Abstract
Our laboratory’s investigations into mechanisms of protective immunity against Francisella tularensis Live Vaccine Strain (LVS) have uncovered mediators important in host defense against primary infection, as well as those correlated with successful vaccination. One such potential correlate was IL-12p40, a pleiotropic cytokine that promotes Th1 T cell function as part of IL-12p70. LVS-infected IL-12p40 deficient knockout (KO) mice maintain a chronic infection, but IL-12p35 KO mice clear LVS infection; thus the role that IL-12p40 plays in immunity to LVS is independent of the IL-12p70 heterodimer. IL-12p40 can also partner with IL-23p19 to create the heterodimeric cytokine IL-23. Here, we directly tested the role of IL-23 in LVS resistance, and found IL-23 to be largely dispensable for immunity to LVS following intradermal or intranasal infection. IL-23p19 KO splenocytes were fully competent in controlling intramacrophage LVS replication in an in vitro overlay assay. Further, antibody responses in IL-23p19 KO mice were similar to those of normal wild type mice after LVS infection. IL-23p19 KO mice or normal wild type mice that survived primary LVS infection survived maximal doses of LVS secondary challenge. Thus p40 has a novel role in clearance of LVS infection that is unrelated to either IL-12 or IL-23.
Highlights
Francisella tularensis is an intracellular bacterium that causes tularemia in humans, an infection which may present in different forms depending on the route of inoculation [1]
Given the disparity in the phenotypes between IL-12p40 KO mice and IL-12p35 KO mice during Live Vaccine Strain (LVS) infection, here we examined the role of p19 as a component of IL-23 during systemic and respiratory LVS infection, using IL-23p19 KO mice [24,25]
To determine the role that IL-23 plays in resistance to LVS, we employed IL-23 p19 deficient KO mice
Summary
Francisella tularensis is an intracellular bacterium that causes tularemia in humans, an infection which may present in different forms depending on the route of inoculation [1]. A live attenuated vaccine strain (denoted LVS) was developed using F. tularensis type B holarctica [2,3]. While this vaccine is not licensed for use in humans, it is an excellent tool for studying both primary and secondary immunity to F. tularensis in various animal model systems, including mice, rats, guinea pigs, and rabbits [4,5]. The murine model has been used to study primary and adaptive immunity to virulent strains of F. tularensis, as well as to LVS. Once vaccinated by primary infection, mice survive high doses of secondary challenge by either IN delivery or by intraperitoneal (IP) injection, a route by which the LD50 is ,10 CFU in naıve mice
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