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Disease tolerance can preserve host homeostasis and limit the negative impact of infections. We report that vaccinated mice survived pulmonary challenge with the extremely virulent SchuS4 strain of Francisella tularensis for at least 100 days, despite the persistence of large numbers (~104) of organisms. Transfer of 100 of these resident bacteria to naive animals caused 100% lethality, demonstrating that virulence was maintained. Tissue damage in the lung was limited over the course of infection and was associated with increased levels of amphiregulin. Mice depleted of CD4+ cells had reduced amphiregulin and succumbed to infection. In addition, neutralization of interferon-γ or depletion of CD8+ cells resulted in increased pathogen loads, bacteremia, and death of the host. Conversely, depletion of Ly6G+ neutrophils had no effect on survival and actually resulted in reduced bacterial levels. Understanding the interplay between host resistance and disease tolerance will provide new insights into the understanding of chronic infectious diseases. [ABSTRACT FROM AUTHOR]