Identification of Immunogenic Salmonella enterica Serotype Typhi Antigens Expressed in Chronic Biliary Carriers of S. Typhi in Kathmandu, Nepal

Abstract

Salmonella enterica serotype Typhi can colonize and persist in the biliary tract of infected individuals, resulting in a state of asymptomatic chronic carriage. Chronic carriers may act as persistent reservoirs of infection within a community and may introduce infection to susceptible individuals and new communities. Little is known about the interaction between the host and pathogen in the biliary tract of chronic carriers, and there is currently no reliable diagnostic assay to identify asymptomatic S. Typhi carriage. To study host-pathogen interactions in the biliary tract during S. Typhi carriage, we applied an immunoscreening technique called in vivo-induced antigen technology (IVIAT), to identify potential biomarkers unique to carriers. IVIAT identifies humorally immunogenic bacterial antigens expressed uniquely in the in vivo environment, and we hypothesized that S. Typhi surviving in the biliary tract of humans may express a distinct antigenic profile. Thirteen S. Typhi antigens that were immunoreactive in carriers, but not in healthy individuals from a typhoid endemic area, were identified. The identified antigens included a number of putative membrane proteins, lipoproteins, and hemolysin-related proteins. YncE (STY1479), an uncharacterized protein with an ATP-binding motif, gave prominent responses in our screen. The response to YncE in patients whose biliary tract contained S. Typhi was compared to responses in patients whose biliary tract did not contain S. Typhi, patients with acute typhoid fever, and healthy controls residing in a typhoid endemic area. Seven of 10 (70%) chronic carriers, 0 of 8 bile culture-negative controls (0%), 0 of 8 healthy Bangladeshis (0%), and 1 of 8 (12.5%) Bangladeshis with acute typhoid fever had detectable anti-YncE IgG in blood. IgA responses were also present. Further evaluation of YncE and other antigens identified by IVIAT could lead to the development of improved diagnostic assays to identify asymptomatic S. Typhi carriers. Salmonella enterica serotype Typhi is the cause of typhoid fever and infects over 21 million individuals and causes 200,000 deaths each year. With adequate treatment, most patients recover from their acute stage of illness and clear infection. However, a small percentage of S. Typhi infected individuals develop a chronic but asymptomatic infection in the biliary tract that can persist for decades. Since S. Typhi is a human-restricted pathogen, chronic carriers may act as reservoirs of infection. Correctly identifying and treating asymptomatic chronic carriers could be critical for ultimate control of typhoid fever. Using an immunoscreening technique called in vivo-induced antigen technology (IVIAT), we have identified potential biomarkers unique to S. Typhi chronic carriers. Further evaluation of these antigens could lead to the development of improved diagnostic assays to detect asymptomatic S. Typhi carriers in typhoid endemic zones, and to an improved understanding of the pathogenesis of S. Typhi in the chronic carrier state.