Influenza-Host Interplay and Strategies for Universal Vaccine Development

Abstract

Influenza is an annual epidemic and an occasional pandemic caused by pathogens that are responsible for infectious respiratory disease. Humans are highly susceptible to the infection mediated by influenza A viruses (IAV). The entry of the virus is mediated by the influenza virus hemagglutinin (HA) glycoprotein that binds to the cellular sialic acid receptors and facilitates the fusion of the viral membrane with the endosomal membrane. During IAV infection, virus-derived pathogen-associated molecular patterns (PAMPs) are recognized by host intracellular specific sensors including toll-like receptors (TLRs), C-type lectin receptors, retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) either on the cell surface or intracellularly in endosomes. Herein, we comprehensively review the current knowledge available on the entry of the influenza virus into host cells and the molecular details of the influenza virus-host interface. We also highlight certain strategies for the development of universal influenza vaccines.

Keywords: adaptive immune response; immunopathology; influenza A virus; innate immune response; universal influenza vaccine.

Figure 1

Influenza A virus endocytosis and hemagglutinin proteins (HA) conformational change. (A) Process of the entry of influenza virus into host cell. The virus binds to sialic acid-containing proteins on the cell surface receptors by association with the viral hemagglutinin proteins (HA1, HA2). HAs also bind to the sialic acid-containing Ca²⁺ channel to trigger intracellular Ca²⁺ oscillations. The virus is then internalized by endocytosis. Acidification of the endosome causes a conformational change in the HA proteins that leads to a fusion between the viral membrane and the endosomal membrane. This allows the escape of the viral RNA and proteins into the cytoplasm. (B) Structure of the HA of IAV. The trimeric complex of HA is shown with one monomer highlighted in color (HA1; red, HA2; blue, and the receptor binding pocket; green). (C) The pre- and post-fusion conformations of HA [4]. This figure was created using BioRender (Toronto, ON, Canada).

Figure 2

The intracellular cytoplasmic pattern-recognition receptor RIG-I is essential for the control of RNA virus infection. Upon IAV recognition, RIG-I recruits the adaptor MAVS protein to activate the IKKα–IKKβ and TBK1–IKKϵ complexes, which are responsible for the activation of the IRF 3 and IRF7 transcription factors. These transcription factors then translocate into the nucleus and cooperatively induce IRF dependent type I IFNs and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) dependent pro-inflammatory cytokines and chemokines. This is followed by the binding of the IFNAR1 and IFNAR2 to their cognate receptor, which leads to the transcriptional activation of ISGs by the JAK/STAT signaling pathway. The products of ISGs are key factors limiting pathogen spreading. Moreover, ssRNA from IAVs can prime the inflammasome by activating a TLR inducing NF-κB activation and the expression of NLRP3, ASC, and preforms of IL-18 and IL-1β. A second activation signal is provided by the oligomerization of the NLRP3 complex and recruitment of ASC and procaspase-1, allowing the processing and cleavage of pro-IL-1β and pro-IL-18 precursors into their bioactive mature forms (IL-18 and IL-1β). NLRP3 can be activated by imbalances in potassium ion concentration in intracellular vesicles through the ATP-gated P2 × 7 channel and responses of mitochondrial reactive oxygen species. This figure was created using BioRender. RIG-1;retinoic acid-inducible gene-1, MAVS; mitochondrial antiviral signaling adaptor, IKKα; nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (IκB) kinase α, IKKβ; IκB kinase β, IKKϵ; IκB kinase ϵ, TBK1; TRAF family member-associated NF-kappa-B activator (TANK)-binding kinase 1, IRF; interferon-regulatory factors, IFNs; Interferons, NF-κB; Nuclear Factor kappa-light-chain-enhancer of activated B cells, IFNAR1; Interferon Alpha And Beta Receptor Subunit 1, IFNAR2; Interferon Alpha And Beta Receptor Subunit 2, ISGs; interferon-stimulated gene, JAK/STAT; Janus kinase (JAK)/signal transducer and activator of transcription (STAT), ssRNA; single stranded RNA, TLR; Toll like receptor, NLRP3; nucleoside oligomerization domain (NOD), leucine-rich repeat (LRR), and pyrin domain (PYD) domain-containing protein 3, ASC; Apoptosis-associated speck-like protein containing a CARD, IL-18; Interleukin 18, IL-1β; Interleukin 1β, ATP-gated P2X7; Adenosine triphosphate (ATP)-gated purinergic P2X7 receptor.

Figure 3

A schematic model showing the balance between successful viral clearance and a life-threatening immunopathology following influenza infection. (A) The excessive response to influenza infection results in the development of influenza immunopathology despite efficient viral clearance. The excessive inflammation sustained by an uncontrolled host response can induce epithelial disruption and lung damage. (B) Low immune response with immune escape from host immunosurveillance may increase viral replication, which in turn induces a strong release of secretory molecules. (C) The adequate cell mediated immunity with vaccination can control lung viral load without a severe lung pathology. This figure was created using the BioRender software.

Figure 4

Universal IAV vaccination approaches. (A) Chimeric hemagglutinins (cHAs) consist of the exotic globular head domains and the conserved H2 stalk domain. (B) Mixture of virus like particles (VLPs) that express multiple subtypes of HA (C) Combination approaches with Matrix protein 1 (M1) and nucleoprotein (NP) with virus vectors or DNA vectors. (D) Vaccination strategies based on conserved M2 ectodomain (M2e).