Beta-Coronaviruses use lysosomal organelles for cellular egress
autophagy/lysosome biochemistry cell biology virology
Authors: Ghosh et al.
Link to paper: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3654626
Journal/ Pre-Print: SSRN, currently under Cell
Tags: Autophagy/Lysosome, Biochemistry, Cell Biology, Virology
The murine coronavirus MHV is secreted through a lysosome-dependent secretory pathway.
Lysosomal disturbance of MHV interferes with MHC-I cross-presentation and thus the antigen-specific CD8 T cell response.
SARS-CoV-2 is detected in lysosomes and can increase lysosomal pH (analogous to MHV)
This study sought to investigate the modes of egress of beta-coronaviruses. The authors base most of their results on the murine hepatitis virus (MHV) model and complement sporadically with data from SARS-CoV-2-infected Vero cells. The preprint shows that MHV egresses through an atypical lysosomal secretion pathway that does not involve the trans-Golgi network (as Brefeldin does not limit viral egress). Eventually, the virus (MHV as well as SARS-CoV-2) arrives in the lysosome and there neutralises lysosomal pH. The weakened pH is no longer capable to support the function of lysosomal enzymes. The authors can show that the egress of MHV is Arl8-dependent; unfortunately, they don’t show this for SARS-CoV-2. Lastly, the authors demonstrate that antigen processing is impaired due to the weakened lysosomal pH during viral infection leading to a possible way of beta-coronaviruses to escape immune surveillance.
Impact for SARS-CoV2/COVID19 research efforts
Understand the virology and/or cell biology of SARS-CoV2/COVID19
Though limited, the study gives a general idea of the egress mechanisms of beta-coronavirus family members (here in particular the murine MHV). Some of the data shown were replicated for SARS-CoV-2; however, it remains unclear if SARS-CoV-2 uses the exact same egress mechanism.
In vitro study
Strengths and limitations of the paper
Novelty: The egress mechanism for beta-coronaviruses was not very clear until now. The paper shows nicely that the egress is occurring through an ER-lysosome dependent mechanism that involves Arl8, which could be an interesting therapeutic target.
Standing in the field:Addresses the unanswered question of how coronaviruses egress from
cells. Previous reports have not found a consensus.
Appropriate statistics:Occasional omission of statistical testing. Broadly statistical analysis
preformed and presented well.
Viral model used:The main viral model used in this study was murine hepatitis virus (a murine beta-coronavirus). Sporadically, SARS-CoV-2-infected Vero cells have been used.
Translatability:Low, despite showing an interesting target (here Arl8) for blocking MHV egress. It remains unclear if this protein would be also a good target for SARS-CoV-2.
Translatability of the findings for SARS-CoV-2.
It would have been good to see if monesin could block the egress of MHV as it is trapping some cytokines in a lysosomal compartment and it would be interesting to know if the virus uses a similar secretion pathway as some cytokines do.
Almost all of the work and certainly the most convincing data are based on the murine model - MHV. It would be good if authors could recapitulate experiments for SARS-CoV2, most notably the cryo-electron micrographs showing virions inside of lysosomes and antigen presentation assays - to prove the lysosomal mechanism is conserved between the two viruses.
The authors claim that endosomal uptake is limited during MHV infection and therefore the virions could not enter lysosomes though this pathway. However, the possibility that the virions visualised within lysosomes may have been reinternalized remains.
It would be interesting if the authors looked at drugs known to promote lysosomal acidification to see if they had anti SARS-CoV2 activity. For example the FDA approved therapeutics colforsin and forskolin.