2.2 - Resolvins and viral infections
Most studies on resolvins and viruses have focused on respiratory viruses, including SARS-CoV-2 infection. One study found no difference in serum or plasma levels of Resolvins D1 to D5 between healthy volunteers and COVID-19 patients (Regidor et al, 2021). Meanwhile, another study found downregulated levels of RvD1 and RvD3 in the plasma of critically ill COVID-19 patients (Palmas et al, 2021). However, a small sample size may have contributed to the inconsistency between these findings. Decreased systemic levels of RvD1 and RvE4 were linked to poor prognosis and reduced survival of patients with COVID-19 (Palmas et al, 2021). In contrast, levels of all RvD1 to D5 (except RvD3) were higher in the BAL fluid of COVID-19 patients compared to control individuals (Archambault et al, 2021), potentially reflecting an attempt by the host to dampen inflammation in the lungs. Additionally, a RvD6 isomer decreased the expression of ACE2 receptor and pro-inflammatory cytokine levels in vitro (Pham et al, 2021). Finally, treatment of macrophages with RvD1 and RvD2 upon SARS-CoV-2 infection reduced levels of TNF, IL-6, IL-8, CCL2, and CCL3 cytokines (Recchiuti et al, 2021). Although data on endogenous levels of these molecules during COVID-19 are still elusive, their exogenous administration may hold great promise against the disease.
During coinfection with Streptococcus pneumoniae (S. pneumoniae ) and influenza A virus (H3N2), treatment with AT-RvD1 during the acute phase of infection ameliorated lung inflammation in mice, reducing neutrophil elastase activity, parenchymal inflammation, infiltrated neutrophils, and monocytes. In vitro , RvD1 treatment decreased TNF and IL-8 mRNA during H3N2 infection (Wang et al, 2017). Additionally, BALB/C mice infected with H3N2 and treated with RvD1 had reduced airway inflammation and phosphorylation of NF-κB p65 and IkBα (Guo et al, 2020). Importantly, in both studies, RvD1 did not affect viral titers of H3N2. In line with this findings, Morita and colleagues showed that treatment with RvD1 or RvD2 in A549 cells did not decrease viral titers during H1N1 infection (Morita et al, 2013). Similarly, topical treatment with RvD1 in rats infected with herpes simplex virus (HSV) did not decrease viral titers at different time points analyzed, although it decreased parameters of inflammation in the cornea of infected rats (Rajasagi et al, 2017). This suggests that RvD1 modulates the host response without altering its capacity to deal with pathogen replication.
In the context of RSV infection, different subtypes of resolvins may have varying effects on the host. For instance, treatment with RvD1 was found to be associated with increased viral loads in the lungs and a lower antibody response upon reinfection in mice (de Freitas et al., 2021). Conversely, RvE1 was shown to be beneficial against RSV: RvE1 treatment restored the M2 phenotype of macrophages that were infected with RSV (Shirey et al., 2014). Furthermore, RvE1 was found to have beneficial effects against HSV-1. RvE1 treatment decreased inflammation caused by HSV-1 infection in the cornea, reduced the levels of IL-6, IFN-γ, and CXCL-1, and increased the levels of IL-10 (Rajasagi et al., 2011). Taken together, these studies demonstrate that resolvins can alleviate inflammation caused by viruses, in addition to stimulating markers of resolution, such as M2 macrophage polarization. Overall, these molecules show great promise in the fight against viral infections.