By delivering the invading pathogens to the lysosomes for degradation so as to discard them, autophagy is believed to be an important part of the host defense system. The process of degrading foreign microbial invaders by autophagy is known as xenophagy (Levine, 2005). The function of xenophagy to eliminate invading viruses, bacteria, fungi, or parasites, makes it an important immune player in pathogen infection. During viral infection, host autophagy can degrade viral particles, viral components, and the host factors required by viruses for their replication; therefore, host autophagy functions as a key innate antiviral response (Figure 2).

The first evidence of autophagy functions as antiviral means came from Sindbis viral infection. During its infection, overexpression of Beclin 1 (the mammalian Atg6 ortholog) in neurons could inhibit the Sindbis virus spread, reduce cellular apoptosis, and protect against fatal Sindbis virus encephalitis (Liang et al., 1998), whereas Atg5 (an essential component for the formation of autophagosomes in mammalian cells) deficiency in Sindbis-infected neurons leads to delayed clearance of viral proteins, accumulation of the p62 (also known as SQSTM1) adaptor protein, and increased cell death in neurons (Mizushima et al., 2001). Moreover, an in vitro study found that p62 could interact with Sindbis capsid protein and targets the viral capsid to the autophagosome (Orvedahl et al., 2010). Orvedahl et al. (2011) further found that Smad-Ubiquitin Regulatory Factor 1 (SMURF1), a HECT-domain ubiquitin ligase, is not required for general autophagy, but is needed by selective autophagy, such as virophagy and mitophagy. Moreover, they found that SMURF1 could interact with p62 and target Sindbis capsid to autophagosomes for virophagy. Fanconi anemia group C protein (FANCC) was also found to play an essential role in virophagy and mitophagy; its deficiency could inhibit the autophagic clearance of viruses (virophagy) and make mice more susceptible to lethal viruses (Sumpter et al., 2016). FANCC plays its role by interacting with the Sindbis capsid protein and therefore contributes to preventing viral infection (Minton, 2016; Sumpter et al., 2016). Besides Sindbis, SMURF1 and FANCC also inhibit HSV-1 infection through autophagy, indicating that these two proteins probably play virophagic factor functions during viral infection (Orvedahl et al., 2011; Sumpter et al., 2016).

Picornaviruses are archetypical non-enveloped viruses, which are a major cause of human and veterinary infections that lead to various diseases, such as polio and the common cold (Zhang et al., 2020). Host galectin 8 could detect picornaviruses and inhibit their infection through autophagy to degrade the viral genomic RNA (Staring et al., 2017). Specifically, the picornaviruses that enter the host will puncture the endosomal membrane and release their genome into the host cytoplasm, which causes the exposure of β-galactosides. Galectin-8 could specifically recognize β-galactosides and therefore marks the permeated endosomes for autophagic degradation.

As a small, enveloped RNA virus that mainly targets human hepatocytes, hepatitis C virus (HCV) is a major cause of liver cirrhosis and hepatocellular carcinoma worldwide (Zeisel et al., 2013; Kaplan, 2020). The prevention measures for HCV are absent and the current antiviral treatment for it is limited because of resistance, toxicity, and high costs (Zeisel et al., 2011; Hickman et al., 2015). Because of the discovery of HCV, the 2020 Nobel Prize in Physiology or Medicine has been awarded to Harvey J. Alter, Michael Houghton, and Charles M. Rice (Burki, 2020; Hoofnagle and Feinstone, 2020). Kim et al. (2016) found that the overexpression of endoplasmic reticulum (ER) protein SCOTIN inhibits HCV replication and infectious virion production in cells transfected with HCV. A further study found that SCOTIN could interact with HCV non-structural 5A (NS5A) protein, a critical factor for HCV replication, and target NS5A to autophagosomes for degradation. Moreover, inhibition of autophagy by silencing ATG7 or administering lysosomal inhibitors could relieve the suppressive effect of SCOTIN on HCV replication. They also showed that SCOTIN is merely a substrate for degradation of autophagy, but not affecting the whole process of autophagy; of note, the binding of transmembrane/proline-rich domain (TMPRD) of SCOTIN with Domain-II of NS5A is critically required for the trafficking of autophagosomal and NS5A degradation (Kim et al., 2016). These results suggest that autophagy restricts HCV replication through SCOTIN to target HCV NS5A protein to autophagosomes for degradation.

