Cytopathogenesis of Sendai virus in well-differentiated primary pediatric bronchial epithelial cells.
Sendai virus (SeV) is a murine respiratory virus of considerable interest as a gene therapy or vaccine vector, as it is considered nonpathogenic in humans. However, little is known about its interaction with the human respiratory tract. To address this, we developed a model of respiratory virus infection based on well-differentiated primary pediatric bronchial epithelial cells (WD-PBECs). These physiologically authentic cultures are comprised of polarized pseudostratified multilayered epithelium containing ciliated, goblet, and basal cells and intact tight junctions. To facilitate our studies, we rescued a replication-competent recombinant SeV expressing enhanced green fluorescent protein (rSeV/eGFP). rSeV/eGFP infected WD-PBECs efficiently and progressively and was restricted to ciliated and nonciliated cells, not goblet cells, on the apical surface. Considerable cytopathology was evident in the rSeV/eGFP-infected cultures postinfection. This manifested itself by ciliostasis, cell sloughing, apoptosis, and extensive degeneration of WD-PBEC cultures. Syncytia were also evident, along with significant basolateral secretion of proinflammatory chemokines, including IP-10, RANTES, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), interleukin 6 (IL-6), and IL-8. Such deleterious responses are difficult to reconcile with a lack of pathogenesis in humans and suggest that caution may be required in exploiting replication-competent SeV as a vaccine vector. Alternatively, such robust responses might constitute appropriate normal host responses to viral infection and be a prerequisite for the induction of efficient immune responses.
Villenave
Rémi
R
Queen's University Belfast, Medical Biology Centre, Belfast BT9 7BL, Northern Ireland.
Touzelet
Olivier
O
Thavagnanam
Surendran
S
Sarlang
Severine
S
Parker
Jeremy
J
Skibinski
Grzegorz
G
Heaney
Liam G
LG
McKaigue
James P
JP
Coyle
Peter V
PV
Shields
Michael D
MD
Power
Ultan F
UF
D001980:Bronchi / Q000166:cytology* / Q000276:immunology / Q000473:pathology / Q000821:virology; D002454:Cell Differentiation; D002478:Cells, Cultured; D002648:Child; D016207:Cytokines / Q000276:immunology; D003588:Cytopathogenic Effect, Viral; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology / Q000473:pathology / Q000821:virology*; D005260:Female; D006801:Humans; D008297:Male; D010253:Respirovirus Infections / Q000276:immunology / Q000473:pathology / Q000821:virology*; D029082:Sendai virus / Q000502:physiology*; D014779:Virus Replication
D016207:Cytokines
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