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Lactoferrin-Hexon Interactions Mediate CAR-Independent Adenovirus Infection of Human Respiratory Cells
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Avdelningen för virologi.
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Avdelningen för virologi. Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany.ORCID-id: 0000-0001-5109-9408
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Avdelningen för virologi.
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2020 (Engelska)Ingår i: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 94, nr 14, artikel-id e00542-20Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Virus entry into host cells is a complex process that is largely regulated by access to specific cellular receptors. Human adenoviruses (HAdVs) and many other viruses use cell adhesion molecules such as the coxsackievirus and adenovirus receptor (CAR) for attachment to and entry into target cells. These molecules are rarely expressed on the apical side of polarized epithelial cells, which raises the question of how adenoviruses—and other viruses that engage cell adhesion molecules—enter polarized cells from the apical side to initiate infection. We have previously shown that species C HAdVs utilize lactoferrin—a common innate immune component secreted to respiratory mucosa—for infection via unknown mechanisms. Using a series of biochemical, cellular, and molecular biology approaches, we mapped this effect to the proteolytically cleavable, positively charged, N-terminal 49 residues of human lactoferrin (hLF) known as human lactoferricin (hLfcin). Lactoferricin (Lfcin) binds to the hexon protein on the viral capsid and anchors the virus to an unknown receptor structure of target cells, resulting in infection. These findings suggest that HAdVs use distinct cell entry mechanisms at different stages of infection. To initiate infection, entry is likely to occur at the apical side of polarized epithelial cells, largely by means of hLF and hLfcin bridging HAdV capsids via hexons to as-yet-unknown receptors; when infection is established, progeny virions released from the basolateral side enter neighboring cells by means of hLF/hLfcin and CAR in parallel.

IMPORTANCE: Many viruses enter target cells using cell adhesion molecules as receptors. Paradoxically, these molecules are abundant on the lateral and basolateral side of intact, polarized, epithelial target cells, but absent on the apical side that must be penetrated by incoming viruses to initiate infection. Our study provides a model whereby viruses use different mechanisms to infect polarized epithelial cells depending on which side of the cell—apical or lateral/basolateral—is attacked. This study may also be useful to understand the biology of other viruses that use cell adhesion molecules as receptors.

Ort, förlag, år, upplaga, sidor
American Society for Microbiology , 2020. Vol. 94, nr 14, artikel-id e00542-20
Nyckelord [en]
adenovirus, CAR, cellular receptor, lactoferrin, tropism
Nationell ämneskategori
Mikrobiologi inom det medicinska området
Identifikatorer
URN: urn:nbn:se:umu:diva-173890DOI: 10.1128/JVI.00542-20ISI: 000550190300011PubMedID: 32376620Scopus ID: 2-s2.0-85087533884OAI: oai:DiVA.org:umu-173890DiVA, id: diva2:1456652
Forskningsfinansiär
Knut och Alice Wallenbergs Stiftelse, 2013.0019Tillgänglig från: 2020-08-06 Skapad: 2020-08-06 Senast uppdaterad: 2023-03-24Bibliografiskt granskad

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Persson, DavidLenman, AnnasaraFrängsmyr, LarsAhlm, ClasArnberg, Niklas

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Persson, DavidLenman, AnnasaraFrängsmyr, LarsAhlm, ClasPlückthun, AndreasArnberg, Niklas
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