Canedo-Marroquín Gisela, Soto Jorge A, Andrade Catalina A, Bueno Susan M, Kalergis Alexis M
Millennium Institute of Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
Centre for Biomedical Research and Innovation, Faculty of Dentistry, Universidad de los Andes, Santiago 7620157, Chile.
Antioxidants (Basel). 2022 Jul 26;11(8):1453. doi: 10.3390/antiox11081453.
The human respiratory syncytial virus (hRSV) is the leading cause of severe lower respiratory tract infections in infants. Because recurrent epidemics based on reinfection occur in children and adults, hRSV has gained interest as a potential primary pathogen favoring secondary opportunistic infections. Several infection models have shown different mechanisms by which hRSV promotes immunopathology to prevent the development of adaptive protective immunity. However, little is known about the long-lasting effects of viral infection on pulmonary immune surveillance mechanisms. As a first approach, here we evaluated whether a primary infection by hRSV, once resolved, dampens the host immune response to a secondary infection with an attenuated strain of () strain referred as to Bacillus Calmette-Guerin (BCG). We analyzed leukocyte dynamics and immunomodulatory molecules in the lungs after eleven- and twenty-one-days post-infection with , using previous hRSV infected mice, by flow cytometry and the expression of critical genes involved in the immune response by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). Among the latter, we analyzed the expression of Heme Oxygenase (HO)-1 in an immunization scheme in mice. Our data suggest that a pre-infection with hRSV has a conditioning effect promoting lung pathology during a subsequent mycobacterial challenge, characterized by increased infiltration of innate immune cells, including interstitial and alveolar macrophages. Our data also suggest that hRSV impairs pulmonary immune responses, promoting secondary mycobacterial colonization and lung survival, which could be associated with an increase in the expression of HO-1. Additionally, BCG is a commonly used vaccine that can be used as a platform for the generation of new recombinant vaccines, such as a recombinant BCG strain expressing the nucleoprotein of hRSV (rBCG-N-hRSV). Therefore, we evaluated if the immunization with rBCG-N-hRSV could modulate the expression of HO-1. We found a differential expression pattern for HO-1, where a higher induction of HO-1 was detected on epithelial cells compared to dendritic cells during late infection times. This is the first study to demonstrate that infection with hRSV produces damage in the lung epithelium, promoting subsequent mycobacterial colonization, characterized by an increase in the neutrophils and alveolar macrophages recruitment. Moreover, we determined that immunization with rBCG-N-hRSV modulates differentially the expression of HO-1 on immune and epithelial cells, which could be involved in the repair of pulmonary tissue.
人呼吸道合胞病毒（hRSV）是婴儿严重下呼吸道感染的主要病因。由于儿童和成人会因再次感染而出现反复流行，hRSV作为一种可能引发继发性机会性感染的潜在原发性病原体受到了关注。几种感染模型显示了hRSV促进免疫病理以阻止适应性保护性免疫发展的不同机制。然而，关于病毒感染对肺部免疫监视机制的长期影响知之甚少。作为第一步，我们在此评估hRSV的原发性感染一旦消退，是否会削弱宿主对减毒株（卡介苗菌株，简称BCG）继发性感染的免疫反应。我们使用先前感染hRSV的小鼠，在感染BCG后11天和21天，通过流式细胞术分析肺内白细胞动态和免疫调节分子，并通过实时定量逆转录聚合酶链反应（RT-qPCR）分析免疫反应中关键基因的表达。在后者中，我们在小鼠免疫方案中分析了血红素加氧酶（HO）-1的表达。我们的数据表明，hRSV的预感染具有调节作用，在随后的分枝杆菌攻击期间促进肺部病理变化，其特征是包括间质和肺泡巨噬细胞在内的固有免疫细胞浸润增加。我们的数据还表明，hRSV损害肺部免疫反应，促进继发性分枝杆菌定植和肺部存活，这可能与HO-1表达增加有关。此外，BCG是一种常用疫苗，可以用作生成新的重组疫苗的平台，例如表达hRSV核蛋白的重组BCG菌株（rBCG-N-hRSV）。因此，我们评估了用rBCG-N-hRSV免疫是否能调节HO-1的表达。我们发现HO-1有不同的表达模式，在感染后期，上皮细胞中HO-1的诱导高于树突状细胞。这是第一项证明hRSV感染会对肺上皮造成损伤、促进随后分枝杆菌定植的研究，其特征是中性粒细胞和肺泡巨噬细胞募集增加。此外，我们确定用rBCG-N-hRSV免疫可不同程度地调节免疫细胞和上皮细胞上HO-1的表达，并可能参与肺组织的修复。