As a sensor of cytosolic DNA that activates the type I interferon pathway, cyclic GMP-AMP synthase (cGAS) could bind to microbial or self-DNA in the cytoplasm and therefore supervises infections or tissue damage (Sun et al., 2013). Specifically, cGAS is activated through binding with cytosolic DNA, which could further catalyze GTP and ATP to be cyclic GMP-AMP (cGAMP) (Wu et al., 2013). As a second messenger of cell, cGAMP could bind to and activate the stimulator of interferon genes (STING) (Ishikawa and Barber, 2008; Saitoh et al., 2009; Burdette et al., 2011; Wu et al., 2013; Zhang et al., 2013), which then recruits and activates the tank-binding kinase 1 (TBK1) causing the phosphorylation of the transcription factor IRF3 to induce the production of type I interferons and other cytokines (Cai et al., 2014; Liu et al., 2015; Zhang et al., 2019). Besides the important function in activating the immune response, STING could also activate autophagy during viral infections (Gui et al., 2019; Liu et al., 2019). Gui et al. (2019) showed that the binding of cGAMP with STING leads to the interaction of STING with SEC24C, causing the budding of STING from the endoplasmic reticulum into the COP-II vesicles and forming the endoplasmic reticulum–Golgi intermediate compartment (ERGIC), which functions as the membrane source for WIPI2 recruitment and LC3 lipidation, and finally causing the formation of autophagosomes targeting cytosolic DNA or DNA viruses to the lysosome for degradation (Gui et al., 2019). STING induces autophagy that is dependent on WIPI2 and ATG5, whereas other regulators of autophagy such as Beclin 1, Atg9a, ULK1, and p62 are not required (Gui et al., 2019; Liu et al., 2019). Interestingly, Gui et al. (2019) also showed that STING from the sea anemone is also able to induce autophagy but not interferons in response to the stimulation of cGAMP, which suggests that the cGAS-STING pathway-induced autophagy is probably an ancient and highly conserved mechanism that predates the emergence of the type I interferon pathway in vertebrates to eliminate the invading viruses.

How is autophagy induced in mammalian cells during viral infection? By using genome-wide short interfering RNA screens, the endosomal protein sorting nexin 5 (SNX5) is found to be required merely for virus-induced autophagy, but not for basal level autophagy or stress-induced autophagy (Dong et al., 2021). Deletion of SNX5 makes cultured cells more susceptible to viral infection, and mice deficient in SNX5 have a high lethality after infection with several human viruses (Dong et al., 2021). Moreover, they found that SNX5 could interact with PI3KC3-C1 and promote its activation at endosomes and therefore contributes to the initiation of autophagy during viral infection.

Collectively, host cells detect the invading viruses and activate the autophagy, which targets viruses to the lysosomes for degradation through the interaction of host protein with the viral protein. Future studies should focus on exploring additional viruses that can be selectively degraded by autophagy and clarifying the specific mechanisms involved in this process.

As the first line of defense against virus infection, the host innate immune system plays essential roles in recognizing invading viruses and inducing anti-viral responses to prevent viral invasion and pathogenesis before the generation of more specific protection by the adaptive immune system (Takeuchi and Akira, 2007; Koyama et al., 2008; Figure 3). The host innate immune system recognizes invading viruses by several classes of germline-encoded pattern-recognition receptors (PRRs), which could specifically recognize the pathogen-associated molecular patterns (PAMPs), such as viral DNA, viral double-stranded RNA (dsRNA), viral single-stranded RNA (ssRNA), or viral surface glycoproteins (Akira et al., 2006; Chan and Gack, 2016). The recognition of viral components by PRRs will induce the infected cells and other immune cells to produce type I interferons (IFNs) to aid in eliminating the invading viruses (Medzhitov, 2007).

