期刊
ELIFE
卷 10, 期 -, 页码 -出版社
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.69708
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资金
- National Institutes of Health [R01AI132633, T32AI007538]
- Swedish Research Council [2018-02646]
- Pew Charitable Trusts
- Swedish Research Council [2018-02646] Funding Source: Swedish Research Council
Research using CRISPR/Cas9 technology to knockout candidate hantavirus receptors in human endothelial cells found that the loss of beta 3 integrin, beta 1 integrin, and/or DAF had little or no effect on hantavirus entry, while loss of protocadherin-1 significantly reduced virus entry and infection. Major host molecules necessary for hantavirus entry by PCDH1-independent mechanisms are yet to be discovered.
Hantaviruses are RNA viruses with known epidemic threat and potential for emergence. Several rodent-borne hantaviruses cause zoonoses accompanied by severe illness and death. However, assessments of zoonotic risk and the development of countermeasures are challenged by our limited knowledge of the molecular mechanisms of hantavirus infection, including the identities of cell entry receptors and their roles in influencing viral host range and virulence. Despite the long-standing presumption that beta 3/beta 1-containing integrins are the major hantavirus entry receptors, rigorous genetic loss-of-function evidence supporting their requirement, and that of decay-accelerating factor (DAF), is lacking. Here, we used CRISPR/Cas9 engineering to knockout candidate hantavirus receptors, singly and in combination, in a human endothelial cell line that recapitulates the properties of primary microvascular endothelial cells, the major targets of viral infection in humans. The loss of beta 3 integrin, beta 1 integrin, and/or DAF had little or no effect on entry by a large panel of hantaviruses. By contrast, loss of protocadherin-1, a recently identified entry receptor for some hantaviruses, substantially reduced hantavirus entry and infection. We conclude that major host molecules necessary for endothelial cell entry by PCDH1-independent hantaviruses remain to be discovered.
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