Protectins PCTR1 and PD1 Reduce Viral Load and Lung Inflammation During Respiratory Syncytial Virus Infection in Mice

Abstract

Viral pneumonias are a major cause of morbidity and mortality, owing in part to dysregulated excessive lung inflammation, and therapies to modulate host responses to viral lung injury are urgently needed. Protectin conjugates in tissue regeneration 1 (PCTR1) and protectin D1 (PD1) are specialized pro-resolving mediators (SPMs) whose roles in viral pneumonia are of interest. In a mouse model of Respiratory Syncytial Virus (RSV) pneumonia, intranasal PCTR1 and PD1 each decreased RSV genomic viral load in lung tissue when given after RSV infection. Concurrent with enhanced viral clearance, PCTR1 administration post-infection, decreased eosinophils, neutrophils, and NK cells, including NKG2D+ activated NK cells, in the lung. Intranasal PD1 administration post-infection decreased lung eosinophils and Il-13 expression. PCTR1 increased lung expression of cathelicidin anti-microbial peptide and decreased interferon-gamma production by lung CD4+ T cells. PCTR1 and PD1 each increased interferon-lambda expression in human bronchial epithelial cells in vitro and attenuated RSV-induced suppression of interferon-lambda in mouse lung in vivo. Liquid chromatography coupled with tandem mass spectrometry of RSV-infected and untreated mouse lungs demonstrated endogenous PCTR1 and PD1 that decreased early in the time course while cysteinyl-leukotrienes (cys-LTs) increased during early infection. As RSV infection resolved, PCTR1 and PD1 increased and cys-LTs decreased to pre-infection levels. Together, these results indicate that PCTR1 and PD1 are each regulated during RSV pneumonia, with overlapping and distinct mechanisms for PCTR1 and PD1 during the resolution of viral infection and its associated inflammation.

Cysteinyl Maresins Reprogram Macrophages to Protect Mice from Streptococcus pneumoniae after Influenza A Virus Infection

“…Here, the discordant kinetics for viral clearance and pathogen-initiated inflammatory responses are indicative of an excessive and prolonged induction of genes for viral host defense that persisted long after their essential roles in viral clearance and suggest a risk window of adaptive homeostasis, where intervention with proresolving mediators that dampen IFN signaling could mitigate post-IAV risk for secondary bacterial infection. Along these lines, DHA-derived protectins, a related family of SPMs, can decrease IFN expression after mouse respiratory syncytial virus infection ( 43 ). Additionally, harnessing proresolving pathways with SPMs, including MCTR3, was recently shown to reverse leukocyte defects in patients with severe COVID-19 ( 44 ).…”

RvD1 treatment during primary infection modulates memory response increasing viral load during respiratory viral reinfection

“…RSV infection increase the levels of leukotrienes, 5-LO (Behera et al, 1998), COX-2, and PGE2 (Walker et al, 2021), and treatment with COX-2 inhibitors decreases lung pathology associated with RSV infection (Richardson et al, 2005). Intranasal administration of the SPM, protectin D1 (PD1) and protectin conjugates in tissue regeneration 1 (PCTR1), reduce viral load during RSV infection (Walker et al, 2021). Also, consumption ômega-3 during pregnancy, the precursor for RvDs production, can protect the offspring children under the age of two from asthmatic symptoms and respiratory infections (Bisgaard et al, 2016).…”

Protectins: Their biosynthesis, metabolism and structure-functions

“…Furthermore, topical application of PCTR1 (100 ng/day) to mice with full-thickness dorsal skin wounds, showed enhanced wound closure in the early stages of wounding, in accordance with accelerated keratinocyte migration [32]. Recently Levy and co-workers, using a mice model of respiratory syncytial virus (RSV) pneumonia, reported that PCTR1 and PD1 each reduced the viral load in mice, dampening lung inflammation significantly [33]. Moreover, when PCTR1 was administrated post-infection, the levels of eosinophils, neutrophils and NK cells were all reduced; the same was observed for the interferon-gamma production by lung CD4 + T cells [33].…”

“…Recently Levy and co-workers, using a mice model of respiratory syncytial virus (RSV) pneumonia, reported that PCTR1 and PD1 each reduced the viral load in mice, dampening lung inflammation significantly [33]. Moreover, when PCTR1 was administrated post-infection, the levels of eosinophils, neutrophils and NK cells were all reduced; the same was observed for the interferon-gamma production by lung CD4 + T cells [33]. Of interest, PCTR1 and PD1 each enhanced interferon-lambda expression in human bronchial epithelial cells.…”

“…Of interest, PCTR1 and PD1 each enhanced interferon-lambda expression in human bronchial epithelial cells. In vivo studies, combined with LC/MS-MS analyses of lung exudates, showed that the resolution of RSV infected mice was associated with increased levels of both PCTR1 and PD1, while the levels of cysteinyl-leukotrienes decreased, compared to pre-infection levels [33]. Hence, PCTR1 and PD1 are each regulated during RSV pneumonia infections.…”