8.3  Direct and indirect effects of n-3 PUFAs on the viral load
Although EPA and DHA have been widely used to ameliorate chronic inflammatory diseases their effect on viral infections remains limited (Das, 2018; Husson et al., 2016; Ingram, Eaton, Erdos, Tedder, & Vreeland, 1982; Juers, Rogers, McCurdy, & Cook, 1976; Territo & Golde, 1979). Some evidence indicates EPA, DHA and other dietary unsaturated fatty acids can inactivate viruses by directly causing leakage or lysis of the viral envelopes, which will disrupt the membrane integrity or activate the humoral immune system to produce antibodies against these pathogens (Das, 2018, Das, 2020a; Hilmarsson, Larusson, & Thormar, 2006; Kohn, Gitelman, & Inbar, 1980). Morita et al. demonstrated n-3 PUFA-derived lipid mediator, protectin D1, exhibits antiviral activity, markedly attenuates influenza A virus replication and improves survival in severe influenza infection in male C57Bl/6J mice. This study highlighted the importance of the endogenous protectin D1 as an innate suppressor of influenza virus replication attenuating lethal infection (Morita et al., 2013). In another study, Ramon et al. evaluated the ability of 17-HDHA, a SPM derived from DHA, for improving the immune response to H1N1 influenza virus. The results showed 17-HDHA was able to enhance the humoral immunity against viruses by increasing the number of antibody-secreting cells and the levels of H1N1 antibodies, which resulted in greater protection against live H1N1 influenza infection in mice (Ramon et al., 2014). More recently, Braz-De-Melo highlighted the beneficial effects of n-3 PUFAs against viral infections by showing that DHA pre-treatment to neuroblastoma SH-SY5Y cells infected with Zika virus increased their viability and proliferation, restored mitochondrial function, reduced viral load and triggered an anti-inflammatory response identifying n-3 PUFAs as useful therapeutic tools in combating viruses (Braz-De-Melo et al., 2019). Additionally, Yan et al. has shown that EPA and DHA can inhibit the replication of both enterovirus A71 and coxsackievirus A16 the most common causes of hand, foot, and mouth disease (Yan et al., 2019). Collectively, we can conclude that n-3 PUFAs have the capability to attenuate viral infections via both direct effects on membrane integrity and indirect mechanisms activating the humoral response to decrease overall viral load.
In contrast, the immunosuppressive effects of EPA and DHA supplementation can decrease the immune response against viral infections and thus compromising removal from the body. C57BL/6J mice supplemented with fish oil and infected with H1N1 influenza virus showed a 40% higher mortality rate and 70% higher viral load compared to the corresponding control. Moreover, the treated mice had markedly reduced numbers of CD8+ T lymphocytes and reduced mRNA expression of inflammatory mediators IL-6 and TNF-α (Schwerbrock, Karlsson, Shi, Sheridan, & Beck, 2009). Similarly, BALB/c mice fed a high-fat diet rich in EPA and DHA had reduced levels of IFN-γ, serum immunoglobulin G and lung immunoglobulin A-specific antibodies following infection with the influenza virus, indicating a virus-specific lung T cell cytotoxicity. These results suggested supplementation with a diet rich in EPA and DHA could impair immune response by delaying virus clearance. However, differences noticed during the course of infection did not affect the ultimate outcome as n-3 PUFA-fed mice were finally able to clear the virus and returned to pre-infection food consumption and body weight similar to the control group (Byleveld, Pang, Clancy, & Roberts, 1999; Byleveld, Pang, Clancy, & Roberts, 2000). Importantly, other factors contribute to these opposite results, for example, an initial weight loss is typically observed when mice are supplemented with fish oil (Byleveld et al., 1999). In addition, thoroughly controlled animal studies have not been conducted with the SARS-CoV-2 virus and significant variations between viruses should be considered. Therefore, further research is needed to understand the role of EPA and DHA in the immune response related specifically to SARS-CoV-2 viral infections.