Gopalakrishnan Vancheswaran, Sparklin Ben, Kim Jung Hwan, Bouquet Jerome, Kehl Margaret, Kenny Tara, Morehouse Christopher, Caceres Carolina, Warrener Paul, Hristova Ventzislava A, Wilson Susan, Shandilya Harini, Barnes Arnita, Ruzin Alexey, Wang Junmin, Oberg Lisa, Angermann Bastian, McCrae Christopher, Platt Adam, Muthas Daniel, Hess Sonja, Tkaczyk Christine, Sellman Bret R, Ostridge Kristoffer, Belvisi Maria G, Wilkinson Tom M A, Staples Karl J, DiGiandomenico Antonio
Bioinformatics, Research and Early Development, Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
Bacterial Vaccines, Research and Early Development, Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
Respir Res. 2025 Jan 30;26(1):45. doi: 10.1186/s12931-025-03113-z.
Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by airway obstruction and inflammation. Non-typeable Haemophilus influenzae (NTHi) lung infections are common in COPD, promoting frequent exacerbations and accelerated lung function decline. The relationship with immune responses and NTHi are poorly understood. Herein, we comprehensively characterized the respiratory microbiome and mycobiome of patients while investigating microbial dynamics and host immune changes attributable to NTHi killing activity. Mild-to-moderate COPD patients encompassing frequent and infrequent exacerbators and healthy volunteers (HV) were enrolled. Microbial composition, proteomics and NTHi killing activity was analyzed using bronchoalveolar lavage fluid (BALF). In addition, antigen-antibody titers in sera to COPD pathogens were determined using a multiplex assay. Differential abundance analysis revealed an enrichment of Actinobacteria and Bacteroidetes in the BALF of COPD and HV subjects respectively. Significant differences in the IgA titer response were observed against NTHi antigens in COPD vs. HV. Notably, there was also significantly greater killing activity against NTHi in BALF from COPD vs. HV subjects (OR = 5.64; 95% CI = 1.75-20.20; p = 0.001). Stratification of COPD patients by NTHi killing activity identified unique microbial and protein signatures wherein Firmicutes, Actinobacteria and haptoglobin were enriched in patients with killing activity. We report that differences in host immune responses and NTHi-killing activity are associated with microbiome changes in mild-to-moderate COPD. This is suggestive of a potential link between the respiratory microbiome and immune activity against NTHi in the context of COPD pathogenesis even at this disease stage.
慢性阻塞性肺疾病（COPD）是一种以气道阻塞和炎症为特征的慢性肺部疾病。非典型流感嗜血杆菌（NTHi）肺部感染在COPD中很常见，会导致频繁发作并加速肺功能下降。人们对其与免疫反应和NTHi的关系了解甚少。在此，我们全面表征了患者的呼吸道微生物组和真菌微生物组，同时研究了归因于NTHi杀伤活性的微生物动态变化和宿主免疫变化。纳入了包括频繁和不频繁急性加重患者的轻至中度COPD患者以及健康志愿者（HV）。使用支气管肺泡灌洗液（BALF）分析微生物组成、蛋白质组学和NTHi杀伤活性。此外，使用多重检测法测定血清中针对COPD病原体的抗原抗体滴度。差异丰度分析显示，放线菌门和拟杆菌门分别在COPD患者和HV受试者的BALF中富集。在COPD患者与HV受试者中，观察到针对NTHi抗原的IgA滴度反应存在显著差异。值得注意的是，COPD患者的BALF对NTHi的杀伤活性也显著高于HV受试者（OR = 5.64；95% CI = 1.75 - 20.20；p = 0.001）。根据NTHi杀伤活性对COPD患者进行分层，确定了独特的微生物和蛋白质特征，其中厚壁菌门、放线菌门和触珠蛋白在具有杀伤活性的患者中富集。我们报告，宿主免疫反应和NTHi杀伤活性的差异与轻至中度COPD中的微生物组变化有关。这表明，即使在该疾病阶段，在COPD发病机制的背景下，呼吸道微生物组与针对NTHi的免疫活性之间可能存在潜在联系。
