β-Coronaviruses use lysosomal organelles for cellular egress

Altan‐Bonnet, Nihal; Altan‐Bonnet, Grégoire; Ghosh, Sourish; Dellibovi-Ragheb, Teegan A.; Pak, Eowyn; Qiu, Qi; Fisher, Matthew; Takvorian, Peter M.; Bleck, Christopher K. E.; Hsu, Victor; Perlman, Stanley; Straus, Marco R.; Whittaker, Gary R.; Haan, C Am de

doi:10.1101/2020.07.25.192310

Cited by 9 publications

(11 citation statements)

References 55 publications

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“…Interestingly, this phenomenon is not restricted to viruses, as it has also been described for intracellular uropathogenic E. coli [20]. Related with our results, a recent preprint describes how beta-coronaviruses, which are enveloped viruses, could exploit the lysosomes for virus egress by disrupting lysosomal acidification [31]. These results, and ours, reveal a potentially unanticipated wide diversity of egress mechanism using lysosomes by different viral families.…”

Section: Discussionsupporting

confidence: 86%

A non-enveloped arbovirus released in lysosome-derived extracellular vesicles induces super-infection exclusion

Labadie

Roy

2020

Preprint

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22Recent developments on extracellular-vesicles (EVs) containing multiple virus particles challenge 23 the rigid definition of non-enveloped viruses. However, how non-enveloped viruses hijack cell 24 machinery to promote non-lytic release in EVs, and their functional roles, remain to be clarified. Here 25 we used Bluetongue virus (BTV) as a model of a non-enveloped arthropod-borne virus and observed 26 that the majority of viruses are released in EVs, both in vitro and in the blood of infected animals. 27Based on the cellular proteins detected in these EVs, and use of inhibitors targeting the cellular 28 degradation process, we demonstrated that these extracellular vesicles are derived from secretory 29 lysosomes, in which the acidic pH is neutralized upon the infection. Moreover, we report that secreted 30EVs are more efficient than free-viruses for initiating infections, but that they trigger super-infection 31 exclusion that only free-viruses can overcome. These results suggest that secreted EVs and free-32 viruses do not share a common receptor. 33 Author summary 34Recent discoveries of non-enveloped virus secreted in EVs opened the door to new developments in 35 our understanding of the transmission and pathogenicity of these viruses. In particular, how these 36 viruses hijack the host cellular secretion machinery, and the role of these EVs compared with free-37 virus particles remained to be explored. Here, we tackled these two aspects, by studying BTV, an 38 emerging arthropod-borne virus causing epidemics worldwide. We showed that this virus is mainly 39 released in EVs, in vivo and in the blood of infected animals, and that inhibition of the cell degradation 40 machinery decreases the release of infectious EVs, but not free-virus particles. We found that BTV 41 is responsible for neutralizing the pH of lysosomes, which are important organelles of the cell 42 degradation machinery. Our results highlight unique features for a virus released in EVs, explaining 43 how BTV transits in lysosomes without being degraded. Interestingly, we observed that EVs are more 44 infectious than free-virus particles, but only free-viruses are able to overcome the super-infection 45 exclusion, which is a common cellular defense mechanism. In conclusion, our study stresses the dual 46 role played by both forms, free and vesicular, in the virus life cycle. 47 48 49 50 51 52 53

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Section: Discussionsupporting

confidence: 86%

A non-enveloped arbovirus released in lysosome-derived extracellular vesicles induces super-infection exclusion

Labadie

Roy

2020

Preprint

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“…Open reading frames (ORF) that are encoded in the viral RNA genome are translated into virus proteins which replicate and efficiently pack the viral genome into nascent viral particles and support the egress of mature virus particles 9 . Indeed, the virus interactome is primarily derived from virus-virus rather than virus-host interactions 10 , and interactions with host proteins might be actively avoided to prevent any impairment of virus particle formation.…”

