| Summary: | <i>Francisella tularensis</i> subspecies <i>tularensis</i> (<i>Ftt)</i> is extremely virulent for humans when inhaled as a small particle aerosol (<5 µm). Inhalation of ≥20 viable bacteria is sufficient to initiate infection with a mortality rate ≥30%. Consequently, in the past, <i>Ftt</i> became a primary candidate for biological weapons development. To counter this threat, the USA developed a live vaccine strain (LVS), that showed efficacy in humans against inhalation of virulent <i>Ftt</i>. However, the breakthrough dose was fairly low, and protection waned with time. These weaknesses triggered extensive research for better vaccine candidates. Previously, we showed that deleting the <i>clpB</i> gene from virulent <i>Ftt</i> strain, SCHU S4, resulted in a mutant that was significantly less virulent than LVS for mice, yet better protected them from aerosol challenge with wild-type SCHU S4. To date, comprehensive searches for correlates of protection for SCHU S4 Δ<i>clpB</i> among molecules that are critical signatures of cell-mediated immunity, have yielded little reward. In this study we used transcriptomics analysis to expand the potential range of molecular correlates of protection induced by vaccination with SCHU S4 Δ<i>clpB</i> beyond the usual candidates. The results provide proof-of-concept that unusual host responses to vaccination can potentially serve as novel efficacy biomarkers for new tularemia vaccines.
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