Predicting pathogen-specific CD8 T cell immune responses from a modeling approach.

The primary CD8 T cell immune response constitutes a major mechanism to fight an infection by intra-cellular pathogens. We aim at assessing whether pathogen-specific dynamical parameters of the CD8 T cell response can be identified, based on measurements of CD8 T cell counts, using a modeling approach. We generated experimental data consisting in CD8 T cell counts kinetics during the response to three different live intra-cellular pathogens: two viruses (influenza, vaccinia) injected intranasally, and one bacteria (Listeria monocytogenes) injected intravenously. All pathogens harbor the same antigen (NP68), but differ in their interaction with the host. In parallel, we developed a mathematical model describing the evolution of CD8 T cell counts and pathogen amount during an immune response. This model is characterized by 9 parameters and includes relevant feedback controls. The model outputs were compared with the three data series and an exhaustive estimation of the parameter values was performed. By focusing on the ability of the model to fit experimental data and to produce a CD8 T cell population mainly composed of memory cells at the end of the response, critical parameters were identified. We show that a small number of parameters (2-4) define the main features of the CD8 T cell immune response and are characteristic of a given pathogen. Among these parameters, two are related to the effector CD8 T cell mediated control of cell and pathogen death. The parameter associated with memory cell death is shown to play no relevant role during the main phases of the CD8 T cell response, yet it becomes essential when looking at the predictions of the model several months after the infection.

Determinants of measles seroprevalence among pregnant women in Paris, France.

Non-immune pregnant women are at risk of severe measles. As the measles vaccination is contraindicated during pregnancy, women should be vaccinated before conception or during the postpartum period. Nevertheless, measles serology is not recommended during pregnancy in France, and there are no data available concerning measles susceptibility and its associated risk factors among pregnant women. The socio-demographic determinants of measles seronegativity have been identified in a prospective cohort of 826 pregnant women in Paris, France. Measles seronegativity was 10.41% (95% CI 8.32-12.50). Women from higher socio-economic groups, born in France after 1980, were more frequently seronegative.

Sodium valproate does not augment Prpsc in murine neuroblastoma cells.

Sodium valproate (VPA) has been reported to increase the accumulation of the pathologic isoform of prion protein (PrPsc) in scrapie-infected murine neuroblastoma cells. In this study, the effect of VPA on PrPsc accumulation was investigated in murine N2a neuroblastoma cells chronically infected with scrapie strain 22L (N2a-22L). No accumulation of PrPsc was detected after short-term (3 days) or long-term (21 days) treatment of N2a-22L cells with 4.8, 12, 18 or 24 microM VPA. Higher VPA concentrations (240 and 600 microM) also failed to augment PrPsc expression. In conclusion, in our experimental conditions, no deleterious effect was induced by VPA on prions replication.

Similar increased serum dipeptidyl peptidase IV activity in chronic hepatitis C and other viral infections.

BACKGROUND: Dipeptidyl peptidase IV is a transmembrane enzyme widely expressed in many cell types, but also present as a soluble form in biological fluids. Its abnormal activity is sometimes associated with liver disease related pathologies. OBJECTIVES: The aim of this study was to evaluate the clinical relevance of changes in serum DPPIV activity in hepatitis C and other viral infections. STUDY DESIGN: DPPIV activity was assessed by using a microplate-based colorimetric assay on serum from 88 subjects: 12 healthy uninfected controls, 10 patients with primary biliary cirrhosis (PBC) as a reference group, 36 HCV-infected patients, and patients suffering from viral infections of different etiologies. Levels of DPPIV activity were compared with: (1) those of other serum biochemical parameters such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transpeptidase (GGT), and bilirubin concentrations; and (2) criteria representative of liver histological status. RESULTS: Compared with healthy subjects, DPPIV activity was significantly increased during viral infections and in PBC (P<0.01). In HCV-infected patients, the median activity (interquartile range, IQR), 29.78 IU/l (24.66-35.95), differed significantly (P<0.05) from that of controls: 21.42 (19.76-24.93). No correlation was observed between DPPIV activity and either ALT, AST, bilirubin, or the stage of liver fibrosis and necroinflammatory activity, although GGT was moderately correlated (r=0.58, P<0.05). CONCLUSIONS: Although we confirmed an elevation of serum DPPIV activity in PBC, it seems to be a non-specific phenomenon common to viral infections. The absence of correlation between serum DPPIV and markers of liver disease in HCV-infected patients, suggests that this activity originates not only from the liver, but also from other sources such as peripheral blood cells involved in the control of viral infections.

Comparative analysis of translation efficiencies of hepatitis C virus 5' untranslated regions among intraindividual quasispecies present in chronic infection: opposite behaviors depending on cell type.

Hepatitis C virus (HCV) RNA translation initiation is dependent on the presence of an internal ribosome entry site (IRES) that is found mostly in its 5' untranslated region (5' UTR). While exhibiting the most highly conserved sequence within the genome, the 5' UTR accumulates small differences, which may be of biological and clinical importance. In this study, using a bicistronic dual luciferase expression system, we have examined the sequence of 5' UTRs from quasispecies characterized in the serum of a patient chronically infected with HCV genotype 1a and its corresponding translational activity. Sequence heterogeneity between IRES elements led to important changes in their translation efficiency both in vitro and in different cell cultures lines, implying that interactions of RNA with related transacting factors may vary according to cell type. These data suggest that variants occasionally carried by the serum prior to reinfection could be selected toward different compartments of the same infected organism, thus favoring the hypothesis of HCV multiple tropism.