Anti-PD-L1 Therapy Does Not Improve Survival in a Murine Model of Lethal Staphylococcus aureus Pneumonia

• Type of Material: Article
• Authors: Colleen S Curran, National Institutes of Health, Bethesda; Lindsay Busch, Emory University; Yan Li, National Institutes of Health, Bethesda; Xizhong Cui, National Institutes of Health, Bethesda; Junfeng Sun, National Institutes of Health, Bethesda; Peter Q Eichacker, National Institutes of Health, Bethesda; Parizad Torabi-Parizi, National Institutes of Health, Bethesda
• Language: English
• Date: 2021-05-19
• Publisher: OXFORD UNIV PRESS INC
• Publication Version: Final Published Version
• Copyright Statement: Published by Oxford University Press for the Infectious Diseases Society of America 2021.
• Final Published Version (URL): http://dx.doi.org/10.1093/infdis/jiab274
• Title of Journal or Parent Work: JOURNAL OF INFECTIOUS DISEASES
• Volume: 224
• Issue: 12
• Start Page: 2073
• End Page: 2084
• Grant/Funding Information: This work was supported by intramural research funds from the National Institutes of Health Clinical Center.
• Keywords: Microbiology; Infectious Diseases; PD-L1; CLEARANCE; SEPSIS; Immunology; pneumonia; INHIBITION; Life Sciences & Biomedicine; sepsis; immunotherapy; MICE; EXPRESSION; INFECTION; RISK; CYTOKINES; Science & Technology; Staphylococcus aureus
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Background: Staphylococcus aureus (SA) bacterial pneumonia is a common cause of sepsis in intensive care units. Immune checkpoint inhibitors (CPIs) that target programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have been proposed for the treatment of sepsis. However, in our systematic review of sepsis preclinical models, none of the models examined CPIs in pneumonia. Methods: Mice were inoculated intratracheally with vehicle control, low dose (LD)- or high dose (HD)-SA. Immune cell recruitment and checkpoint molecule expression were examined at 4, 24, and 48 hours after infection. Infected animals, treated with control or anti-PD-L1 antibodies, were assessed for survival, bacterial burden, lung immunophenotypes, and mediator production. Results: LD-SA and HD-SA produced lethality of 15% and 70%, respectively, by 168 hours. At 24 hours, LD-infected animals exhibited increased lung monocyte PD-L1 expression (P = .0002) but lower bacterial counts (P = .0002) compared with HD animals. By 48 hours, either infection induced lung neutrophil and macrophage PD-L1 expression (P < .0001). Anti-PD-L1 treatment at the time of infection and at 24 hours following infection with low to high doses of SA reduced PD-L1 detection but did not affect survival or bacterial clearance. Conclusions: Anti-PD-L1 therapy did not alter survival in this pneumonia model. Preclinical studies of additional common pathogens and septic foci are needed.