Abstract
Background: Human monocyte inflammatory responses differ between virulent and attenuated Francisella infection.Results: A mixed infection model showed that the virulent F. tularensis Schu S4 can attenuate inflammatory cytokine responses to the less virulent F. novicida in human monocytes.Conclusion: F. tularensis dampens inflammatory response by an active process.Significance: This suppression may contribute to enhanced pathogenicity of F. tularensis. Francisella tularensis is a Gram-negative facultative bacterium that can cause the disease tularemia, even upon exposure to low numbers of bacteria. One critical characteristic of Francisella is its ability to dampen or subvert the host immune response. Previous work has shown that monocytes infected with highly virulent F. tularensis subsp. tularensis strain Schu S4 responded with a general pattern of quantitatively reduced pro-inflammatory signaling pathway genes and cytokine production in comparison to those infected with the less virulent related F. novicida. However, it has been unclear whether the virulent Schu S4 was merely evading or actively suppressing monocyte responses. By using mixed infection assays with F. tularensis and F. novicida, we show that F. tularensis actively suppresses monocyte pro-inflammatory responses. Additional experiments show that this suppression occurs in a dose-dependent manner and is dependent upon the viability of F. tularensis. Importantly, F. tularensis was able to suppress pro-inflammatory responses to earlier infections with F. novicida. These results lend support that F. tularensis actively dampens human monocyte responses and this likely contributes to its enhanced pathogenicity.
Highlights
Francisella tularensis is the highly infectious Gram-negative causative agent of the disease tularemia (Sjostedt, 2007)
Previous work has shown that monocytes infected with highly virulent F. tularensis subsp. tularensis strain Schu S4 responded with a general pattern of quantitatively reduced pro-inflammatory signaling pathway genes and cytokine production in comparison to those infected with the less virulent related F. novicida
By using mixed infection assays with F. tularensis and F. novicida, we show that F. tularensis actively suppresses monocyte pro-inflammatory responses
Summary
Francisella tularensis is the highly infectious Gram-negative causative agent of the disease tularemia (Sjostedt, 2007). One critical characteristic of F. tularensis is its ability to attenuate the host inflammatory immune response. Early studies in humans showed that Francisella-infected individuals exhibited diminished cytokine responses to endotoxin (Greisman et al, 1963). F. tularensis infection does not lead to a classic pro-inflammatory cytokine response, which in turn results in insufficient numbers of immune cells recruited to infection sites (Bosio et al, 2007). Murine studies have corroborated the findings of Griesman et al (Greisman et al, 1963), where challenge with LPS after infection does not lead to the production of pro-inflammatory cytokines such as TNF-α in mouse cell lines or in vivo (Telepnev et al, 2003, 2005; Bosio et al, 2007). Human monocyte inflammatory responses differ between virulent and attenuated Francisella infection
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