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Autophagy in Virus Infection: History
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Subjects: Immunology | Infectious Diseases | Virology
Contributor: Karan Chawla

Virus-infected cells trigger a robust innate immune response and facilitate virus replication. Autophagy is a cellular degradation pathway operated at the basal level to maintain homeostasis and is induced by external stimuli for specific functions. The degradative function of autophagy is considered a cellular anti-viral immune response. However, autophagy is a double-edged sword in viral infection; viruses often benefit from it, and the infected cells can also use it to inhibit viral replication. In addition to viral regulation, autophagy pathway proteins also function in autophagy-independent manners to regulate immune responses. Since viruses have co-evolved with hosts, they have developed ways to evade the anti-viral autophagic responses of the cells. 

  • autophagy
  • innate immunity
  • anti-viral response

1. Introduction

Virus infection triggers a robust cellular immune response via activating the pattern recognition receptors [1][2][3]. The innate immune response is critical to ensure an immediate anti-viral response and also to help shape the adaptive immune responses [4][5]. In addition to triggering the anti-viral signaling pathways, the virus-infected cells can induce autophagy in the infected cells [6][7]. Autophagy, which can be translated literally as “self-eating”, is a cellular catabolic process required to regulate many cellular functions [8]. Basal level autophagy is required for maintaining cellular homeostasis, and autophagy is often induced in various disease conditions and infections [9]. The catabolic property of autophagy is primarily utilized as a cellular immune response to inhibit viral replication by degrading viral proteins. However, many viruses often exploit autophagy to replicate effectively within infected cells [10]. Therefore, a careful balance between the pro-viral and anti-viral functions of autophagy is important. It is also evident that viruses that do not rely on the machinery of autophagy for replication can still benefit from the components of the pathway. Moreover, autophagy pathway components can participate in autophagy-independent cellular functions. The therapeutic targeting of autophagy pathway components may provide clinical options for the treatment of viral and non-viral diseases [11][12].

2. Autophagy as a Pro-Viral Cellular Response

Several viruses often exploit autophagy to facilitate virus replication. The viruses use either a specific structure or a component of the autophagy machinery to promote their replication. HCV uses autophagy in several steps of the viral life cycle; HCV infection activates cellular autophagy, and the inhibition of this process results in decreased viral production. While autophagy inhibition does not affect viral entry, it is necessary to replicate viral RNA and translation [13]. HCV generates autophagosomes, using caveolin 1, caveolin 2, and annexin A2 to generate energy for its replication and promote virion assembly. Additionally, it uses the exocytosis pathway to release progeny virions [14]. As demonstrated, HCV serves as an excellent model of autophagy as a pro-viral mechanism, but countless other viruses similarly utilize parts of the process, many of which are mentioned here (Table 1).
Table 1. Virus-induced autophagy as a pro-viral response.
Virus Viral Protein Mechanism References
Human Parainfluenza Virus 3 (HPIV3)   Induces autophagy through AMPK for replication [6][15][16]
Measles Virus (MeV) MeV-C protein MeV binds CD46 to induce initial autophagy
C protein binds host IRGM to induce a second autophagy wave after viral replication, to prevent cell death		 [17][18]
Sendai Virus (SeV)   Induces autophagy through AMPK for replication [6]
Encephalomyocarditis Virus (EMCV) Non-structural proteins 2C and 3D (NS2C/3D) Induces autophagy through the ER stress pathway [19]
Dengue Virus (DENV) NS2B/3 Induces ER stress through XBP1 and lipophagy to use the resulting ATP [14][20]
West Nile Virus (WNV) NS2B/3 Induces lipophagy to use the resulting ATP [14]
Hepatitis C Virus (HCV) NS3/4A Interacts with host annexin-A2 to use autophagosomal lipid rafts during viral RNA translation [14][21]
Coxsackievirus B   Induces autophagy, to use the membrane for viral RNA replication [22]
Influenza A Virus (IAV) M2 protein LC3-interacting region M2 protein interacts with LC3 to relocate the virus to the plasma membrane for budding [23]
Herpes Simplex Virus-1 (HSV-1) TAP-blocking protein Promotes use of autophagosome for protection during antigen presentation [14]
Herpes Simplex Virus-2 (HSV-2)   Maintains basal level of autophagy for infection [24]
Varicella Zoster Virus (VZV)   Induction of autophagy for viral glycoprotein synthesis [25]
Human Immunodeficiency Virus (HIV-1) Viral protein u (Vpu) Removes BST2 from the viral budding sites to allow the spread of new virions [26]
Picornaviruses facilitate the formation of autophagosomes to facilitate viral replication, but they block the binding of lysosomes to these autophagosomes. During poliovirus infection, the use of rapamycin, an activator of autophagy, results in increased viral replication. Encephalomyocarditis virus (EMCV) uses its non-structural proteins 2C and 3D to generate ER stress, inducing autophagy and promoting its replication [19]. In Coxsackievirus B3 (CVB3) infection, the inhibition of autophagy by the deletion of Atg5 results in the inhibition of virus replication, specifically in pancreatic acinar cells [22]. Herein have shown that the Sendai virus (SeV), a paramyxovirus, also depends on cellular autophagy for viral replication [6]. The pharmacological or genetic inhibition of autophagy blocks SeV replication in vitro. SeV uses AMPK, the kinase required to initiate the autophagy pathway, to facilitate virus replication. The inhibition of AMPK by chemicals or genetic approaches blocks SeV replication. Herein has also shown that AMPK inhibition attenuates human parainfluenza virus (HPIV3) and respiratory syncytial virus (RSV) replication. The inhibition of autophagy and AMPK also attenuate RSV replication and pathogenesis in mice [27]. HPIV3 also triggers mitophagy to inhibit cellular anti-viral responses to IFN, thus advancing its replication [15][16]. During measles virus (MeV) infection, autophagy prevents host-cell death, thereby activating pro-survival pathways that favor viral replication [17]. Coronaviruses also use this autophagic membrane remodeling mechanism to generate viral membranes, as a crucial step in their life cycle [14]. Dengue virus (DENV) induces autophagy by the activation of AMPK, ultimately inducing the formation of a double-membrane vesicle that encloses lipid droplets. This form of autophagy is called lipophagy, which leads to the degradation of lipid droplets via β-oxidation to generate ATP for viral replication [14][28]. Lipophagy, a subset of autophagy where lipid droplets are mobilized within membraned vesicles, serves as a source of energy during infection with flaviviruses such as DENV and WNV. DENV infection leads to the induction of several innate immune responses. However, Dengue virus evades recognition by the host PRRs by replicating within the endoplasmic reticulum, while still using lipids through autophagy and delaying apoptosis to prevent its clearance [20].
The role of autophagy in herpesvirus replication is complex. Varicella-Zoster virus (VZV) has been shown to initiate autophagy upon infection; the chemical inhibition of autophagy or knocking down ATG5 results in decreased viral titer and viral proteins. Autophagy is thus required for the VZV life cycle, and this virus-induced autophagy results in enhanced viral protein synthesis [25]. In contrast to other viruses, HSV-2 does not induce autophagy but instead uses a basal level of autophagy for its own benefit [24]. The inhibition of autophagy in the setting of HSV-2 infection has been shown to hamper viral replication; however, the process is not needed for viral entry into cells. The formation of a double-membrane autophagosome may serve as a protected environment for the generation of progeny virions. HSV-1 replication does not depend on the autophagy pathway. Herein showed that HSV-1 replication remains unaltered in ATG5-knockdown cells [29]. However, the chemical or genetic inhibition of AMPK attenuates HSV-1 replication. AMPK inhibition in ATG5 knockdown cells also blocks HSV-1 replication. In murine gammaherpesvirus 68 (MHV68) infection, autophagy supports viral reactivation within macrophages. The induction of systemic inflammation, mediated by macrophagic IFN-ɣ, results in the suppression of autophagy genes. Thus, specifically in myeloid cells, Atg genes not only support MHV68 reactivation but also dampen systemic inflammation to curb autophagy inhibition [30].

