6 Mouse; CCL17 gene; CD19 gene; CD4 Positive T Lymphocytes; Cells; Chronic Obstructive Airway Disease; Chronic lung disease; Clinical; Cyst; Data; Development; Epidemic; Functional disorder; Generations; HIV; Helper-Inducer T-Lymphocyte; Host Defense; IgG1; Immune response; Immunity; Immunosuppression; Inbred BALB C Mice; Individual; Infection; Interferons; Interleukin-10; Interleukin-13; Interleukin-17; Interleukin-4; Interleukin-5; Life Cycle Stages; Lung; Macrophage Activation; Mediating; Mediator of activation protein; Mus; Patients; Phenotype; Pilot Projects; Plasma; Play; Pneumocystis; Pneumocystis Infections; Pneumocystis carinii Pneumonia; Population; Predisposing Factor; Production; Proteins; Reporter; Resistance; Role; SCID Mice; STAT4 gene; Serum; Source; Structure of parenchyma of lung; T cell response; TNFSF5 gene; Th2 Cells; Time; Transgenic Mice; adaptive immunity; cytokine; diphtheria toxin receptor; lymph nodes; mRNA Expression; macrophage; novel; pathogen; public health relevance; response; rituximab; tool; transcription factor

DESCRIPTION (provided by applicant): Pneumocystis has risen to the forefront of lethal, opportunistic lung infections as a result of its close association with the HIV epidemic, yet this atypical fungal pathogen is becoming increasingly associated with pharmacologic-driven immunosuppression as well as patients with chronic lung diseases such as COPD. We have recently investigated the role of transcription factor STAT4 in lung immunity to P. murina. We have discovered that Stat4-/- mice on the C57BL/6 background are resistant to P. murina infection while Stat4-/- mice on the BALB/c background are susceptible (Myers et al. submitted, PLoS Pathogens). To our surprise, although having lower Th1 (IFN-y) responses, both BL/6 Stat4-/- and Balb/c Stat4-/- mice unexpectedly demonstrated significantly impaired CD4+ Th2 (IL-4, IL-5 and IL-13) responses in the lung. In spite of this, BL/6 Stat4-/-, but not Balb/c Stat4/-, mice maintained an enhanced M2 macrophage signature (higher Retnla/FIZZ-1 mRNA expression and CCL17/TARC protein levels). In contrast to lung CD4+ T cells, BL/6 Stat4-/- mice demonstrated enhanced CD4+ Th2 responses in the draining lymph nodes and enhanced P. murina-specific IgG1, IgG2b and IgG2c levels in sera, neither of which were observed in BALB/c Stat4-/- mice. Together, these results suggest that protective immunity to P. murina when lung CD4+ T cell responses are impaired involves systemic CD4+ Th2 responses driving optimal B cell responses (Ab production) and a local type 2 response (IL-4/IL-13) in the lungs, which may not be CD4+ T cell in origin, driving M2 macrophage development. This is further supported by new preliminary data showing that compared to non-colonized HIV- infected individuals, Pneumocystis-colonized HIV-infected individuals have significantly lower plasma levels of the Th2 cytokines IL-4, IL-5 and IL-13, but no difference in the levels of IFN-y, IL-17A or IL-10. In preliminary studies, we show that CD4(-)/CD49b(-)/SiglecF(-)/ICOS(+) innate helper type 2 cells were significantly increased in lung tissue of C57BL/6 mice at 2 weeks post-P. murina challenge, suggesting a potential role for this cell population in generating type 2 responses in the lung during P. murina infection. In other studies, employing CD19-DTR mice, which are CD19-Cre mice crossed with Cre-inducible diphtheria toxin receptor (DTR) transgenic mice, we found that CD4+ Th1 and Th2 responses were attenuated in the lymph nodes of mice when B cells were depleted prior to P. murina infection, yet B cell depletion resulted in enhanced CD4+ Th2 and Th17 responses in the lung. Collectively, our data leads us to hypothesize that the generation of type 2 and Th2 responses mediate protective lung immunity against Pneumocystis. To address this hypothesis, we have proposed the following two independent, interrelated Aims: (1) to define the development of local and systemic type 2/Th2 responses during P. murina lung infection and (2) define the role of B cells in the development of local and systemic CD4+ T cell responses during P. murina lung infection.

描述（由申请人提供）：由于肺囊虫与HIV流行密切相关，它已经上升到致死性机会性肺部感染的前沿，然而这种非典型真菌病原体正越来越多地与药理学驱动的免疫抑制以及慢性肺部疾病（如COPD）患者相关。我们最近研究了转录因子STAT4在肺对鼠双球菌免疫中的作用。我们发现C57BL/6基因背景的Stat4-/-小鼠对P. murina感染具有抗性，而BALB/c基因背景的Stat4-/-小鼠对P. murina感染具有易感性（Myers等人提交，PLoS Pathogens）。令我们惊讶的是，尽管具有较低的Th1 （IFN-y）应答，但BL/6 Stat4-/-和Balb/c Stat4-/-小鼠出人意料地显示出肺中CD4+ Th2 （IL-4， IL-5和IL-13）应答显著受损。尽管如此，BL/6 Stat4-/-，而Balb/c Stat4/-，小鼠保持增强的M2巨噬细胞特征（更高的Retnla/FIZZ-1 mRNA表达和CCL17/TARC蛋白水平）。与肺CD4+ T细胞相比，BL/6 Stat4-/-小鼠在引流淋巴结中的CD4+ Th2反应增强，血清中P. murna特异性IgG1， IgG2b和IgG2c水平增强，而BALB/c Stat4-/-小鼠均未观察到这两种情况。总之，这些结果表明，当肺CD4+ T细胞反应受损时，对鼠弓形虫的保护性免疫涉及全身CD4+ Th2反应驱动最佳B细胞反应（Ab产生）和肺局部2型反应（IL-4/IL-13），这可能不是CD4+ T细胞的起源，驱动M2巨噬细胞的发育。新的初步数据进一步支持了这一点，表明与未定植的HIV感染者相比，肺囊虫定植的HIV感染者血浆中Th2细胞因子IL-4、IL-5和IL-13的水平显著降低，但IFN-y、IL-17A和IL-10的水平没有差异。在初步研究中，我们发现在p后2周，C57BL/6小鼠肺组织中CD4(-)/CD49b(-)/SiglecF(-)/ICOS（+）先天辅助性2型细胞显著增加。提示该细胞群在鼠假体感染期间在肺部产生2型反应的潜在作用。在其他研究中，我们使用CD19-DTR小鼠，即CD19-Cre小鼠与cree诱导的白喉毒素受体（DTR）转基因小鼠杂交，发现在感染P. murina之前，当B细胞被耗尽时，小鼠淋巴结中的CD4+ Th1和Th2反应减弱，而B细胞的消耗导致肺中的CD4+ Th2和Th17反应增强。总的来说，我们的数据使我们假设2型和Th2反应的产生介导了肺对肺囊虫的保护性免疫。为了解决这一假设，我们提出了以下两个独立的、相互关联的目的：(1)确定鼠肺感染期间局部和全身2型/Th2反应的发展；(2)确定B细胞在鼠肺感染期间局部和全身CD4+ T细胞反应发展中的作用。