Response Modifiers: Tweaking the Immune Response Against Influenza A Virus

Abstract

Despite causing pandemics and yearly epidemics that result in significant morbidity and mortality, our arsenal of options to treat influenza A virus (IAV) infections remains limited and is challenged by the virus itself. While vaccination is the preferred intervention strategy against influenza, its efficacy is reduced in the elderly and infants who are most susceptible to severe and/or fatal infections. In addition, antigenic variation of IAV complicates the production of efficacious vaccines. Similarly, effectiveness of currently used antiviral drugs is jeopardized by the development of resistance to these drugs. Like many viruses, IAV is reliant on host factors and signaling-pathways for its replication, which could potentially offer alternative options to treat infections. While host-factors have long been recognized as attractive therapeutic candidates against other viruses, only recently they have been targeted for development as IAV antivirals. Future strategies to combat IAV infections will most likely include approaches that alter host-virus interactions on the one hand or dampen harmful host immune responses on the other, with the use of biological response modifiers (BRMs). In principle, BRMs are biologically active agents including antibodies, small peptides, and/or other (small) molecules that can influence the immune response. BRMs are already being used in the clinic to treat malignancies and autoimmune diseases. Repurposing such agents would allow for accelerated use against severe and potentially fatal IAV infections. In this review, we will address the potential therapeutic use of different BRM classes to modulate the immune response induced after IAV infections.

Influenza Vaccines: Successes and Continuing Challenges

“…Kinases are one class of biological response modifiers that has been investigated for intervention strategies against influenza viruses. Host kinases not only regulate influenza virus entry and replication, but are also integral components of various antiviral and inflammatory pathways allowing them to shape the immune response (reviewed in [ 157 ] and [ 158 ]). The therapeutic potential of targeting kinases has long been recognized in the field of oncology.…”

Development and Effects of Influenza Antiviral Drugs

“…Thus far, the World Health Organization still believes that vaccines are the best way to prevent and control an influenza pandemic; however, influenza viruses constantly undergo genetic changes and require vaccines that match the circulating influenza strains to be effective, so seasonal influenza vaccines have to be modified annually [ 16 , 17 , 18 , 19 ]. In addition, the application of vaccines has also been limited due to the side effects and storage difficulty [ 17 ]. Therefore, the study of antiviral drugs is increasingly imperative [ 16 , 20 ].…”

Novel Fatty Acid in Cordyceps Suppresses Influenza A (H1N1) Virus-Induced Proinflammatory Response Through Regulating Innate Signaling Pathways

“… 9 − 11 Activation of these molecules triggers signal transduction pathways, leading to the production of proinflammatory cytokines and the subsequent clearance of the virus. 11 In an otherwise healthy individual, IV causes mild infections, and virus clearance can be accomplished without causing damage in the respiratory tract. 12 However, IV infections caused by pandemic or highly pathogenic strains can lead to fulminant viral pneumonia in a high-risk population, including infants, young children, pregnant women, or the elderly, who progress to acute respiratory distress syndrome (ARDS) or even die.…”

“…It is widely accepted that not only virus replication competence but also host immune response contribute to disease outcome in IV disease . Early recognition of IVs is mediated by pattern recognition receptors (PRRs) such as toll-like receptors (TLRs) and retinoic acid inducible gene-I (RIG-I) in respiratory epithelial cells and alveolar macrophages. − Activation of these molecules triggers signal transduction pathways, leading to the production of proinflammatory cytokines and the subsequent clearance of the virus . In an otherwise healthy individual, IV causes mild infections, and virus clearance can be accomplished without causing damage in the respiratory tract .…”