Autophagy and Respiratory Viruses: Mechanisms, Viral Exploitation, and Therapeutic Insights

Abstract

Respiratory viruses, such as influenza virus, rhinovirus, coronavirus, and respiratory syncytial virus (RSV), continue to impose a heavy global health burden. Despite existing vaccination programs, these infections remain leading causes of morbidity and mortality, especially among vulnerable populations like children, older adults, and immunocompromised individuals. However, the current therapeutic options for respiratory viral infections are often limited to supportive care, underscoring the need for novel treatment strategies. Autophagy, particularly macroautophagy, has emerged as a fundamental cellular process in the host response to respiratory viral infections. This process not only supports cellular homeostasis by degrading damaged organelles and pathogens but also enables xenophagy, which selectively targets viral particles for degradation and enhances cellular defense. However, viruses have evolved mechanisms to manipulate the autophagy pathways, using them to evade immune detection and promote viral replication. This review examines the dual role of autophagy in viral manipulation and host defense, focusing on the complex interplay between respiratory viruses and autophagy-related pathways. By elucidating these mechanisms, we aim to highlight the therapeutic potential of targeting autophagy to enhance antiviral responses, offering promising directions for the development of effective treatments against respiratory viral infections.

Keywords: HPIV; adenovirus; autophagy; coronavirus; influenza virus; respiratory syncytial virus (rsv); respiratory viruses.

Figure 1

Schematic illustration of autophagy pathways. (A) Macroautophagy (autophagy), which includes phagophore formation and expansion, autophagosome and lysosome fusion, and cargo degradation; (B) microautophagy, the lysosome takes up soluble particulates by protrusion or invagination; and (C) CMA, a selective degradation mechanism for specific proteins. This figure was created with BioRender.com. Licensing Right: VB27W582O8.

Figure 2

Schematic illustration of influenza virus interaction with autophagy. Influenza virus induces mitochondrial damage through viral NP and PB1-F2 proteins by release of ROS and IFN dysregulation that induces viral replication. The NP and M2 viral proteins, by attachment to LC3 and NS1 proteins through the interaction of BECN1 with PK3C3, induce autophagosome accumulation. Upregulation of HSP90AA1 and the involvement of the AKT/mTOR signaling pathway following viral infection cause autophagosome accumulation. This figure was created with BioRender.com. Licensing Right: HP27RKPZNV.

Figure 3

Schematic illustration of RSV interaction with autophagy. The RSV NS1 protein inhibits the mTOR-S6KP70 signaling pathway that triggers autophagosome accumulation. The NS2 protein stabilizes Beclin1 via ISGylation. This interaction causes the successful induction of autophagosome accumulation. RSV may cause cholesterol accumulation in lysosomes and weaken VAP-A and ORP1L binding which enables autophagosome accumulation. AMPK activation during RSV infection induces autophagy by inhibiting the mTOR pathway and activation of autophagosome degradation. The LDLR knock out inhibits RSV infection by mediating lysosomal cholesterol metabolism and autophagy. The production of inflammatory cytokines and the activation of apoptosis are inhibited by the enhanced process of autophagy. This figure was created with BioRender.com. Licensing Right: KV27RKQMGG.

Figure 4

Schematic illustration of SARS-CoV-2 interaction with autophagy. SARS-CoV-2 starts its life cycle via interaction with ACE2. The virus activates ULK-1-Atg13 and VPS34-VPS15-BECN1 complexes that cause autophagosome accumulation, downregulates BECN1, IP3K, and ATG14, and inhibits phagophore formation. The ORF7a decreases lysosomal acidity. Nsp1 downregulates the lysosome-related genes and decreases lysosomal acidity. NSP6 disrupts lysosome acidification through interaction with ATP6AP1. NSP6, by interaction with ATP6AP1, blocks the assembly of the SNARE complex and triggers a cytokine storm (ARDS). Nsp15 promotes the degradation of KPNA1 and inhibits type I interferon response by inhibiting phosphorylated IRF3. ORF3a blocks the assembly of the SNARE complex. All these events lead to autophagosome accumulation. This figure was created with BioRender.com. Licensing Right: GN27RKQUQC.

Figure 5

Schematic illustration of HPIV interaction with autophagy. HPIV3 P protein blocks degradation of autophagosomes. STX17 interacts with SNAP29 protein in the SNARE complex. SNAP29 interacts with VAMP8 in the lysosome membrane. P protein binds to SNAP29 and prevents its interaction with STX17, thus inhibiting autophagosome degradation. HPIV3 is recognized by RLRs with CARD, which binds with MAVS and recruits IKK and TRAF, which in turn causes production of IFN and pro-inflammatory cytokines. The M protein of HPIV3 binds to TUFM and causes mitochondrial sequestration. It mediates the formation of autophagosomes by interaction with LC3. HPIV2 V protein suppresses the interaction between NCOA4 and ferritin, allowing the virus to grow effectively in an environment rich in iron and ROS. Insufficient autophagy leads to the accumulation of autophagosomes, which elevates extracellular viral production. This figure was created with BioRender.com. Licensing Right: LT27RKR4W1.

Figure 6

Schematic illustration of AdV interaction with autophagy. The PVI of the AdV damages the membrane and allows the AdV to enter the cytosol and nucleus. Gal-8 and LC3 proteins recruit impaired endosomes, which induce an autophagic response. The host BAG3 WW domain interacts with PVI. Additionally, PVI promotes the expression of BAG3. The AdV escapes autophagy with Rab5–Rab7 exchange during the transition from early to late endosomes. The PPxY motif of PVI sequestrates Nedd4.2, a ubiquitin ligase preventing autophagosome development and enhancing the infectivity. This figure was created with BioRender.com. Licensing Right: QO27RKRE2Z.