Influenza

Influenza is a communicable respiratory infection caused by influenza viruses. During infection, influenza viruses take over and use cell signaling pathways—activated by the host cell primarily for antiviral functions—for their replication and survival (1). These pathways, including the MAPK pathways, PI3K/AKT signaling, and Wnt/β-catenin signaling, are crucial to the pathogenesis of influenza viruses, making them potential targets for effective antiviral therapies and universal and lasting influenza vaccines (2). 

Influenza viruses are single-stranded, segmented, negative-sense RNA viruses and are members of the family Orthomyxoviridae (3). Four influenza virus types have been identified and are grouped according to their integral proteins into A, B, C, and D. Only influenza types A, B, and C are known to infect and cause respiratory illness in humans. In particular, influenza A has been recognized to have the widest host range and is most likely to evolve into highly pathogenic strains (1).

The pathogenesis of influenza A relies on the complex interaction between the viral proteins and host factors, including immune system function, age, underlying health conditions, microbiome, sex, and genetic factors. And it occurs in two phases: the first phase determines the virus infectivity and consequent inflammation, which, in turn, determines whether the second phase will lead to disease control or exacerbation (3).

The first phase begins with infection and can happen for up to three days. Low or no pre-existing immunity in the host leads to a high viral load and increased inflammation. On the other hand, pre-existing immunity or effective antiviral immunity results in less viral replication and inflammation (3).

In relatively young and healthy adults, the second phase may be marked by control of virus replication and resolution of the disease. However, excessive inflammation and severe diseases may also characterize the second phase in the presence of host factors like genetic susceptibility, aging, pre-existing condition, and obesity.  Severe diseases may also develop with an aberrant immune response (3).

Viral proteins hemagglutinin (HA) and neuraminidase (NA) play significant roles in the pathophysiology of influenza and are the primary targets of neutralizing antibodies developed from acquired immunity (4). HA is responsible for viral entry, attachment, and replication as it targets epithelial cells of the upper respiratory tract and binds virions to them to initiate cellular infection. On the other hand, NA releases virions from infected cells to spread them to adjacent epithelial cells (5).

Viral genome replication in the epithelial cells induces cell death. Though cell death is part of the host defense mechanism against the virus, when excessive and uncontrolled, it may lead to undesirable outcomes like a ‘cytokine storm,’ a hyperinflammatory state that may lead to lung injury and death (6).

Cytokine storm is a phenomenon in which the overproduction and release of proinflammatory cytokines, such as IFNα/β, TNF-α, IL-1, IL-6, IL-8, CCL2, CCL5, and CXCL10, results in an aggressive proinflammatory response and poor control of anti-inflammatory responses (7,8). Also known as hypercytokinemia, this state may predict disease progression and is one of the major causes of death from severe influenza. The H5N1 virus is associated with excessive cytokine production, likely contributing to the severe disease characteristic of H5N1 infections (7).  

Because the influenza A virus lacks a metabolic system, it must depend on and target the host cell metabolic system, particularly lipid metabolism, to promote viral replication (9). Lipid metabolism is essential to key events in the virus life cycle, including viral entry and interaction with host cells, membrane fusion, and viral assembly and budding. Phospholipid, for instance, contributes to making cells susceptible to virus infection and is critical to the fusion, infectivity, and release of progeny virions (9).

The MAPK pathways, which include ERK, JNK, and p38 signaling pathways, are also implicated in influenza virus pathogenesis. These pathways become activated with influenza A virus infection and contribute to regulating the expression of genes involved in regulating viral infection and replication (10). p38 and JNK, for instance, have been linked to the expression of cytokines and chemokines, like RANTES (CCL5) and TNF (11).

Likewise, the P13K/AKT pathways become activated with influenza infection and are required in different stages of virus infection and replication (12). For example, P13K is needed for proviral functions like efficient viral entry in the early stages of infection and suppression of premature apoptosis at later stages. But these pathways also play antiviral roles, like promoting the activation of IRF3, a key mediator of the innate immune response to infection (1).

Other pathways that are hijacked and exploited by the influenza A virus during infection to complete its life cycle in host cells include the NF-κB signaling pathway, Wnt/β-catenin pathway, TLR/RIG-I signaling, and PKR signaling.  Researchers posit that therapeutic interventions that target these signaling pathways rather than viral proteins may be more effective for treating the disease and preventing the development of severe disease while limiting the possibility of drug-resistant strains emerging (13).

References

1. Ehrhardt C, Ludwig S. A new player in a deadly game: influenza viruses and the PI3K/Akt signaling pathway. Cell Microbiol. 2009;11(6):863-871.

2. Kumar R, Khandelwal N, Thachamvally R, et al. Role of MAPK/MNK1 signaling in virus replication. Virus Res. 2018;253:48-61.

3. Gounder AP, Boon ACM. Influenza Pathogenesis: The Effect of Host Factors on Severity of Disease. J Immunol. 2019;202(2):341-350.

4. Yu J, Sun X, Goie JYG, Zhang Y. Regulation of Host Immune Responses against Influenza A Virus Infection by Mitogen-Activated Protein Kinases (MAPKs). Microorganisms. 2020;8(7):1067.

5. Kosik I, Yewdell JW. Influenza Hemagglutinin and Neuraminidase: Yin⁻Yang Proteins Coevolving to Thwart Immunity. Viruses. 2019;11(4):346.

6. Gui R, Chen Q. Molecular Events Involved in Influenza A Virus-Induced Cell Death. Front Microbiol. 2022;12:797789. Published 2022 Jan 7.

7. Li H, Bradley KC, Long JS, et al. Internal genes of a highly pathogenic H5N1 influenza virus determine high viral replication in myeloid cells and severe outcome of infection in mice. PLoS Pathog. 2018;14(1):e1006821. Published 2018 Jan 4.

8. Guo XJ, Thomas PG. New fronts emerge in the influenza cytokine storm. Semin Immunopathol. 2017;39(5):541-550.

9. Zhou Y, Pu J, Wu Y. The Role of Lipid Metabolism in Influenza A Virus Infection. Pathogens. 2021;10(3):303. Published 2021 Mar 5.

10. Mohanta TK, Sharma N, Arina P, Defilippi P. Molecular Insights into the MAPK Cascade during Viral Infection: Potential Crosstalk between HCQ and HCQ Analogues. Biomed Res Int. 2020;2020:8827752. Published 2020 Dec 31.

11. Dong W, Wei X, Zhang F, et al. A dual character of flavonoids in influenza A virus replication and spread through modulating cell-autonomous immunity by MAPK signaling pathways. Sci Rep. 2014;4:7237. Published 2014 Nov 28.

12. Hirata N, Suizu F, Matsuda-Lennikov M, Edamura T, Bala J, Noguchi M. Inhibition of Akt kinase activity suppresses entry and replication of influenza virus. Biochem Biophys Res Commun. 2014;450(1):891-898.

13. lanz O. Development of cellular signaling pathway inhibitors as new antivirals against influenza. Antiviral Res. 2013;98(3):457-468.