2.3 - Resolvins and bacterial infections
A wide range of studies have demonstrated the effects of resolvins in various model of bacterial infections. For example, treatment with RvD1 reduced inflammation and neutrophil infiltrates during P. aureoginosa infection in mice (Lee et al., 2022). In the case ofCitrobacter rodentium (C. rodentium ) infection, post-infection treatment with RvD1 plus RvD5 decreased bacterial loads, reduced inflammation, and rescued mice from lethality (Diaz et al., 2017). Accordingly, administration of RvD2 limited neutrophil infiltration, enhanced phagocytosis and bacteria clearance, and expedited inflammation resolution in Escherichia coli (E. coli ) and S. aureus infections (Chiang et al., 2015). RvD3 treatment improved bacterial clearance, efferocytosis, and accelerated resolution during peritonitis induced by E. coli infection, making it a promising agent against E. coli (Norris et al., 2018). Additionally, treatment with approximately 0.1nM concentrations of RvD4 proved effective against S. aureus infection in mice (Winkler et al., 2016). In vitro studies also demonstrated the immune modulation of RvD1, RvD2, and RvD5 during E. coliinfection in human macrophages, resulting in a decrease in the production of pro-inflammatory cytokines (Palmer et al., 2011; Werz et al., 2018).
Resolvins have shown efficacy in both sepsis and sepsis-like models. For instance, in a murine model of sepsis induced by cecal ligation and puncture (CLP), delayed systemic treatment with RvD1 increased bacterial clearance, improved mouse survival, and decreased neutrophil influx and cytokine production, such as TNF (Chen et al., 2014). In a model of sepsis induced by D-galactosamine (GalN), mice treated with RvD1 concurrently with D-GalN injection exhibited a lower number of neutrophil accumulations and decreased levels of HMGB1 and CCL2 in serum (Murakami et al., 2011). Other studies have demonstrated the potential of RvD1, RvD2, RvE1, and AT-RvD1 treatment, as well as the protective effect of endogenous levels of these lipids, in various sepsis models. These treatments increased mouse survival, reduced bacterial load, and suppressed pro-inflammatory cytokine production (Chiang et al., 2012; Chen et al., 2020; Silva et al., 2021; Svahn et al., 2016, see Table 1 and Supplementary Table 1). Importantly, administration of RvD1 in conjunction with antibiotics expedited the resolution of peritonitis, indicating the potential of resolvins to be used as adjutants in traditional bacterial infection and septic condition treatments (Chiang et al., 2012).
RvD1 has garnered significant attention in pre-clinical models of lung infection due to its ability to ameliorate lung damage, reduce inflammation, and decrease bacterial loads. Studies conducted in mice have demonstrated the positive effects of RvD1 or AT-RvD1 treatment in response to various pathogens such as E. coli , P. aeruginosa , and Nontypeable Haemophilus influenzae (NTHi) (Codagnone et al., 2018; Croasdell et al., 2016; Abdulnour et al., 2016; Wang et al., 2017; Sekheri et al., 2020; Isopi et al., 2020; Bhat et al., 2021). These effects of RvD1 were primarily attributed to a significant decrease in neutrophil accumulation. Additionally, RvD1 could accelerate the resolution phase in the lungs, either alone or in combination with antibiotics against P. aureoginosa (Gao et al., 2020). Other classes of resolvins, such as RvE1 and RvD2, also demonstrated beneficial effects. RvD2 decreased bacterial load in the lungs duringP. aeruginosa infection (Walker et al., 2022; Sundarasivarao et al., 2022). Treatment with RvE1 in mice decreased neutrophil accumulation, improved E. coli clearance, and dampened cytokine production (Seki et al., 2010).
In summary, these results demonstrate that resolvins, especially RvD1, show promise as therapeutic candidates against a range of bacterial infections, either alone or in combination with antibiotic treatments.