Transcriptional response in the peripheral blood of patients infected with Salmonella enterica serovar Typhi

Abstract

We used microarrays and transcriptional profiling of peripheral blood to investigate the host response of 29 individuals who contracted typhoid fever in the Mekong Delta region of Vietnam. Samples were taken over a nine month period encompassing acute disease, convalescence, and recovery. We found that typhoid fever induced a distinct and highly reproducible signature in the peripheral blood that changed during treatment and convalescence, returning in the majority of cases to the "normal" profile as measured in healthy uninfected controls. Unexpectedly, there was a strong, distinct signature of convalescence present at day 9 after infection that remained virtually unchanged one month after acute infection and in some cases persisted as long as nine months despite a complete clinical recovery in all patients. Patients who retain the convalescent signature may be genetically or temporarily incapable of developing an effective immune response and may be more susceptible to reinfection, relapse, or the establishment of a carrier state.

Fig. 1.

Unsupervised hierarchical clustering of T1, T28, and T9M samples from typhoid patients and healthy controls using the 1,403 transcripts with greatest variance in abundance. A larger version of the sample dendrogram is shown to the right. Colored bars represent the time point for each sample, and the color key is shown in the legend. The three major branches of the dendrogram are named as shown beside the diagram: recovery and control, convalescent typhoid, and acute typhoid clusters; these contain the majority of the healthy control (HC and Ty-T9M), convalescent (Ty-T28), and acute (Ty-T1) samples, respectively.

Fig. 2.

Temporal changes in gene expression in typhoid patients. Transcripts (1,082) determined by SAM analysis to vary significantly in abundance from the HC samples at T1, T28, or T9M in the typhoid samples were hierarchically clustered; arrays were clustered by time point. Red indicates high expression, and green indicates low expression as shown in the legend; gray indicates missing data. Pearson correlation coefficients and P values were calculated for the expression of every gene and each CP [percent neutrophils, percent lymphocytes, body temperature, gender, percent hematocrit (HCT), and platelets (PLT)] across a selected set of 85 samples that had full clinical data. The plots to the right of the clusters show the negative log₁₀ of the P value signed according to the sign of the calculated correlation coefficient. The P values are plotted as moving averages of three genes (along the vertical axis). The red vertical lines on each plot indicate a P value of 0.05. Gene clusters (–8) referred to in the text are demarcated by horizontal yellow lines.