3. Therapeutic Application of Autophagy in Virus Infection

The autophagy pathway can be targeted for therapeutic applications in many diseases, including viral infection [31]. However, because autophagy plays a dual role in viral infection and the immune response, it might be complex to target the autophagy pathway for anti-viral therapy. For example, chloroquine and hydroxychloroquine, originally approved as COVID-19 treatments, are inhibitors of the autophagy pathway [32]. Numerous reports suggest that SARS-CoV-2 entry may depend on the autophagy pathway; therefore, these autophagy inhibitors may be used to counteract the replication of the CoV-2 virus. Herein has shown that auranofin, an anti-rheumatic compound, induces autophagy to degrade IRF3 [33]. Auranofin has also been shown to inhibit SARS-CoV-2 replication [34]; whether auranofin degrades a viral protein or a pro-viral host protein in this context will require future evaluation. Oncolytic viruses, which are often used in anti-cancer therapy, may function by inducing the autophagy pathway [35]. Anti-retroviral drugs have been shown to impact the cellular autophagy pathway [36]. For example, it was shown that autophagy-promoting drugs, such as everolimus (chemotherapy), carbamazepine (anticonvulsant), and rapamycin (immunotherapy) restricted HIV-1 replication in a cell-specific manner [37]. This highlights the importance of developing and testing new drugs that act on autophagy and re-evaluating previously approved drugs that could be repurposed for therapeutic intervention. The group recently characterized a screening strategy that would be useful in repurposing FDA-approved small compounds [38]. Virus-specific therapeutics that impact the autophagy pathway will require in-depth investigation before becoming viable treatment options.

4. Conclusions and Future Directions

Autophagy has been studied extensively in virus infection; however, it is not entirely clear how the viruses specifically utilize or are inhibited by autophagy. Similarly, how autophagy regulates the cellular responses to virus infection is under-studied. Since many autophagy-related proteins have roles in regulating ubiquitination, it would be interesting to assess them in autophagy-independent cellular functions. For example, the Atg5-Atg12 complex is involved in RLR signaling, independent of autophagy function [39]. Since viruses have co-evolved along with inhibiting various steps of autophagy, it is considered an anti-viral response of the host. However, viruses may block parts of the autophagy machinery while exploiting other proteins involved in autophagy for their own benefit. Virophagy, the engulfment of the entire virion, although reported in the case of SINV, is not entirely understood. This mechanism could be relevant in anti-viral action against other viruses as well and needs to be studied further. Another factor that is thought to be critical in virophagy is the type of cell involved [40]. The contribution of cell-specific autophagy is, thus, another aspect that needs to be better understood. It is known that this mechanism exists in most cells, but the importance of the activation of this phenomenon in certain cell types over others, and its role in anti-viral activity, could improve our understanding of innate immunity. Several autophagic proteins have been found to interact with viral proteins, ranging across five RNA virus families, as part of an interactome study [41]. These have yet to be studied in terms of a direct role in the restriction of viruses.

This entry is adapted from the peer-reviewed paper 10.3390/immuno2010012

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