Treating Influenza Infection, From Now and Into the Future

Abstract

Influenza viruses (IVs) are a continual threat to global health. The high mutation rate of the IV genome makes this virus incredibly successful, genetic drift allows for annual epidemics which result in thousands of deaths and millions of hospitalizations. Moreover, the emergence of new strains through genetic shift (e.g., swine-origin influenza A) can cause devastating global outbreaks of infection. Neuraminidase inhibitors (NAIs) are currently used to treat IV infection and act directly on viral proteins to halt IV spread. However, effectivity is limited late in infection and drug resistance can develop. New therapies which target highly conserved features of IV such as antibodies to the stem region of hemagglutinin or the IV RNA polymerase inhibitor: Favipiravir are currently in clinical trials. Compared to NAIs, these treatments have a higher tolerance for resistance and a longer therapeutic window and therefore, may prove more effective. However, clinical and experimental evidence has demonstrated that it is not just viral spread, but also the host inflammatory response and damage to the lung epithelium which dictate the outcome of IV infection. Therapeutic regimens for IV infection should therefore also regulate the host inflammatory response and protect epithelial cells from unnecessary cell death. Anti-inflammatory drugs such as etanercept, statins or cyclooxygenase enzyme 2 inhibitors may temper IV induced inflammation, demonstrating the possibility of repurposing these drugs as single or adjunct therapies for IV infection. IV binds to sialic acid receptors on the host cell surface to initiate infection and productive IV replication is primarily restricted to airway epithelial cells. Accordingly, targeting therapies to the epithelium will directly inhibit IV spread while minimizing off target consequences, such as over activation of immune cells. The neuraminidase mimic Fludase cleaves sialic acid receptors from the epithelium to inhibit IV entry to cells. While type III interferons activate an antiviral gene program in epithelial cells with minimal perturbation to the IV specific immune response. This review discusses the above-mentioned candidate anti-IV therapeutics and others at the preclinical and clinical trial stage.

The Establishment and Validation of the Human U937 Cell Line as a Cellular Model to Screen Immunomodulatory Agents Regulating Cytokine Release Induced by Influenza Virus Infection

“…Their use in animal experiments has shown to reduce the mortality of H1N1 and H3N2-infected mice. More importantly, in the retrospective study of human drug use, the use of statins is associated with a reduction in influenza-induced lethality (Liu et al 2009;Mehrbod et al 2014;Davidson 2018). Serotonin reuptake inhibitors can alleviate lung inflammation in mice induced by the H1N1 influenza virus and reduce mortality in mice (Sharma et al 2013).…”

“…Several studies have shown that cytokine storms are directly associated with influenza-induced fatal acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) (Tisoncik et al 2012;Short et al 2014). Antiviral treatments, which target viral components, are prone to develop drug-resistant viruses and have a narrow time window for their administration; they are also unable to control the excessive proinflammatory response that occurs in the late stage of infection (Davidson 2018). Therefore, the attenuation of the host inflammatory response with immunomodulators may represent a good strategy for combating severe influenza.…”

“…In recent years, a few immunomodulatory agents, including proteinase-activated receptor 1 (PAR1) antagonist (Khoufache et al 2013), sphingosine-1-phosphate (S1P1) receptor 1 agonists (Teijaro et al 2011), and tyrosine protein kinase (TPK) inhibitors (Florence et al 2018), have shown protective effects in animal models including alleviating the pulmonary inflammatory reaction and increasing survival rates. However, the lack of efficient cell-based screening models is a great impediment in the development of anti-inflammatory drugs targeting influenza-induced cytokine storms (Davidson 2018). Animal models, despite being ideal for studying potential antiinflammatory therapeutics, are very costly and time-consuming.…”

Alternative Experimental Models for Studying Influenza Proteins, Host–Virus Interactions and Anti-Influenza Drugs

“…To date, only two antiviral drug classes, with some usefulness, are available and very few are under development or in trials [8]. The drugs available in the clinic are Matrix 2 (M2) ion channel inhibitors, (e.g., amantadine and rimantadine) and neuraminidase (NA) inhibitors (e.g., oseltamivir and zanamivir) [6].…”

B-cell restriction – an alternative piece to the puzzle

“…37 Influenza benefits from both genetic drift and shift. 20,38 These dynamic instabilities produce vast amounts of variant viruses, many of which may be non-productive progeny. However, with each replicative cycle of the virus some amino acid compositional variationsmutations, are produced that do not compromise viral infection.…”