Impact of macrophage and dendritic cell subset elimination on antiviral immunity, viral clearance and production of type 1 interferon.
We report herein that vesicular stomatitis virus (VSV) induced a concurrent primary Th1 (T helper 1) and Th2 cytokine response detectable ex vivo. Liposome-encapsulated clodronate-mediated elimination of CD8- marginal dendritic cells (DCs) and splenic macrophages (m Phi), but not CD8+ interdigitating DCs, prior to infection resulted in a markedly diminished chemokine and Th1 (IL-2, interferon-gamma) cytokine response, although the Th2 response (IL-4) remained relatively intact. Repopulation with marginal DCs and marginal metallophilic macrophages (MMM) restored Th1 cytokine profiles but did not restore chemokine responsiveness or reduce VSV-induced morbidity/mortality. Chemokine competency returned approximately 4 weeks post-depletion, which correlated temporally with repopulation of the spleen with marginal zone macrophages (MZM) and red pulp macrophages (RPM). Unexpectedly, virus-induced morbidity persisted for over 1 month post-depletion and was associated with virus dissemination and distinctive histological lesions in the liver. Depletion of interferon-producing plasmacytoid dendritic cells did not account for virus-induced morbidity because serum levels of type I interferon were not diminished in Cl2MBP-liposome-treated mice. Thus, distinct m Phi subsets are critical for chemokine production and viral clearance, and, in their absence, VSV disseminates even in the presence of high titers of interferon.
Ciavarra
Richard P
RP
Department of Microbiology and Molecular and Cell Biology, Eastern Virginia Medical School, 700 Olney Road, Norfolk, VA 23501, USA. ciavarrp@evms.edu
Taylor
Lisa
L
Greene
Amy R
AR
Yousefieh
Nazita
N
Horeth
Dale
D
van Rooijen
Nico
N
Steel
Christina
C
Gregory
Betsy
B
Birkenbach
Mark
M
Sekellick
Margaret
M
D000818:Animals; D016827:CD8 Antigens / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D007370:Interferon Type I / Q000097:blood; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018353:Rhabdoviridae Infections / Q000097:blood / Q000276:immunology* / Q000821:virology; D013154:Spleen / Q000276:immunology; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology*
D016827:CD8 Antigens; D007370:Interferon Type I; D007376:Interleukin-2; D015847:Interleukin-4; D007371:Interferon-gamma