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Nikhil Prasad  Fact checked by:Thailand Medical News Team Feb 01, 2024  3 weeks, 2 days, 16 hours, 37 minutes ago

COVID-19 News: SARS-CoV-2 Spike Protein Induces Macropinocytosis In Macrophages Via PKC-NADPH Oxidase Signaling

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COVID-19 News: SARS-CoV-2 Spike Protein Induces Macropinocytosis In Macrophages Via PKC-NADPH Oxidase Signaling
Nikhil Prasad  Fact checked by:Thailand Medical News Team Feb 01, 2024  3 weeks, 2 days, 16 hours, 37 minutes ago
COVID-19 News: The ongoing COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spurred a global effort to understand its pathogenesis, particularly the mechanisms underlying viral entry into host cells. While the primary receptor for SARS-CoV-2 entry is angiotensin-converting enzyme 2 (ACE2), emerging evidence suggests the involvement of alternative pathways, including macropinocytosis, in viral uptake.

SARS-CoV-2 Spike Protein Induces Macropinocytosis In Macrophages Via PKC-NADPH Oxidase Signaling
Recombinant SARS-CoV-2 spike proteins stimulate fluid-phase macropinocytosis in human macrophages. Primary human PBMC-derived macrophages were incubated with FITC-dextran (100 µg/mL) and treated with vehicle (PBS) or spike protein subunits S1 (A), RBD (B), and S2 (C) (1 µg/mL, 4 h) ± EIPA (25 µM, 30 min preincubation). FITC-dextran internalization was analyzed via FACS. (D) Quantification of the number of ruffles per cell in vehicle-, S1-, and S1+EIPA-treated THP1 macrophages normalized to total cell number. (E) THP1 macrophages were treated with spike protein subunits (1 µg/mL, 30 min) ± EIPA (25 µM, 30 min preincubation) and processed for SEM. Analysis of SEM images demonstrated emerging membrane projections (orange arrows), fully formed dorsal ruffles (green arrows), and circularized membrane protrusions forming cups (red arrow). Data are presented as means ± SD. ** p < 0.005; **** p < 0.0001. P values were calculated using one way ANOVA with Tukey’s test for multiple comparisons. Scale bars are 5 µm.

Macropinocytosis, a process characterized by the nonspecific internalization of extracellular fluid and solutes, has garnered attention for its potential role in SARS-CoV-2 infection. This COVID-19 News report delves into recent findings elucidating the stimulation of macropinocytosis by SARS-CoV-2 spike protein subunits, shedding light on its implications for COVID-19 pathogenesis.
Understanding Macropinocytosis
Macropinocytosis, a form of endocytosis, involves the engulfment of large volumes of extracellular fluid, solutes, and membrane by cells through the formation of large endocytic vesicles called macropinosomes. This process is orchestrated by membrane protrusions, known as ruffles, which ensnare extracellular material and internalize it into the cell. Macropinocytosis plays diverse roles in cellular physiology, including nutrient uptake, immune surveillance, and pathogen entry. Notably, viruses such as HIV-1, Ebola virus, and now, SARS-CoV-2, exploit macropinocytosis as an entry mechanism, highlighting its significance in viral infections.
Unraveling SARS-CoV-2 Entry Mechanisms
Recent studies have unveiled the ability of SARS-CoV-2 spike protein subunits, namely S1 and S2, to stimulate macropinocytosis in hu man and murine macrophages. This discovery raises intriguing questions about the interplay between the virus and host cells, particularly in tissues relevant to COVID-19 pathogenesis. Alveolar epithelial cells and macrophages, integral components of the respiratory system, are primary targets for SARS-CoV-2 infection, making them crucial focal points for investigating viral entry mechanisms.
Insights from Experimental Studies
Flow cytometry analyses using fluid-phase markers revealed that SARS-CoV-2 spike protein subunits induce macropinocytosis in both human and murine macrophages, independent of ACE2 receptor engagement. Pharmacological inhibition and genetic knockout experiments further validated the role of macropinocytosis in spike protein-induced internalization, underscoring the specificity of this pathway in viral entry. Scanning electron microscopy provided visual confirmation of membrane ruffling upon spike protein stimulation, highlighting the dynamic cellular changes associated with macropinocytosis.
Cell-Type Specific Responses
Interestingly, while macrophages readily undergo spike protein-induced macropinocytosis, alveolar epithelial cells exhibit minimal responsiveness to these stimuli. This cell-type specificity suggests intricate regulatory mechanisms governing viral entry, which may influence tissue tropism and disease outcomes in COVID-19. The differential susceptibility of cell types to macropinocytosis modulation by SARS-CoV-2 warrants further investigation into the underlying molecular mechanisms and their implications for viral pathogenesis.
Mechanistic Insights and Therapeutic Implications
Elucidating the signaling pathways involved in spike protein-induced macropinocytosis provides valuable insights into potential therapeutic targets for COVID-19. Mechanistic studies have implicated protein kinase C (PKC), phosphoinositide 3-kinase (PI3K), and NADPH oxidase 2 (Nox2) signaling in mediating this process. Inhibition of these pathways attenuated spike protein-induced macropinocytosis, highlighting them as potential targets for intervention strategies aimed at disrupting viral entry and propagation.
Implications for COVID-19 Pathogenesis
The discovery of macropinocytosis as a facilitator of SARS-CoV-2 entry sheds new light on the intricate interplay between the virus and host cells during infection. Macrophages, equipped with robust phagocytic capabilities, serve as frontline defenders against viral invaders but can also become unwitting hosts for viral replication. Dysregulation of macrophage function by SARS-CoV-2 may contribute to the cytokine storm and tissue damage observed in severe COVID-19 cases. Furthermore, the differential response of alveolar epithelial cells underscores the complexity of viral tropism and tissue-specific pathogenesis in COVID-19.
In summary, the identification of macropinocytosis as a novel entry mechanism for SARS-CoV-2 expands our understanding of COVID-19 pathogenesis. By unraveling the intricate interplay between the virus and host cells, particularly in tissues relevant to respiratory infection, researchers gain valuable insights into potential therapeutic targets and intervention strategies. Continued investigation into the molecular mechanisms governing viral entry and host cell responses holds promise for the development of targeted therapies to mitigate the impact of COVID-19 on global health.
This study highlights the significance of macropinocytosis in SARS-CoV-2 infection and underscores the importance of further research to elucidate its role in COVID-19 pathogenesis.
The study findings were published in the peer reviewed journal: Antioxidants.
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