Inhibition of host-directed gene expression by the
matrix (M)
protein of
vesicular stomatitis virus (VSV) effectively blocks host
antiviral responses, promotes virus replication, and disables the host cell. However, dendritic cells (DC) have the capacity to resist these effects and remain functional during VSV
infection. Here, the mechanisms of DC resistance to M
protein and their subsequent maturation were addressed. Flt3L-derived murine bone marrow dendritic cells (FDC), which phenotypically resemble resident splenic DC, continued to synthesize cellular
proteins and matured during single-cycle (high-multiplicity) and multicycle (low-multiplicity)
infection with VSV.
Granulocyte-macrophage colony-stimulating factor (
GM-CSF)-derived myeloid DC (GDC), which are susceptible to M
protein effects, were nevertheless capable of maturing, but the response was delayed and occurred only during multicycle
infection. FDC resistance was manifested early and was
type I interferon (IFN) receptor (IFNAR) and MyD88 independent, but sustained resistance required IFNAR. MyD88-dependent signaling contributed to FDC maturation during single-cycle
infection but was dispensable during multicycle
infection. Similar to FDC, splenic DC were capable of maturing in vivo during the first 24 h of
infection with VSV, and neither
Toll-like receptor 7 (TLR7) nor MyD88 was required. We conclude that FDC resistance to M
protein is controlled by an intrinsic, MyD88-independent mechanism that operates early in
infection and is augmented later in
infection by type I IFN. In contrast, while GDC are not intrinsically resistant, they can acquire resistance during multicycle
infection. In vivo, splenic DC resist the inhibitory effects of VSV, and as in multicycle FDC
infection, MyD88-independent signaling events control their maturation.