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2012 ; 109
(30
): 12117-22
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Hematopoietic-specific targeting of influenza A virus reveals replication
requirements for induction of antiviral immune responses
#MMPMID22778433
Langlois RA
; Varble A
; Chua MA
; García-Sastre A
; tenOever BR
Proc Natl Acad Sci U S A
2012[Jul]; 109
(30
): 12117-22
PMID22778433
show ga
A coordinated innate and adaptive immune response, orchestrated by antigen
presenting cells (APCs), is required for effective clearance of influenza A virus
(IAV). Although IAV primarily infects epithelial cells of the upper respiratory
tract, APCs are also susceptible. To determine if virus transcription in these
cells is required to generate protective innate and adaptive immune responses, we
engineered IAV to be selectively attenuated in cells of hematopoietic origin.
Incorporation of hematopoietic-specific miR-142 target sites into the
nucleoprotein of IAV effectively silenced virus transcription in APCs, but had no
significant impact in lung epithelial cells. Here we demonstrate that inhibiting
IAV replication in APCs in vivo did not alter clearance, or the generation of
IAV-specific CD8 T cells, suggesting that cross-presentation is sufficient for
cytotoxic T lymphocyte activation. In contrast, loss of in vivo virus infection,
selectively in APCs, resulted in a significant reduction of retinoic
acid-inducible gene I-dependent type I IFN (IFN-I). These data implicate the
formation of virus replication intermediates in APCs as the predominant trigger
of IFN-I in vivo. Taking these data together, this research describes a unique
platform to study the host response to IAV and provides insights into the
mechanism of antigen presentation and the induction of IFN-I.