caa a22 4500 528786768 20190923032428.0 cr unu---uuuuu 180924e20120924xx s 000 0 eng 10.3929/ethz-b-000057318 doi 10.1371/journal.pone.0045433 doi (ETHRESEARCH)oai:www.research-collection.ethz.ch:20.500.11850/57318 Live Attenuated S. Typhimurium Vaccine with Improved Safety in Immuno-Compromised Mice [Elektronische Daten] [Balamurugan Periaswamy, Lisa Maier, Vikalp Vishwakarma, Emma; id_orcid 0000-0002-2473-1145 Wetter Slack, Marcus Kremer, Helene L. Andrews-Polymenis, Michael McClelland, Andrew J. Grant, Mrutyunjay Suar, Wolf-Dietrich; id_orcid 0000-0002-9892-6420 Hardt] PLoS ONE Open access ethresearch Live attenuated vaccines are of great value for preventing infectious diseases. They represent a delicate compromise between sufficient colonization-mediated adaptive immunity and minimizing the risk for infection by the vaccine strain itself. Immune defects can predispose to vaccine strain infections. It has remained unclear whether vaccine safety could be improved via mutations attenuating a vaccine in immune-deficient individuals without compromising the vaccine's performance in the normal host. We have addressed this hypothesis using a mouse model for Salmonella diarrhea and a live attenuated Salmonella Typhimurium strain (ssaV). Vaccination with this strain elicited protective immunity in wild type mice, but a fatal systemic infection in immune-deficient cybb−/−nos2−/− animals lacking NADPH oxidase and inducible NO synthase. In cybb−/−nos2−/− mice, we analyzed the attenuation of 35 ssaV strains carrying one additional mutation each. One strain, Z234 (ssaV SL1344_3093), was >1000-fold attenuated in cybb−/−nos2−/− mice and ≈100 fold attenuated in tnfr1−/− animals. However, in wt mice, Z234 was as efficient as ssaV with respect to host colonization and the elicitation of a protective, O-antigen specific mucosal secretory IgA (sIgA) response. These data suggest that it is possible to engineer live attenuated vaccines which are specifically attenuated in immuno-compromised hosts. This might help to improve vaccine safety. Creative Commons Attribution 3.0 Unported http://creativecommons.org/licenses/by/3.0 ethresearch Periaswamy Balamurugan joint author Maier Lisa joint author Vishwakarma Vikalp joint author Wetter Slack Emma; id_orcid 0000-0002-2473-1145 joint author Kremer Marcus joint author Andrews-Polymenis Helene L. joint author McClelland Michael joint author Grant Andrew J. joint author Suar Mrutyunjay joint author Hardt Wolf-Dietrich; id_orcid 0000-0002-9892-6420 joint author PLoS ONE Lawrence, KS, USA : Public Library of Science 7 (9), p. e45433 1932-6203 http://hdl.handle.net/20.500.11850/57318 text/html WWW-Backlink auf das Repository (Open access) 1 Journal Article ethresearch ETHRESEARCH 856 40 http://hdl.handle.net/20.500.11850/57318 text/html WWW-Backlink auf das Repository (Open access) ETHRESEARCH 700 1- Periaswamy Balamurugan joint author ETHRESEARCH 700 1- Maier Lisa joint author ETHRESEARCH 700 1- Vishwakarma Vikalp joint author ETHRESEARCH 700 1- Wetter Slack Emma; id_orcid 0000-0002-2473-1145 joint author ETHRESEARCH 700 1- Kremer Marcus joint author ETHRESEARCH 700 1- Andrews-Polymenis Helene L. joint author ETHRESEARCH 700 1- McClelland Michael joint author ETHRESEARCH 700 1- Grant Andrew J. joint author ETHRESEARCH 700 1- Suar Mrutyunjay joint author ETHRESEARCH 700 1- Hardt Wolf-Dietrich; id_orcid 0000-0002-9892-6420 joint author ETHRESEARCH 773 0- PLoS ONE Lawrence, KS, USA : Public Library of Science 7 (9), p. e45433 1932-6203 BK010053 XK010053 XK010000 ETHRESEARCH ETHRESEARCH ETHRESEARCH Journal Article Open access