Section: Introductionmentioning

confidence: 99%

The Host Interactome of Spike Expands the Tropism of SARS-CoV-2

Bamberger

Pankow

Martínez‐Bartolomé

et al. 2021

Preprint

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The SARS-CoV-2 virus causes severe acute respiratory syndrome (COVID-19) and has rapidly created a global pandemic. Patients that survive may face a slow recovery with long lasting side effects that can afflict different organs. SARS-CoV-2 primarily infects epithelial airway cells that express the host entry receptor Angiotensin Converting Enzyme 2 (ACE2) which binds to spike protein trimers on the surface of SARS-CoV-2 virions. However, SARS-CoV-2 can spread to other tissues even though they are negative for ACE2. To gain insight into the molecular constituents that might influence SARS-CoV-2 tropism, we determined which additional host factors engage with the viral spike protein in disease-relevant human bronchial epithelial cells (16HBEo-). We found that spike recruited the extracellular proteins laminin and thrombospondin and was retained in the endoplasmatic reticulum (ER) by the proteins DJB11 and FBX2 which support re-folding or degradation of nascent proteins in the ER. Because emerging mutations of the spike protein potentially impact the virus tropism, we compared the interactome of D614 spike with that of the rapidly spreading G614 mutated spike. More D614 than G614 spike associated with the proteins UGGT1, calnexin, HSP7A and GRP78/BiP which ensure glycosylation and folding of proteins in the ER. In contrast to G614 spike, D614 spike was endoproteolytically cleaved, and the N-terminal S1 domain was degraded in the ER even though C-terminal S2-only proteoforms remained present. D614 spike also bound more laminin than G614 spike, which suggested that extracellular laminins may function as co-factors for an alternative, S2-only dependent virus entry. Because the host interactome determines whether an infection is productive, we developed a novel proteome-based cell type set enrichment analysis (pCtSEA). With pCtSEA we determined that the host interactome of the spike protein may extend the tropism of SARS-CoV-2 beyond mucous epithelia to several different cell types, including macrophages and epithelial cells in the nephron. An S2-only dependent, alternative infection of additional cell types with SARS-CoV-2 may impact vaccination strategies and may provide a molecular explanation for a severe or prolonged progression of disease in select COVID-19 patients.

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“…There, nucleocapsids consisting of progeny genomes bound by N protein interact with the envelope proteins and bud into the ERGIC lumen. Virions are believed to reach the extracellular space by bulk transport, although transport through lysosomal compartments was recently suggested as an alternative ( Ghosh et al, 2020 ). A fraction of S protein reaches the plasma membrane, causing cell fusion with neighboring infected cells and the formation of multinucleated giant cells that are characteristic of COVID-19 lung pathology ( Masters and Perlman, 2013 ; Bryce et al, 2020 ).…”

Section: Brief Overview Of Sars-cov-2mentioning

confidence: 99%

“…The term "cytokine storm" has been applied to COVID-19; however, it is unclear whether this condition is unique to or even representative of most patients with this disease (Lukan, 2020;Mudd et al, 2020). Emerging evidence suggests that mechanically ventilated COVID-19 patients may have suppressed type I interferon responses, suggesting a more complex picture than simple hypercytokinemia (Giamarellos-Bourboulis et al, 2020;Hadjadj et al, 2020;Mudd et al, 2020). The second form of systemic pathology is hypercoagulation, resulting in microthrombus formation and, somewhat counterintuitively, bleeding (Al-Samkari et al, 2020;Bryce et al, 2020).…”

Section: A Brief Overview Of Covid-19mentioning

confidence: 99%

A Timely Call to Arms: COVID-19, the Circadian Clock, and Critical Care

et al. 2021

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We currently find ourselves in the midst of a global coronavirus disease 2019 (COVID-19) pandemic, caused by the highly infectious novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we discuss aspects of SARS-CoV-2 biology and pathology and how these might interact with the circadian clock of the host. We further focus on the severe manifestation of the illness, leading to hospitalization in an intensive care unit. The most common severe complications of COVID-19 relate to clock-regulated human physiology. We speculate on how the pandemic might be used to gain insights on the circadian clock but, more importantly, on how knowledge of the circadian clock might be used to mitigate the disease expression and the clinical course of COVID-19.

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β-Coronaviruses use lysosomal organelles for cellular egress

Cited by 9 publications

References 55 publications

A non-enveloped arbovirus released in lysosome-derived extracellular vesicles induces super-infection exclusion

A non-enveloped arbovirus released in lysosome-derived extracellular vesicles induces super-infection exclusion

The Host Interactome of Spike Expands the Tropism of SARS-CoV-2

A Timely Call to Arms: COVID-19, the Circadian Clock, and Critical Care

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