RR:C19 Evidence Scale rating by reviewer:
Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.
The manuscript by Ghosh et al., proposes that the beta-coronavirus MHV, a pathogen of mice, uses lysosomes to exit cells. The virus could be inducing a deacidification of lysosomes, something that would avoid degradation of viral particles. This pathway might be regulated by the Arf-like small GTPase Arl8b and could have an impact on antigen presentation pathways.
The results are preliminary and do not fully support the conclusions. A detailed study of live-cell imaging is missing. The authors do not demonstrated that the co-localization of virus particles with lysosomes could be due to virus re-entry. An electron microscopy study showing how viral particles could be transported from other membranous compartments to lysosomes is missing. Moreover, this pathway has been already described in detail for the human reovirus, in an article published last May by the Journal of Cell Biology. This reference and important information about the description of this novel virus egress pathway by Fernández de Castro et al., 2020, are also missing in the manuscript. Finally, the authors assume that human SARS-CoV-2 and mouse MHV could behave in a similar way, but this is highly speculative because they provide no solid data about it. In conclusion, the results are interesting and will stimulate further research in the field but the authors should develop this study further. Adetailed live-cell imaging and electron microscopy studies should be done to compare they findings with MHV and the previous work of Fernandez de Castro et al., published in J. Cell Biol., that should be cited in the Introduction. Finally there is a very interesting work by Bartenschlager and colleagues describing how SARS-CoV-2 use intracellular membranes. The authors should consider this information to complete their study, looking for potential connections between the coronavirus replication factory and the lysosomal egress pathway of MHV. 3D light and electron microscopy would be of great help to understand these connections and how the pathway works.