Viral apoptotic mimicry

Journal name:
Nature Reviews Microbiology
Volume:
13,
Pages:
461–469
Year published:
DOI:
doi:10.1038/nrmicro3469
Published online

Abstract

As opportunistic pathogens, viruses have evolved many elegant strategies to manipulate host cells for infectious entry and replication. Viral apoptotic mimicry, defined by the exposure of phosphatidylserine — a marker for apoptosis — on the pathogen surface, is emerging as a common theme used by enveloped viruses to promote infection. Focusing on the four best described examples (vaccinia virus, dengue virus, Ebola virus and pseudotyped lentivirus), we summarize our current understanding of apoptotic mimicry as a mechanism for virus entry, binding and immune evasion. We also describe recent examples of non-enveloped viruses that use this mimicry strategy, and discuss future directions and how viral apoptotic mimicry could be targeted therapeutically.

At a glance

Figures

  1. Classic apoptotic mimicry.
    Figure 1: Classic apoptotic mimicry.

    During classic apoptotic mimicry, a virus acquires host cell phosphatidylserine and incorporates it into the viral membrane. Exposed phosphatidylserine on the viral surface binds directly or indirectly to phosphatidylserine receptors, which facilitate virus entry or infection. Shown are several potential strategies that viruses may use to acquire phosphatidylserine in their membranes during assembly. Ebola virus (EBOV) has been shown to bud from plasma membrane microdomains, or lipid rafts, that are highly enriched for phosphatidylserine in the external leaflet. Furthermore, it has been proposed that vaccinia virus (VACV), which acquires its membrane within the host cytoplasm and exits host cells by inducing cell lysis, derives its membrane from endoplasmic reticulum (ER) sheets generated by the rupture of ER cisternae. Finally, dengue virus (DENV) and other flaviviruses derive their membrane via ER budding. Although these examples cover a range of mechanisms, it is also possible that phosphatidylserine enrichment is facilitated by the viral modulation of lipid flippases or of apoptosis (not illustrated). Recent evidence indicates that phosphatidylserine exposed on the viral surface binds to both direct phosphatidylserine receptors, such as T cell immunoglobulin and mucin receptor (TIM) proteins, and indirect phosphatidylserine receptors, such as AXL and tyrosine protein kinase receptor 3 (TYRO3), which require phosphatidylserine-bridging molecules. Both EBOV and DENV have been shown to use both direct and indirect phosphatidylserine receptors, whereas VACV has only been shown to use the indirect receptor AXL. Whether EBOV and DENV can engage these various receptors simultaneously or whether VACV can use other phosphatidylserine receptors has not been determined. For some viruses, such as EBOV and VACV, engagement of phosphatidylserine receptors triggers their internalization by macropinocytosis. For other viruses, including DENV, binding of phosphatidylserine to receptors on the host cell surface induces clathrin-mediated uptake, which is an alternative mechanism of endocytosis. After internalization, downstream signalling cascades promote additional steps of infection.

  2. Non-classic apoptotic mimicry.
    Figure 2: Non-classic apoptotic mimicry.

    In non-classic apoptotic mimicry, non-enveloped viruses use alternative means to engage phosphatidylserine receptors. For instance, the non-enveloped polyomavirus simian virus 40 (SV40), which exits cells by lysis, mimics the phosphatidylserine-bridging molecule GAS6 to engage tyrosine protein kinase receptor 3 (TYRO3)–AXL–MER (TAM) family receptors. By sharing structural homology with GAS6, the SV40 major structural protein VP1 engages the indirect phosphatidylserine receptor AXL to initiate internalization. Another non-enveloped virus, hepatitis A virus (HAV), probably hijacks phosphatidylserine-containing membranes by budding into cellular organelles known as multivesicular bodies (MVBs). When the MVBs fuse with the plasma membrane, the HAV particles cloaked in the cell-derived envelope are released in a process thought to be akin to exosome egress. The phosphatidylserine-enriched exosome-like particles bind to T cell immunoglobulin and mucin receptor 1 (TIM1) on target cells. To facilitate bulk virus transfer, poliovirus (PV) virions are captured by autophagosome-like double-membrane vesicles. The outer membrane of these vesicles fuses with the cell surface to release phosphatidylserine-rich vesicles containing multiple PV virions. Both PV receptors and phosphatidylserine in these vesicles are required for subsequent infection. However, the phosphatidylserine receptors required remain undefined.

  3. Viral apoptotic mimicry and immune evasion.
    Figure 3: Viral apoptotic mimicry and immune evasion.

    The clearance of apoptotic cells and debris induces an anti-inflammatory response. Binding of apoptotic cells to phosphatidylserine receptors and the subsequent engulfment of these cells by phagocytes initiates the production of anti-inflammatory cytokines such as interleukin-10 (IL-10) and transforming growth factor-β (TGFβ). This initiates a feed-forward suppression of the innate immune response at the level of transcription, and this suppression is dependent on prolonged signalling through signal transducer and activator of transcription (STAT) family proteins. Akin to apoptotic cells, enveloped viruses, including pseudotyped lentivirus vectors and West Nile virus, are thought to use apoptotic mimicry to dampen innate immune responses. Binding of an enveloped virus complexed to bridging molecules (such as GAS6) promotes the activation of tyrosine protein kinase receptor 3 (TYRO3)–AXL–MER (TAM) family receptors, which heterodimerize with type I interferon receptor (IFNAR) to induce suppressor of cytokine signalling 1 (SOCS1) and SOCS3 expression, and this in turn inhibits IFNAR and Toll-like receptor (TLR) signalling. Although phosphatidylserine receptors are often studied individually, it is likely that viruses using apoptotic mimicry can simultaneously engage different phosphatidylserine receptors to modulate various innate immune and anti-inflammatory pathways and thus promote immune evasion. Of note, T cell immunoglobulin and mucin receptor (TIM) family phosphatidylserine receptors are not included in the figure owing to a lack of evidence for their participation in the dampening of immune response by viruses.

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Affiliations

  1. Ali Amara is at Institut National de la Santé et de la Recherche Médicale U944 and Centre National de la Recherche Scientifique UMR 7212, Laboratoire de Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France.

  2. Jason Mercer is at the Medical Research Council Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK.

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The authors declare no competing interests.

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Author details

  • Ali Amara

    Ali Amara obtained his Ph.D. from the University of Bordeaux, France, and conducted his postdoctoral research at the Pasteur Institute, Paris, France. He is now the Institut National de la Santé et de la Recherche Médicale (INSERM) Research Director of the Biology of Emerging Viruses group in the Saint-Louis Hospital, Paris. His research aims to decipher how viruses enter target cells and how they exploit the host cell machinery to accomplish their infectious life cycle. He currently uses mosquito-borne viruses (dengue virus, yellow fever virus and West Nile virus) as models. Ali Amara's homepage.

  • Jason Mercer

    Jason Mercer obtained his Ph.D. in the laboratory of Paula Traktman at the Medical College of Wisconsin, Milwaukee, USA, and conducted his postdoctoral research in the laboratory of Ari Helenius at ETH Zurich, Switzerland. He is now Associate Professor of Virus Cell Biology in the Medical Research Council Laboratory for Molecular Cell Biology at University College London, UK. His research group focuses on deciphering the complex interactions between poxviruses and their host cells during infection. Jason Mercer's homepage.

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