Targeting eicosanoid pathways in the development of novel anti-influenza drugs

Abstract

The constant new emergence of life-threatening human respiratory viral pathogens presents new challenges to clinicians who are left with no available therapeutic interventions. Highly pathogenic strains of influenza A virus (IAV) share an enhanced capacity to propagate to the lower airways and paralyze alveolar macrophage antiviral capacity in order to replicate efficiently and cause pathologic inflammation. Following a century of using NSAIDs for the management of influenza symptoms, a number of studies have interrogated their function in the host response to IAV infection. We herein provide an overview of these studies as well as further insight of how pathogenic IAV hijacks the microsomal prostaglandin E synthase-1-dependent prostaglandin E₂ pathway in order to evade host type I interferon-mediated antiviral immunity. We also reflect on the potential beneficial action of microsomal prostaglandin E synthase-1 inhibitory compounds in the treatment of IAV infections and potentially other RNA viruses.

Keywords::

• adaptive immunity
• eicosanoids
• innate immunity
• influenza virus
• macrophage

Financial & competing interests disclosure

This work was supported by the Canadian Institute of Health Research (CIHR) operating grant (MOP-106488) to M Divangahi and M Divangahi holds CIHR New Investigator Award. F Coulombe is supported by a F. Banting and C. Best Canada Graduate Scholarships from CIHR. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Estimated global mortality associated with respiratory infections is approximately four million deaths, annually. Influenza A virus (IAV) epidemics account for more than 40,000 deaths in the USA alone.

• Uncontrollable immunopathology is the major cause of mortality by highly pathogenic stains of IAV in human, non-primates and mice.

• High frequencies of IAV transmission with the lack of effective treatments have a tremendous potential for a pandemic.

• Development of the drugs such as oseltamivir (Tamiflu) targeting IAV is not successful in the long-term, considering the low efficacy of the drug as well as generation of viral drug resistance.

• There is an urgent need for the development of targeted immunotherapy promoting an adequate and effective immune response to IAV infection.

• Prostaglandin E₂ (PGE₂) is one of the best known and well-studied with both pro- and-anti-inflammatory properties; however, PGE₂ production via microsomal prostaglandin E synthase-1 (mPGES-1) often causes inflammation.

• Inhibition of mPGES-1and thus PGE₂ production increases type I interferon which is an essential component of the host anti-viral immunity.

• Future research should emphasize on human clinical trial evaluating the effects of a selective mPGES-1 inhibitor in IAV or other pulmonary viral infections.

Notes