Chau Tran Bao Vu1, Arsa Thammahong2, Hideo Yagita3, Miyuki Azuma4, Nattiya Hirankarn5,6, Patcharee Ritprajak7,8, Asada Leelahavanichkul5,9. 1. Graduate Program in Oral Biology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand. 2. Antimicrobial Resistance and Stewardship Research Unit, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. 3. Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan. 4. Department of Molecular Immunology, Tokyo Medical and Dental University, Tokyo, Japan. 5. Immunology Unit, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. 6. Center of Excellence in Immunology and Immune-mediated Diseases, Department of Microbiology, Chulalongkorn University, Bangkok, Thailand. 7. Department of Microbiology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand. 8. Research Unit in Immuno-Microbial Biochemistry and Bioresponsive Nanomaterials, Department of Microbiology, Chulalongkorn University, Bangkok, Thailand. 9. Translational Research in Inflammation and Immunology Research Unit (TRIRU), Department of Microbiology, Chulalongkorn University, Bangkok, Thailand.
Abstract
BACKGROUND: Nosocomial aspergillosis in patients with sepsis has emerged in the past few years. Blockade of PD-1/PD-L pathway has tended to become a promising therapeutic strategy as it improved the outcome of bacterial sepsis and postsepsis secondary fungal infection. Recently, the controversial effects of PD-1 blockade on infectious diseases, including aspergillosis, have been demonstrated; therefore, the efficacy of anti-PD-1 drug still remains to be elucidated. METHODS: Cecal ligation and puncture (CLP) was conducted as a mouse sepsis model. Aspergillus fumigatus spores were intravenously inoculated on day 5 post-CLP, when the immune cells succumbed to exhaustion. Amphotericin B was medicated together with or without anti-PD-1 treatment after Aspergillus infection. RESULTS: Amphotericin B alone was not effective to treat the CLP-mice with secondary aspergillosis. In contrast, antifungal medication with the adjunctive anti-PD-1 treatment attenuated the fungal burdens in blood and internal organs, and improved the survival rate of the mice with secondary aspergillosis. These outcomes of PD-1 blockade were concurring with the enhanced CD86 expression on splenocytes, the augmented serum IFN-γ, and the dampened IL-10. Activated T cells from anti-PD-1-treated mice also highly increased IFN-γ and diminished IL-10 production. CONCLUSION: The blockade of PD-1 on postsepsis aspergillosis presumably reinvigorated exhausted antigen-presenting cells and T cells by upregulating CD86 expression and IFN-γ production, and dampened IL-10 production, which consequently leaded to the attenuation of secondary aspergillosis. The adjunctive anti-PD-1 therapy may become a promising strategy for the advanced immunotherapy against lethal fungal infection.
BACKGROUND:Nosocomial aspergillosis in patients with sepsis has emerged in the past few years. Blockade of PD-1/PD-L pathway has tended to become a promising therapeutic strategy as it improved the outcome of bacterial sepsis and postsepsis secondary fungal infection. Recently, the controversial effects of PD-1 blockade on infectious diseases, including aspergillosis, have been demonstrated; therefore, the efficacy of anti-PD-1 drug still remains to be elucidated. METHODS: Cecal ligation and puncture (CLP) was conducted as a mousesepsis model. Aspergillus fumigatus spores were intravenously inoculated on day 5 post-CLP, when the immune cells succumbed to exhaustion. Amphotericin B was medicated together with or without anti-PD-1 treatment after Aspergillus infection. RESULTS:Amphotericin B alone was not effective to treat the CLP-mice with secondary aspergillosis. In contrast, antifungal medication with the adjunctive anti-PD-1 treatment attenuated the fungal burdens in blood and internal organs, and improved the survival rate of the mice with secondary aspergillosis. These outcomes of PD-1 blockade were concurring with the enhanced CD86 expression on splenocytes, the augmented serum IFN-γ, and the dampened IL-10. Activated T cells from anti-PD-1-treated mice also highly increased IFN-γ and diminished IL-10 production. CONCLUSION: The blockade of PD-1 on postsepsis aspergillosis presumably reinvigorated exhausted antigen-presenting cells and T cells by upregulating CD86 expression and IFN-γ production, and dampened IL-10 production, which consequently leaded to the attenuation of secondary aspergillosis. The adjunctive anti-PD-1 therapy may become a promising strategy for the advanced immunotherapy against lethal fungal infection.
Authors: Sebastian Wurster; Prema Robinson; Nathaniel D Albert; Jeffrey J Tarrand; Marisa Goff; Muthulekha Swamydas; Jean K Lim; Michail S Lionakis; Dimitrios P Kontoyiannis Journal: J Infect Dis Date: 2020-08-17 Impact factor: 5.226