There are several classes of PRRs with specific functions; virus-derived nucleic acids with distinct features are recognized by these specific host transmembrane or cytosol PRRs (Medzhitov, 2007; Gürtler and Bowie, 2013; Wu and Chen, 2014). As an important group of cytoplasmic RNA sensors, the RIG-I-like receptors (RLRs) are composed of three proteins (RIG-I, MDA5, and LGP2) that are similar in their structure and function, and all of them are able to recognize viral nucleic acid signatures during the viral infections (Rehwinkel and e Sousa, 2010; Bruns and Horvath, 2014). Recently, Hou et al. (2021) have found a novel selective autophagy receptor, CCDC50, which could deliver K63 polyubiquitination-activated RIG-I/MDA5 for degradation by lysosomes during viral infection and therefore negatively regulate the IFNs signaling pathway initiated by RLRs. As the best characterized class of PRR, toll-like receptors (TLRs) are transmembrane receptors that recognize viral nucleic acids within endosomal compartments (Medzhitov, 2007). Both of these two classes of PRR could activate IRF3/IRF7 and NF-κB transcription factors by recruiting mitochondrial antiviral signaling protein (MAVS), leading to the activation of type I interferon (IFN) responses and establishment of antiviral state (Seth et al., 2005; Akira et al., 2006; Medzhitov, 2007).

Lee et al. (2007) first elucidated the key function of autophagy in promoting interferon secretion in plasmacytoid dendritic cells (pDCs). They found that autophagy was required for the transportation of cytosolic viral into the lysosomes and the recognition of ssRNA viruses such as vesicular stomatitis virus (VSV) or Sendai virus (SeV) by TLR7. Moreover, they also found that autophagy was critically needed by pDCs during the production of interferon-α.

As an essential DNA virus sensor, cGAS could prompt IFNs production by generating cGAMP, which binds to and activates an endoplasmic reticulum-associated adaptor protein STING (Sun et al., 2013; Wu et al., 2013). Chen et al. (2016) have found that TRIM14 could block cGAS degradation through selective autophagy and therefore promote innate immune responses during viral infections. Specifically, upon the viral infections, TRIM14 could recruit USP14 to cut the lysine 48 (K48)-linked ubiquitin chains of cGAS at K414, causing inhibition of p62-mediated autophagic degradation of cGAS, therefore promoting the activation of type I interferon signaling to aid the elimination of the invading viruses (Chen et al., 2016).

These studies suggest that host autophagy plays an essential role in activating the innate immune response to eliminate the invading viruses by promoting the infected cells and other immune cells to produce IFNs. However, there are also some studies reporting that autophagy or its components contributed to the negative regulation of host innate immune response (Jounai et al., 2007; Lei et al., 2012; Liang et al., 2014; Jin et al., 2017; Du et al., 2018; Prabakaran et al., 2018). Therefore, during viral infection, the interaction between PRRs and autophagy resulted in the activation and/or inhibition of various host innate immune responses, causing first-rank antiviral effects.

The efficient adaptive immune response is essential for the elimination of invading viruses. The first step of the adaptive immune response is the presentation of peptides of foreign or self-proteins on major histocompatibility complex (MHC) molecules at the cell surface of antigen-presenting cells (APCs) such as dendritic cells and macrophages, which then can be recognized by CD8⁺ or CD4⁺ T lymphocytes (Rammensee et al., 1993; Villadangos, 2001). In general, MHC class I (MHC-I) molecules specifically present antigenic peptides derived from intracellular proteins that have been digested by the proteasomal degradation system, whereas MHC class II (MHC-II) molecules specifically present antigenic peptides stemming from exogenous and membrane proteins that have been degraded by the endosomal/lysosomal system (Neefjes, 1999; Princiotta et al., 2003; Dengjel et al., 2005; Choi et al., 2018). However, there are certain situations where MHC-I molecules could present peptides stemming from exogenous antigens, which is a process called cross-presentation, mainly executed by a specific subset of dendritic cells (DCs) through endocytic and phagocytic pathways (Morón et al., 2004; Joffre et al., 2012; Blander, 2018; Muntjewerff et al., 2020). In addition, the peptides derived from intracellular proteins could also be loaded on MHC-II molecules through the process of autophagy (Nimmerjahn et al., 2003; Dörfel et al., 2005; Paludan et al., 2005; Münz, 2006).

