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Replication in first organPrimary viremia
Secondary viremia
Replication
dissemination
other organs
model of systemic virus infection
Infection
MCMV
-Herpesviridae herpesvirus
-Cytomegalovirus-MCMV: mouse cytomegalovirus
HCMV :major risk factor for immunoincompetent and immunocompromised patients
(AIDS patients and organ transplant recipients)
MCMV: represents the rodent model
MCMV replicates in a broad spectrum of cell types: vascular endothelial cells and
hepatocytes
The Cre-Loxp system
The used Cre-Loxp system
MCMV- flox and –rec replicate in the same manner
Experimental set-up
106 PFU of MCMV flox
Analyses of MCMV-rec and MCMV-flox plaque forming units
EC and HC are important cell types for MCMV replication
Tie2-cre: Cre under control of Tie2 (endothelial tyrosinkinase receptors: only in EC) promoter in vascular ECAlb-cre: Cre under control of albumin promoter in hepatocytes
Hepatocytes are the main producer cell type
Hepatocytes derived MCMV-rec do not disseminate from the liver to other organs (alb-cre)
Alb-cre
Influence of route and dose
Amount of cre expression, the route and dose of infection have no influence on the results
Alb-cre
Virus isolation out of liver
i.v. injection
C57BL/6
Hc-derived MCMV has potential to replicate in spleen and lung
Bidirectional spread of MCMV between EC and Hc
EC and Hc produce virus which can infect neighboring cellsNo explanation that Hc derived virus can’t disseminate
Tie2-cre: MCMV from EC to HcAlb-cre: MCMV from Hc to EC
MCMV infection is controlled by CD3+ cells
Elimination of MCMV is correlated with liver infiltrating T-cellsReason for dissemination stop?
Immunosuppression has no influence on Hc- derived virus dissemination
1 untreated2, 3 -irradiation4 immune suppression by cyclophosphamide 5 proinflammatory stimuli. Con A
No increase of dissemination after immune suppression and proinflammatory stimuli
- untreated+ immunodepleted
summary
- Hepatocytes and EC are target cells of MCMV in vivo (replication)
- HC are important target cells but are not involved in virus dissemination
-Infected EC contribute to viremic dissemination by serving as transport vehicle and
by uptake and release of virus
- Hc derived MCMV never leads to a second viremia (unlike to former publications)
-But what is the reason for that?
-Independent on immune cells or irradiation
-Independent on ability to infect other cells
- IFN???