Cell-in-cell: an emerging player in COVID-19 and immune disorders

Sun, Qiang; Chen, Wei

doi:10.1360/nso/20220001

Cited by 8 publications

(6 citation statements)

References 39 publications

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“…On one hand, SARS-CoV-2 infection could induce syncytia formation in a way dependent on the presence of a unique bi-arginine motif around the furin cleavage site that dictates cell-cell fusion [ 6 ]. The syncytia resulting from infection-induced cell-cell fusion may actively internalize lymphocytes to form heterotypic cell-in-cell structures [ 6 , 38 ], a pathological phenotype mostly documented in human tumors [ 39 – 44 ], and genetically controlled by a set of core elements, including adherens junctions, actomyosin and mechanical ring [ 45 – 49 ]. The formation of cell-in-cell structure frequently leads to the death of the internalized lymphocytes in an acidified lysosome [ 6 , 50 – 52 ], contributing to lymphopenia which was believed to be a causal factor linked to severe COVID-19 [ 53 – 56 ].…”

Section: Discussionmentioning

confidence: 99%

Long-range enhancement of N501Y-endowed mouse infectivity of SARS-CoV-2 by the non-RBD mutations of Ins215KLRS and H655Y

et al. 2022

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Background Rodents, such as mice, are vulnerable targets, and potential intermediate hosts, of SARS-CoV-2 variants of concern, including Alpha, Beta, Gamma, and Omicron. N501Y in the receptor-binding domain (RBD) of Spike protein is the key mutation dictating the mouse infectivity, on which the neighboring mutations within RBD have profound impacts. However, the impacts of mutations outside RBD on N501Y-mediated mouse infectivity remain to be explored. Results Herein, we report that two non-RBD mutations derived from mouse-adapted strain, Ins215KLRS in the N-terminal domain (NTD) and H655Y in the subdomain linking S1 to S2, enhance mouse infectivity in the presence of N501Y mutation, either alone or together. This is associated with increased interaction of Spike with mouse ACE2 and mutations-induced local conformation changes in Spike protein. Mechanistically, the H655Y mutation disrupts interaction with N657, resulting in a less tight loop that wraps the furin-cleavage finger; and the insertion of 215KLRS in NTD increases its intramolecular interaction with a peptide chain that interfaced with the RBD-proximal region of the neighboring protomer, leading to a more flexible RBD that facilitates receptor binding. Moreover, the Omicron Spike that contains Ins214EPE and H655Y mutations confer mouse infectivity > 50 times over the N501Y mutant, which could be effectively suppressed by mutating them back to wild type. Conclusions Collectively, our study sheds light on the cooperation between distant Spike mutations in promoting virus infectivity, which may undermine the high infectiousness of Omicron variants towards mice.

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Section: Discussionmentioning

confidence: 99%

Long-range enhancement of N501Y-endowed mouse infectivity of SARS-CoV-2 by the non-RBD mutations of Ins215KLRS and H655Y

et al. 2022

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“…The multinucleated syncytia were found to be able to internalize infiltrated live lymphocytes, preferentially the CD8 + T cells, to form cell-in-cell structures, a unique phenomenon that is prevalent in tumor tissues [ 123 ] and plays important roles in clonal selection and immune homeostasis and the like [ 124 – 126 ]. By defaults, as taking place in cancer cells, the formation of the cell-in-cell structure primarily resulted in the death of the internalized lymphocytes within syncytia, leading to a rapid elimination, which could be rescued by either blocking syncytia formation or cell-in-cell-mediated death, thus providing a novel target for COVID-19 therapy [ 127 – 130 ]. Interestingly, the two lymphopenia mechanisms seem to exhibit a preference for the targeted lymphocytes, with the autonomous one for CD4 + T cells while the non-autonomous one for CD8 + T cells [ 114 , 122 ], whether the preference also applies to other types of lymphocytes and its biological properties and potential implications warrant further investigation.…”

Section: Adaptive Immunity: Cellular Immunity and Resistance To Sars-...mentioning

confidence: 99%

Immune response in COVID-19: what is next?

Wang

Sun

et al. 2022

Cell Death Differ

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The coronavirus disease 2019 (COVID-19) has been a global pandemic for more than 2 years and it still impacts our daily lifestyle and quality in unprecedented ways. A better understanding of immunity and its regulation in response to SARS-CoV-2 infection is urgently needed. Based on the current literature, we review here the various virus mutations and the evolving disease manifestations along with the alterations of immune responses with specific focuses on the innate immune response, neutrophil extracellular traps, humoral immunity, and cellular immunity. Different types of vaccines were compared and analyzed based on their unique properties to elicit specific immunity. Various therapeutic strategies such as antibody, anti-viral medications and inflammation control were discussed. We predict that with the available and continuously emerging new technologies, more powerful vaccines and administration schedules, more effective medications and better public health measures, the COVID-19 pandemic will be under control in the near future.

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“…Low lymphocyte count may be caused by cell-in-cell (CIC) structures, which are phenomena described by Karl J. Eberth in the 19th century. CIC formations refer to cells internalized by other cells and are phenomena observed in cancer and lymphocytes-in-IECs documented in both COVID-19 and long COVID [ 120 , 121 ]. This may be significant as the internalized lymphocytes, likely infected with SARS-CoV-2, may comprise unique viral reservoirs, maintaining long COVID.…”

Section: Microbial Translocationmentioning

confidence: 99%

Long COVID as a Tauopathy: Of “Brain Fog” and “Fusogen Storms”

Sfera

Rahman

Campo

et al. 2023

IJMS

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Long COVID, also called post-acute sequelae of SARS-CoV-2, is characterized by a multitude of lingering symptoms, including impaired cognition, that can last for many months. This symptom, often called “brain fog”, affects the life quality of numerous individuals, increasing medical complications as well as healthcare expenditures. The etiopathogenesis of SARS-CoV-2-induced cognitive deficit is unclear, but the most likely cause is chronic inflammation maintained by a viral remnant thriving in select body reservoirs. These viral sanctuaries are likely comprised of fused, senescent cells, including microglia and astrocytes, that the pathogen can convert into neurotoxic phenotypes. Moreover, as the enteric nervous system contains neurons and glia, the virus likely lingers in the gastrointestinal tract as well, accounting for the intestinal symptoms of long COVID. Fusogens are proteins that can overcome the repulsive forces between cell membranes, allowing the virus to coalesce with host cells and enter the cytoplasm. In the intracellular compartment, the pathogen hijacks the actin cytoskeleton, fusing host cells with each other and engendering pathological syncytia. Cell–cell fusion enables the virus to infect the healthy neighboring cells. We surmise that syncytia formation drives cognitive impairment by facilitating the “seeding” of hyperphosphorylated Tau, documented in COVID-19. In our previous work, we hypothesized that the SARS-CoV-2 virus induces premature endothelial senescence, increasing the permeability of the intestinal and blood–brain barrier. This enables the migration of gastrointestinal tract microbes and/or their components into the host circulation, eventually reaching the brain where they may induce cognitive dysfunction. For example, translocated lipopolysaccharides or microbial DNA can induce Tau hyperphosphorylation, likely accounting for memory problems. In this perspective article, we examine the pathogenetic mechanisms and potential biomarkers of long COVID, including microbial cell-free DNA, interleukin 22, and phosphorylated Tau, as well as the beneficial effect of transcutaneous vagal nerve stimulation.

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Cell-in-cell: an emerging player in COVID-19 and immune disorders

Cited by 8 publications

References 39 publications

Long-range enhancement of N501Y-endowed mouse infectivity of SARS-CoV-2 by the non-RBD mutations of Ins215KLRS and H655Y

Long-range enhancement of N501Y-endowed mouse infectivity of SARS-CoV-2 by the non-RBD mutations of Ins215KLRS and H655Y

Immune response in COVID-19: what is next?

Long COVID as a Tauopathy: Of “Brain Fog” and “Fusogen Storms”

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