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）：由于与HIV流行密切相关，肺孢子虫已上升到致死性机会性肺部感染的最前沿，但这种非典型真菌病原体越来越多地与药理学驱动的免疫抑制以及慢性肺病（如COPD）患者相关。我们最近研究了转录因子STAT 4在肺免疫鼠疟原虫中的作用。我们已经发现，C57 BL/6背景的Stat 4-/-小鼠对鼠疟原虫感染具有抗性，而BALB/c背景的Stat 4-/-小鼠是易感的（Myers等人提交，PLoS Pathogens）。令我们惊讶的是，尽管具有较低的Th 1（IFN-γ）应答，但BL/6 Stat 4-/-和Balb/c Stat 4-/-小鼠都意外地显示出肺中显著受损的CD 4 + Th 2（IL-4、IL-5和IL-13）应答。尽管如此，BL/6 Stat 4-/-小鼠而不是Balb/c Stat 4/-小鼠保持增强的M2巨噬细胞特征（更高的Retnla/FIZZ-1 mRNA表达和CCL 17/TARC蛋白水平）。与肺CD 4 + T细胞相比，BL/6 Stat 4-/-小鼠表现出引流淋巴结中CD 4 + Th 2应答增强，血清中鼠疟原虫特异性IgG 1、IgG 2b和IgG 2c水平增强，而在BALB/c Stat 4-/-小鼠中均未观察到这两种情况。总之，这些结果表明，当肺CD 4 + T细胞应答受损时，对鼠肺吸虫的保护性免疫涉及驱动最佳B细胞应答（Ab产生）的全身性CD 4 + Th 2应答和肺中的局部2型应答（IL-4/IL-13），其可能不是来源于CD 4 + T细胞，驱动M2巨噬细胞发育。新的初步数据进一步支持了这一点，该数据显示，与未定殖的HIV感染个体相比，肺孢子虫定殖的HIV感染个体具有显著较低的Th 2细胞因子IL-4、IL-5和IL-13的血浆水平，但IFN-γ、IL-17 A或IL-10的水平没有差异。在初步研究中，我们发现在鼠疟原虫攻击后2周，C57 BL/6小鼠肺组织中的CD 4（-）/CD 49 b（-）/SiglecF（-）/ICOS（+）先天辅助2型细胞显著增加，表明该细胞群在鼠疟原虫感染期间在肺中产生2型应答中的潜在作用。在其他研究中，使用CD 19-DTR小鼠，其是与Cre诱导的白喉毒素受体（DTR）转基因小鼠杂交的CD 19-Cre小鼠，我们发现当B细胞在鼠疟原虫感染之前被耗尽时，小鼠淋巴结中的CD 4 + Th 1和Th 2应答减弱，然而B细胞耗尽导致肺中的CD 4 + Th 2和Th 17应答增强。总的来说，我们的数据使我们假设2型和Th 2反应的产生介导了对肺孢子虫的保护性肺免疫。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）确定在鼠肺吸虫肺部感染期间局部和全身2型/Th 2应答的发展和（2）确定在鼠肺吸虫肺部感染期间B细胞在局部和全身CD 4 + T细胞应答的发展中的作用。