Programmed Cell Death in the Pathogenesis of Influenza

Abstract

Influenza is a respiratory disease induced by infection by the influenza virus, which is a member of Orthomyxoviridae family. This infectious disease has serious impacts on public health systems and results in considerable mortality and economic costs throughout the world. Based on several experimental studies, massive host immune reaction is associated with the disease severity of influenza. Programmed cell death is typically induced during virus infection as a consequence of host immune reaction to limit virus spread by eliminating niches for virus propagation without causing inflammation. However, in some viral infectious diseases, such as influenza, in the process of immune reaction, aberrant induction of programmed cell death disturbs the maintenance of organ function. Current reports show that there are different types of programmed cell death that vary in terms of molecular mechanisms and/or associations with inflammation. In addition, these novel types of programmed cell death are associated with pathogenesis rather than suppressing virus propagation in the disease course. Here, we review our current understanding of mechanisms of programmed cell death in the pathogenesis of influenza.

Keywords: influenza; pathogenesis; programmed cell death.

Figure 1

Cytokine-dependent pogrammed cell death (PCD) induction in influenza virus infection. VRNP incorporated in influenza virus particles is released from the particle within the host cellular endosome. The released vgRNA that consists of vRNP engages host endosomatic pattern recognition receptors (PRRs), such as toll like receptors (TLRs). In the host cell cytosol, vRNP also activates cytosolic PRRs. The activation of both endosomatic and cytosolic PRRs stimulate gene induction of type-I interferon (IFN). The secreted type-I IFN binds and activates its specific receptor, IFNARs in an autocrine and paracrine manner. The activated IFNARs stimulate the gene induction of several PCD associated genes, including FasL or TRAIL.

Figure 2

Molecular defined apoptosis induction in influenza virus infection. Type-I IFN-mediated death ligand expression on the host cell surface aggregates death receptor (DR) trimerization. DR trimerization induces aggregation of intracellular adaptor proteins such as Fas-associated protein with death domain (FADD), which binds the cytoplasmic tail of DR. The FADD aggregation also induces pro-caspase-8 aggregation and enzymatic autocatalytic activation. The activated caspase-8 cleaves and activates effector caspase-3 and intracellular BH3 interacting domain death agonist protein (Bid). The activated Bid induces permeabilization of the mitochondrial outer membrane. The permeabilization induces the release of cytochrome-C from the interior of mitochondria. The released cytochrome-C binds caspase-9 and forms apoptosome. The formation of apoptosome induces aggregation and auto-enzymatic activation of caspase-9 to activate caspase-3. The caspase 3 activated by activated caspases 8 and 9 cleaves and inactivates ICAD to induce fragmentation of genomic DNA of cells.

Figure 3

Molecularly-defined necroptosis induction in influenza virus infection. The complex of vRNA and nucleoprotein (NP) and polymerase basic protein 1 (PB1) of the influenza virus is recognized by the Z-DNA-binding protein 1/DNA-dependent activator of IFN-regulatory factors (ZBP1/DAI). The ZBP1/DAI induces oligomerization of receptor-interacting kinase (RIPK)1/3. Within the oligomeric kinase complex (namely, the necrosome), each RIPK phosphorylates and activates together. The activated RIPKs phosphorylate and activate mixed lineage kinase domain-like (MLKL). The phosphorylated MLKL translocates from the cytosol to the cellular membrane. The translocated MLKLs form a cellular channel to permeabilize the cellular membrane.

Figure 4

Molecularly-defined pyroptosis induction in influenza virus infection. Several components of the influenza virus particle are recognized by both CARD-containing and PYD-containing PRRs. Recognition by the PRRs induces aggregation of caspase-1 to activate the cellular enzyme. The aggregation of caspase 1 by PYD-containing PRRs needs the adaptor protein absent in melanoma 2 (AIM2), which contains the PYD and CARD domains on its amino acid structure. The activated caspase 1 cleaves gasdermin D (GADMD), proIL1β or proIL18 to convert these substrates to the active form. The activated GSDMD translocates from the cytosol to the cellular membrane to form a channel. The formation of the channel induces permeabilization of the cellular membrane to release IL1β and IL18. These cytokines, once released, stimulate and recruit neutrophils to the infected local area. The recruited neutrophils endocytose the virus particles and release neutrophil extracellular traps (NET) to capture the pathogens. However, the host tissue damage brought about by the abundant production of NETs should be considered.

Figure 5

PCD induction in host protective immunity and pathogenicity in influenza virus infection. PCDs including apoptosis, necroptosis and pyroptosis are usually mechanisms to limit influenza virus proliferation niches. Especially, necroptosis and pyroptosis associate releasing DAMPs or IL1 that activate and recruit phagocytotic cells such as neutrophils, macrophages and dendritic cells into local virus replication area. The phagocytotic cells produce several inflammatory cytokines including TNFα and IL-6 to promote the accumulation of the cells. High yield of the virus replication often promotes and/or sustains the massive host immunoreactions that cause tissue damages and organ failure.