The procoagulant activity of virus-infected monocytes is TF-dependent. Although influenza infection did not generate a significant reduction in clotting time, the pronounced expression of IL-6 and IL-8 may induce local and/or systemic inflammatory reactions, which may be associated with plaque rupture and atherosclerosis. The lack of production of the anti-inflammatory cytokine IL-10 may even accelerate these processes.
The liver bears unique immune properties that support both immune tolerance and immunity, but the mechanisms responsible for clearance versus persistence of virus-infected hepatocytes remain unclear. Here, we dissect the factors determining the outcome of antiviral immunity using recombinant adenoviruses that reflect the hepatropism and hepatrophism of hepatitis viruses. We generated replication-deficient adenoviruses with equimolar expression of ovalbumin, luciferase, and green fluorescent protein driven by a strong ubiquitous cytomegalovirus (CMV) promoter (Ad-CMV-GOL) or by 100-fold weaker, yet hepatocyte-specific, transthyretin (TTR) promoter (Ad-TTR-GOL). Using in vivo bioluminescence to quantitatively and dynamically image luciferase activity, we demonstrated that Ad-TTR-GOL infection always persists, whereas Ad-CMV-GOL infection is always cleared, independent of the number of infected hepatocytes. Failure to clear Ad-TTR-GOL infection involved mechanisms acting during initiation as well as execution of antigen-specific immunity. First, hepatocyte-restricted antigen expression led to delayed and curtailed T-cell expansion-10,000-fold after Ad-CMV-GOL versus 150-fold after Ad-TTR-GOL-infection. Second, CD8 T-cells primed toward antigens selectively expressed by hepatocytes showed high PD-1/Tim-3/LAG-3/CTLA-4/CD160 expression levels similar to that seen in chronic hepatitis B. Third, Ad-TTR-GOL but not Ad-CMV-GOL-infected hepatocytes escaped being killed by effector T-cells while still inducing high PD-1/Tim-3/LAG-3/CTLA-4/CD160 expression, indicating different thresholds of T-cell receptor signaling relevant for triggering effector functions compared with exhaustion. Conclusion: Our study identifies deficits in the generation of CD8 T-cell immunity toward hepatocyte-expressed antigens and escape of infected hepatocytes expressing low viral antigen levels from effector T-cell killing as independent factors promoting viral persistence. This highlights the importance of addressing both the restauration of CD8 T-cell dysfunction and overcoming local hurdles of effector T-cell function to eliminate virus-infected hepatocytes.
Eingegangen: 18.1.19R3 Angenommen: 5.5.1983 Zusommenfassung -Summary Nach 53jahriger Versuchsdauer wurde der Boden des N-Formen-Versuchs Weihenstephan (Acker-Braunerde, suL, nFK 160mm, pH5.9, Gesamt-C 0.9%, Gesamt-N 0.1 %, T-Wert 15 mvaYlOO g Boden) auf verschiedene Eigenschaften untersucht.Die Diingung mit schwefelsaurem Ammoniak (ssA) erbrachte einen pH-AbfaU auf 4.9 in der Krume; die Versauerung reicht bis 50cm Tiefe. Eine jahrliche Kalkung zu ssA konnte den pH-Wert trotz gleicher Kalkmengen nicht auf der selben Hohe wie Kalkstickstoff (Kst) halten. Die ubrigen Varianten weisen pH-Werte von 5.8 bis 6.0 auf. C,-und N,-Gehalt des Bodens liegen in den Varianten Stallmist, Kst und ssA (+CaO) bei 0.91 bis 0.98%C, ,,ohm N" bzw. mit Nitratdungung bei 0.81 bis 0.87 % C . Stallmist (Stm) und Kalkstickstoff fuhrten zu hoheren Gehalten an Huminsluren und organischer Substanz als Ammonium-und Nitratdungung. Ammoniumdungung steigerte den Fulvosauregehalt.Die biologische Aktivitat der Boden, gemessen an der Aktivitat von 5 verschiedenen Enzymen und der 02-Aufnahme ist im wesentlichen vom pH-Wert abhangig; die hochsten Aktivitaten wurden in der Vanante Kalkstickstoff gefunden (auSer Katalase). Die Aktivitat des stallmistgedungten Bodens liegt nicht hoher als die des ungedungten. Der Anteil des hydrolysierbaren und nichthydrolysierbaren Stickstoffs wurde durch die Diingung (ausgenommen Stm) nicht verandert (einheitlich 12 % nichthydrolysierbarer N). Stallmistdiingung erhohte den nichthydrolysierbaren N auf 14 %.Die Stickstoffnachlieferng im Bebriitungsversuch steht in enger Beziehung zum Gesamt-N-Gehalt des Bodens (r = 0.94). Im Pflanzenversuch ist die Abhangigkeit schwacher (r = 0.72 bis 0.79). Andere EinfluDfaktoren werden diskutiert. Influence of long-term fertilizing with Merent forms of nitrogen fedizer on pH, humic fractions, biologkd activity and dynnmirs of nitrogen of an arable brown earthThe evaluation of soil characteristics in a 53 years field trial (arable brown earth, sandy silty loam, eff.fieldcap. 160mm, pH5,9, totalC0,9%, totalN0,l %, CEC 15meq/100gsoil)gave the following results:Fertilizing with ammonium sulfate decreased pH in topsoil down to 4.9. The acidification reached a depth of 50cm. Liming in addition to ammonium sulfate could not keep pH on the same level as calcium cyanamide did.The other treatments showed pH-values between 5.8 and 6.0 . Total carbon and nitrogen in treatments with farm manure, calcium cyanamide and ammonium sulfate were 0.91 to 0.98 % C, in
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