SARS-CoV-2 cytopathogenesis in cultured cells and in COVID-19 autoptic lung, evidences of lipid involvement.

Nardacci, Roberta; Colavita, Francesca; Castilletti, Concetta; Lapa, Daniele; Matusali, Giulia; Meschi, Silvia; Nonno, Franca Del; Colombo, Daniele; Capobianchi, Maria Rosaria; Zumla, Alimuddin; Ippolito, Giuseppe; Piacentini, Mauro; Falasca, Laura

doi:10.21203/rs.3.rs-39274/v1

Cited by 7 publications

(6 citation statements)

References 8 publications

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“…SARS-CoV-2 virions were detected, alone or in clusters, predominantly in intracellular compartments (i.e. vacuoles) (Figure 3B panels c, d and 3C panel c), as previously shown in different cultured cell lines and lung cells of infected patients 34 . Finally, cells exhibiting a high number of viral particles outside intracellular structures were found (Figure 3C panels a, b) and clear signs of s of degeneration, such as cytoplasm condensation were also observed (Figure 3C panels a, b, d).…”

Section: Ultrastructural Evidences Of Sars-cov-2 Packaging and Cytoto...supporting

confidence: 84%

Human cardiosphere-derived stromal cells exposed to SARS-CoV-2 evolve into hyper-inflammatory/pro-fibrotic phenotype and produce infective viral particles depending on the levels of ACE2 receptor expression

Amendola

Garoffolo

Songia

et al. 2021

Cardiovascular Research

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Aims Patients with severe respiratory syndrome caused by SARS-CoV-2 undergo cardiac complications due to hyper-inflammatory conditions. Although the presence of the virus has been detected in the myocardium of infected patients, and infection of induced pluripotent cells-derived cardiomyocytes has been demonstrated, the reported expression of ACE2 in cardiac stromal cells suggests that SARS-CoV-2 may determine cardiac injury by sustaining productive infection and increasing inflammation. Methods and Results We analyzed expression of ACE2 receptor in primary human cardiac stromal cells derived from cardiospheres, using proteomics and transcriptomics before exposing them to SARS-CoV-2 in vitro. Using conventional and high sensitivity PCR methods, we measured virus release in the cellular supernatants and monitored the intracellular viral bioprocessing. We performed high-resolution imaging to show the sites of intracellular viral production and demonstrated the presence of viral particles in the cells with electron microscopy. We finally used RT-qPCR assays to detect genes linked to innate immunity and fibrotic pathways coherently regulated in cells after exposure to the virus. Conclusions Our findings indicate that cardiac stromal cells are susceptible to SARS-CoV-2 infection and produce variable viral yields depending on the extent of cellular ACE2 receptor expression. Interestingly, these cells also evolved toward hyper-inflammatory/pro-fibrotic phenotypes independently of ACE2 levels. Thus, SARS-CoV-2 infection of myocardial stromal cells could be involved in cardiac injury, and explain the high number of complications observed in severe cases of COVID-19. Translational Perspective In the present investigation, we provide evidence that human cardiac stromal cells, a major component of the non-contractile cellular fraction in the heart can be infected by SARS-CoV-2 in vitro, in direct relationship to the extent of ACE2 receptor expression. Our work also suggests that these cells, when exposed to the virus, can evolve toward inflammatory and fibrotic phenotypes independently of ACE2. In addition to describing a novel cellular target of SARS-CoV-2 in the human heart, our study generates new hypothesis on potential mechanisms underlying cardiac complications observed in COVID-19 patients.

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Section: Ultrastructural Evidences Of Sars-cov-2 Packaging and Cytoto...supporting

confidence: 84%

Human cardiosphere-derived stromal cells exposed to SARS-CoV-2 evolve into hyper-inflammatory/pro-fibrotic phenotype and produce infective viral particles depending on the levels of ACE2 receptor expression

Amendola

Garoffolo

Songia

et al. 2021

Cardiovascular Research

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“…To our knowledge, there are still no experimental structures for the M protein of SARS-CoV-2 that explicitly examine the macromolecular organization of either of these proteins during viral assembly or in formed viral particles. In light of the most recent studies that clearly identify the high involvement of lipids in the pathogenesis and mechanisms of the virus, 26, 27 we hope this work lays the groundwork to further examine the complex dynamics between viral proteins and lipids. Specifically, the roles of M and E – both integral membrane proteins of SARS-CoV-2 – during viral assembly, membrane deformation, virus maturation, and reshaping of the viral particle during binding and fusion to a new host.…”

Section: Introductionmentioning

confidence: 90%

Molecular interactions of the M and E integral membrane proteins of SARS-CoV-2

Monje-Galvan

Voth

2021

Preprint

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Specific lipid-protein interactions are key for cellular processes, and even more so for the replication of pathogens. The COVID-19 pandemic has drastically changed our lives and cause the death of nearly three million people worldwide, as of this writing. SARS-CoV-2 is the virus that causes the disease and has been at the center of scientific research over the past year. Most of the research on the virus is focused on key players during its initial attack and entry into the cellular host; namely the S protein, its glycan shield, and its interactions with the ACE2 receptors of human cells. As cases continue to raise around the globe, and new mutants are identified, there is an urgent need to understand the mechanisms of this virus during different stages of its life cycle. Here, we consider two integral membrane proteins of SARS-CoV-2 known to be important for viral assembly and infectivity. We have used microsecond-long all-atom molecular dynamics to examine the lipid-protein and protein-protein interactions of the membrane (M) and envelope (E) structural proteins of SARS-CoV-2 in a complex membrane model. We contrast the two proposed protein complexes for each of these proteins, and quantify their effect on their local lipid environment. This ongoing work also aims to provide molecular-level understanding of the mechanisms of action of this virus to possibly aid in the design of novel treatments.

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“…It is clear from our results that NIC alters the plasmalogen and TG content early as we observed a significant decrease at 16 h + NIC compared to 16 h without NIC and this host lipid alteration continues to a greater extent at 48 h + NIC compared to 48 h without NIC (Figure 2B). In the absence of NIC treatment, plasmalogens (plasmanyl-PE, −TG, and -PC as well as plasmenyl-LPC, -PE, -LPE, -PC and -TG) were found to be differentially abundant at 48 h as compared to 16 h, which is expected given the cell growth during this time frame (Nahapetian et al, 1986;Nardacci et al, 2021) (Figures 2A,C, and see Supplementary Table S4). However, at the 48 h time point (24 h post drug treatment) NIC reduced the abundance (>2 log2 fold-change) of HexCer-NDS, while in parallel, increased the abundance (>2 log2 fold-change) of plasmenyl-and plasmanyl-TG, PI, plasmanyl-PE and -PC, as well as Bis (monoacylglycerol)phosphates (BMPs) (Figure 2B).…”

Section: Nic Treatment Distinctly Impacts Ether Lipids In the Absence...mentioning

confidence: 81%

Niclosamide as a chemical probe for analyzing SARS-CoV-2 modulation of host cell lipid metabolism

Garrett,

Coatsworth,

Mahmud

et al. 2023

Front. Microbiol.

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IntroductionSARS-CoV-2 subverts host cell processes to facilitate rapid replication and dissemination, and this leads to pathological inflammation.MethodsWe used niclosamide (NIC), a poorly soluble anti-helminth drug identified initially for repurposed treatment of COVID-19, which activates the cells’ autophagic and lipophagic processes as a chemical probe to determine if it can modulate the host cell’s total lipid profile that would otherwise be either amplified or reduced during SARS-CoV-2 infection.ResultsThrough parallel lipidomic and transcriptomic analyses we observed massive reorganization of lipid profiles of SARS-CoV-2 infected Vero E6 cells, especially with triglycerides, which were elevated early during virus replication, but decreased thereafter, as well as plasmalogens, which were elevated at later timepoints during virus replication, but were also elevated under normal cell growth. These findings suggested a complex interplay of lipid profile reorganization involving plasmalogen metabolism. We also observed that NIC treatment of both low and high viral loads does not affect virus entry. Instead, NIC treatment reduced the abundance of plasmalogens, diacylglycerides, and ceramides, which we found elevated during virus infection in the absence of NIC, resulting in a significant reduction in the production of infectious virions. Unexpectedly, at higher viral loads, NIC treatment also resulted in elevated triglyceride levels, and induced significant changes in phospholipid metabolism.DiscussionWe posit that future screens of approved or new partner drugs should prioritize compounds that effectively counter SARS-CoV-2 subversion of lipid metabolism, thereby reducing virus replication, egress, and the subsequent regulation of key lipid mediators of pathological inflammation.

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SARS-CoV-2 cytopathogenesis in cultured cells and in COVID-19 autoptic lung, evidences of lipid involvement.

Cited by 7 publications

References 8 publications

Human cardiosphere-derived stromal cells exposed to SARS-CoV-2 evolve into hyper-inflammatory/pro-fibrotic phenotype and produce infective viral particles depending on the levels of ACE2 receptor expression

Human cardiosphere-derived stromal cells exposed to SARS-CoV-2 evolve into hyper-inflammatory/pro-fibrotic phenotype and produce infective viral particles depending on the levels of ACE2 receptor expression

Molecular interactions of the M and E integral membrane proteins of SARS-CoV-2

Niclosamide as a chemical probe for analyzing SARS-CoV-2 modulation of host cell lipid metabolism

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