Neurovirulence protein ICP34.5, which is expressed by the herpes simplex virus type 1 (HSV-1), could inhibit host autophagy activation through binding with the host autophagy protein Beclin 1 (Orvedahl et al., 2007). HSV-1 virus deficient in the Beclin 1-binding domain of ICP34.5 is unable to block autophagy in neurons and shows a decrease in the ability to cause lethal encephalitis in mice. Deletion of PKR, an autophagy-inducing signaling molecule, could restore the neurovirulence of this Beclin 1-binding mutant virus (Orvedahl et al., 2007). These results suggest that the binding of Beclin 1 with ICP34.5 could inhibit host autophagy and contribute to viral neurovirulence, and the PKR is a Beclin 1 upstream effector during host defense against HSV-1. Moreover, the Us11 protein of HSV-1 could also inhibit host autophagy function by directly interacting with the PKR protein kinase, therefore contributing to the HSV-1 infection and pathogenesis (Lussignol et al., 2013).

Matrix protein 2 of influenza A virus could inhibit autophagy function through blocking the autophagosome–lysosome fusion, causing the enhanced virus-induced cell death of infected cells and elevated viral antigen release (Gannagé et al., 2009; Rossman and Lamb, 2009). Human parainfluenza virus type 3 (HPIV3) could also lead to the incomplete autophagy of host cells through blocking autophagosome fusion with the lysosome, causing an increase in virus production (Ding et al., 2014). Specifically, the viral phosphoprotein (P) binds to SNAP29, blocking its binding to syntaxin 17 (STX17), therefore inhibiting autophagosome–lysosome fusion mediated by these two host SNARE proteins. Autophagosome accumulation due to incomplete autophagy could increase extracellular viral production but does not affect viral protein synthesis, therefore contributing to the viral infection and pathogenesis.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), an enveloped, single-stranded and positive-sense RNA β-coronavirus, is the cause of the COVID-19 pandemic (Wang et al., 2020; Wu et al., 2020; Zhou et al., 2020). ORF3a, an accessory protein of SARS-CoV-2, could strongly inhibit autophagy activity by blocking the fusion of autophagosomes with lysosomes (Hayn et al., 2021; Miao et al., 2021; Qu et al., 2021; Zhang et al., 2021). Specifically, ORF3a is localized in the late endosome and directly interacts with and sequestrates VPS39, an essential component of the homotypic fusion and protein sorting (HOPS) complex, thereby preventing the HOPS complex from interacting with the STX17 or RAB7, which prevented the fusion machinery packaging, leading to an abnormal autophagosome–lysosome fusion. Moreover, SARS-CoV-2-expressed ORF3a and ORF7a can directly induce lysosomes injury and impair their function, such as inhibiting their acidification (Hayn et al., 2021; Koepke et al., 2021; Miao et al., 2021; Shroff and Nazarko, 2021). By doing this, SARS-CoV-2 could escape host lysosome degradation. Besides, the SARS-CoV-2 spike could hijack host autophagy to promote host cell inflammation and apoptosis probably through the ROS-suppressed PI3K/AKT/mTOR signaling (Li et al., 2021).

As a DMV formed during autophagy, autophagosome provides a perfect place for the RNA viral replication through concentration of essential intermediates for viral package and protection of viral RNAs away from the detection by innate immune supervision and degradation. The host autophagy has been required by several viruses such as Coxsackieviruses (CVB) 3, CVB 4, foot and mouth disease virus, HCV, and poliovirus for their own replication, as genetic or pharmacological inhibition of autophagy could decrease viral yields (Taylor and Kirkegaard, 2008; Wong et al., 2008; Yoon et al., 2008; Dreux et al., 2009; O’Donnell et al., 2011). Moreover, some viruses such as dengue virus (DENV), usurp autophagy to enhance their replication by regulating cellular lipid metabolism (Heaton and Randall, 2010). Specifically, DENV infection induces the activation of lipophagy to release free fatty acids, causing an increase of cellular β-oxidation and more ATP generation, which contributes to the replication of DENV.

In summary, host autophagy is a double-edged sword during viral infection and pathogenesis. On the one hand, hosts could utilize their own autophagy to prevent viral infection and pathogenesis; on the other hand, viruses have evolved various strategies by which they hijack and subvert host autophagy to aid their infection and pathogenesis.