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Adenovirus vectors can infect mouse megakaryocytes - implications for vaccine-induced thrombosis/thrombocytopenia
Simon Collett1,2,3, Linda Earnest2, Melissa A Edeling2
1Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia.
Background:
Adenoviruses, adenoviral vector vaccines, and gene delivery systems have been implicated in thrombosis/thrombocytopenia syndrome. The underlying cause remains unknown. We have previously hypothesized that infection of megakaryocytes (MKs), the progenitor cells of platelets, plays a central role in adenovirus- or adenoviral vector-induced thrombosis/thrombocytopenia. Further, recent work has highlighted that the MK population comprises multiple subsets, including cells with immune function, and we propose that this MK subset is involved in adenoviral infection and the subsequent response.
Objectives:
To determine whether MKs are permissive to infection by recombinant adenovirus encoding the SARS-CoV-2 spike protein, and whether infection is associated with phenotypic changes.
Methods:
In this work, we generated adenovirus vectors based on the adenovirus 5 strain, with a green fluorescence protein reporter gene and encoding or not the SARS-CoV-2 Spike protein. Megakaryoblastic cell lines and MKs derived from mouse bone marrow and differentiated with thrombopoietin were exposed to adenoviral vectors, and infection was analyzed using flow cytometry and fluorescence microscopy.
Results:
The primary finding of this study is that MKs were permissive to infection by recombinant adenoviruses carrying the Spike gene of ß-SARS-CoV-2, with higher rates of infection in mature MKs. Furthermore, the effect of adenoviral infection on the cell surface proteins CD41, CD42, and CXCR4 was investigated. Cell cultures stimulated with bacterial lipopolysaccharide, with and without concurrent adenoviral infection, demonstrated that lipopolysaccharide stimulation and adenoviral infection at moderate multiplicity of infection drove increased surface expression of the α chemokine receptor CXCR4, whereas adenoviral infection at a high multiplicity of infection reduced CXCR4 expression.
Conclusion:
We found that adenoviral infection was higher in higher-ploidy CD41+CD42+ and CXCR4hi MKs, implicating these receptors in the MK response to adenoviral infection.
Insights
Adenoviruses can infect megakaryocytes (MKs), the platelet-producing cells. This study shows that SARS-CoV-2 spike protein-encoding adenoviruses infect mature MKs, potentially explaining adenovirus-associated thrombosis.
Area of Science:
- Virology
- Immunology
- Hematology
Background:
- Adenoviruses and adenoviral vectors are linked to thrombosis/thrombocytopenia syndrome.
- The mechanism remains unclear, but megakaryocyte (MK) infection is hypothesized.
- MKs possess immune functions and may be involved in adenoviral responses.
Purpose of the Study:
- To investigate if MKs are susceptible to infection by adenoviruses encoding the SARS-CoV-2 spike protein.
- To determine if adenoviral infection causes phenotypic changes in MKs.
Main Methods:
- Adenovirus 5 vectors encoding SARS-CoV-2 spike protein were generated.
- Megakaryoblastic cell lines and mouse bone marrow-derived MKs were exposed to vectors.
- Infection and cell surface protein expression were analyzed via flow cytometry and microscopy.
Main Results:
- MKs were permissive to adenoviruses encoding the SARS-CoV-2 spike protein, with higher infection rates in mature MKs.
- Adenoviral infection increased CXCR4 expression at moderate doses but decreased it at high doses.
- Higher infection rates were observed in higher-ploidy CD41+, CD42+, and CXCR4hi MKs.
Conclusions:
- MKs are susceptible to adenoviral infection, particularly mature cells.
- Specific MK subsets and receptors (CD41, CD42, CXCR4) are implicated in the response to adenoviral infection.
- Findings may elucidate the pathogenesis of adenovirus-associated thrombosis.
