Survival and Pulmonary Injury After Neonatal Sepsis: PD1/PDL1's Contributions to Mouse and Human Immunopathology.

Eleanor A Fallon,Daithi S Heffernan,Yaping Chen,Alfred Ayala,Chun-Shiang Chung,Monique E De Paepe

doi:10.3389/fimmu.2021.634529

Eleanor A Fallon, Daithi S Heffernan + Show 4 more

Open Access

https://doi.org/10.3389/fimmu.2021.634529

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Abstract

Morbidity and mortality associated with neonatal sepsis remains a healthcare crisis. PD1−/− neonatal mice endured experimental sepsis, in the form of cecal slurry (CS), and showed improved rates of survival compared to wildtype (WT) counterparts. End-organ injury, particularly of the lung, contributes to the devastation set forth by neonatal sepsis. PDL1−/− neonatal mice, in contrast to PD1−/− neonatal mice did not have a significant improvement in survival after CS. Because of this, we focused subsequent studies on the impact of PD1 gene deficiency on lung injury. Here, we observed that at 24 h post-CS (but not at 4 or 12 h) there was a marked increase in pulmonary edema (PE), neutrophil influx, myeloperoxidase (MPO) levels, and cytokine expression sham (Sh) WT mice. Regarding pulmonary endothelial cell (EC) adhesion molecule expression, we observed that Zona occludens-1 (ZO-1) within the cell shifted from a membranous location to a peri-nuclear location after CS in WT murine cultured ECs at 24hrs, but remained membranous among PD1−/− lungs. To expand the scope of this inquiry, we investigated human neonatal lung tissue. We observed that the lungs of human newborns exposed to intrauterine infection had significantly higher numbers of PD1+ cells compared to specimens who died from non-infectious causes. Together, these data suggest that PD1/PDL1, a pathway typically thought to govern adaptive immune processes in adult animals, can modulate the largely innate neonatal pulmonary immune response to experimental septic insult. The potential future significance of this area of study includes that PD1/PDL1 checkpoint proteins may be viable therapeutic targets in the septic neonate.

Highlights

Sepsis remains a devastating illness with high morbidity and mortality despite diagnostic and supportive therapeutic advances over the past several decades [1, 2]
We suggest that improved sepsis survival seen in Programmed cell death receptor-1 (PD1)−/− pups is driven by endorgan effects, sepsis mediated changes in the lung
Edema is clearly evidenced in the lungs of septic WT mice, among the PD1−/− group, the statistically significant increase that we witnessed in the WT is lost

Summary

Introduction

Sepsis remains a devastating illness with high morbidity and mortality despite diagnostic and supportive therapeutic advances over the past several decades [1, 2]. An intra-abdominal source of the sepsis is a predominant driver of this mortality. For the neonatal cohort mortality has remained relatively unchanged despite significant advances in neonatal critical care [6, 7]. Compared to the adult cohort, there is a relative paucity of data regarding the neonatal response to an intra-abdominal septic challenge, let alone an agespecific definition of sepsis criteria [8]. The detrimental effects of neonatal sepsis are thought to arise from an inadequate response of the immature immune system [9]

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