Lassa and Mopeia virus replication in human monocytes/macrophages and in endothelial cells: different effects on IL-8 and TNF-alpha gene expression.
Cells of the mononuclear and endothelial lineages are targets for viruses which cause hemorrhagic fevers (HF) such as the filoviruses Marburg and Ebola, and the arenaviruses Lassa and Junin. A recent model of Marburg HF pathogenesis proposes that virus directly causes endothelial cell damage and macrophage release of TNF-alpha which increases the permeability of endothelial monolayers [Feldmann et al. , 1996]. We show that Lassa virus replicates in human monocytes/macrophages and endothelial cells without damaging them. Human endothelial cells (HUVEC) are highly susceptible to infection by both Lassa and Mopeia (a non-pathogenic Lassa-related arenavirus). Whereas monocytes must differentiate into macrophages before supporting even low level production of these viruses, the virus yields in the culture medium of infected HUVEC cells reach more than 7 log10 PFU/ml without cellular damage. In contrast to filovirus, Lassa virus replication in monocytes/macrophages fails to stimulate TNF-alpha gene expression and even down-regulates LPS-stimulated TNF-alpha mRNA synthesis. The expression of IL-8, a prototypic proinflammatory CXC chemokine, was also suppressed in Lassa virus infected monocytes/macrophages and HUVEC on both the protein and mRNA levels. This contrasts with Mopeia virus infection of HUVEC in which neither IL-8 mRNA nor protein are reduced. The cumulative down-regulation of TNF-alpha and IL-8 expression could explain the absence of inflammatory and effective immune responses in severe cases of Lassa HF.
Lukashevich
I S
IS
Department of Pathology, University of Wisconsin, Madison, Wisconsin, USA.
Maryankova
R
R
Vladyko
A S
AS
Nashkevich
N
N
Koleda
S
S
Djavani
M
M
Horejsh
D
D
Voitenok
N N
NN
Salvato
M S
MS
D001116:Arenaviridae / Q000502:physiology*; D001117:Arenaviridae Infections / Q000276:immunology / Q000821:virology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000821:virology*; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D007835:Lassa Fever / Q000276:immunology / Q000821:virology; D007836:Lassa virus / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000821:virology*; D009000:Monocytes / Q000502:physiology / Q000821:virology*; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014471:Umbilical Veins; D014779:Virus Replication
D016209:Interleukin-8; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha