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Updated: Nov 5, 2025
A Mouse Model to Assess Innate Immune Response to Staphylococcus aureus Infection
Published on: February 28, 2019
Anti-PD-L1 Therapy Does Not Improve Survival in a Murine Model of Lethal Staphylococcus aureus Pneumonia
Colleen S Curran1, Lindsay M Busch2, Yan Li1
1Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
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.
Insights
Immune checkpoint inhibitors targeting PD-1/PD-L1 did not improve survival in a Staphylococcus aureus pneumonia sepsis model. Further preclinical studies with other pathogens are necessary to explore sepsis treatments.
Area of Science:
- Immunology
- Infectious Diseases
- Critical Care Medicine
Background:
- Staphylococcus aureus (SA) bacterial pneumonia is a significant cause of sepsis in intensive care units.
- Immune checkpoint inhibitors (CPIs) targeting programmed cell death protein 1 (PD-1) and its ligand (PD-L1) are being investigated for sepsis treatment.
- Existing preclinical sepsis models have not evaluated CPIs in the context of pneumonia.
Purpose of the Study:
- To investigate the efficacy of anti-PD-L1 antibody therapy in a murine model of Staphylococcus aureus pneumonia-induced sepsis.
- To assess the impact of anti-PD-L1 treatment on survival, bacterial burden, and immune responses during SA pneumonia.
Main Methods:
- Mice were infected with low-dose (LD) or high-dose (HD) SA via intratracheal inoculation.
- Immune cell recruitment and checkpoint molecule expression (PD-L1) were analyzed at various time points.
- Animals received anti-PD-L1 antibody treatment at the time of infection and 24 hours post-infection, with outcomes assessed for survival and bacterial clearance.
Main Results:
- Both LD-SA and HD-SA infections led to significant lethality (15% and 70%, respectively).
- PD-L1 expression increased on lung monocytes, neutrophils, and macrophages following SA infection.
- Anti-PD-L1 treatment reduced PD-L1 detection but did not improve survival rates or reduce bacterial burden in this pneumonia model.
Conclusions:
- Anti-PD-L1 therapy demonstrated no survival benefit in the Staphylococcus aureus pneumonia sepsis model.
- Further preclinical research involving diverse pathogens and septic foci is required to determine the potential of CPIs in sepsis treatment.
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