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Open AccessArticle

Vaccine-Mediated Mechanisms Controlling Francisella tularensis SCHU S4 Growth in a Rat Co-Culture System

1
Department of Clinical Microbiology and Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, SE-901 85 Umeå, Sweden
2
MRIGlobal, Kansas City, MO 64110, USA
3
Department of Mathematics and Mathematical Statistics, Umeå University, SE-901 85 Umeå, Sweden
4
Center for Infectious Disease & Immunity, Department of Internal Medicine, The University of New Mexico Health Science Center, Albuquerque, NM 87131, USA
*
Author to whom correspondence should be addressed.
Pathogens 2020, 9(5), 338; https://doi.org/10.3390/pathogens9050338
Received: 7 April 2020 / Revised: 22 April 2020 / Accepted: 28 April 2020 / Published: 30 April 2020
Francisella tularensis causes the severe disease tularemia. In the present study, the aim was to identify correlates of protection in the rat co-culture model by investigating the immune responses using two vaccine candidates conferring distinct degrees of protection in rat and mouse models. The immune responses were characterized by use of splenocytes from naïve or Live vaccine strain- (LVS) or ∆clpB/wbtC-immunized Fischer 344 rats as effectors and bone marrow-derived macrophages infected with the highly virulent strain SCHU S4. A complex immune response was elicited, resulting in cytokine secretion, nitric oxide production, and efficient control of the intracellular bacterial growth. Addition of LVS-immune splenocytes elicited a significantly better control of bacterial growth than ∆clpB/wbtC splenocytes. This mirrored the efficacy of the vaccine candidates in the rat model. Lower levels of IFN-γ, TNF, fractalkine, IL-2, and nitrite were present in the co-cultures with ∆clpB/wbtC splenocytes than in those with splenocytes from LVS-immunized rats. Nitric oxide was found to be a correlate of protection, since the levels inversely correlated to the degree of protection and inhibition of nitric oxide production completely reversed the growth inhibition of SCHU S4. Overall, the results demonstrate that the co-culture assay with rat-derived cells is a suitable model to identify correlates of protection against highly virulent strains of F. tularensis View Full-Text
Keywords: Francisella tularensis; SCHU S4; in vitro co-culture model; rat immune response; correlates of protection; nitrite Francisella tularensis; SCHU S4; in vitro co-culture model; rat immune response; correlates of protection; nitrite
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Lindgren, H.; Eneslätt, K.; Golovliov, I.; Gelhaus, C.; Rydén, P.; Wu, T.; Sjöstedt, A. Vaccine-Mediated Mechanisms Controlling Francisella tularensis SCHU S4 Growth in a Rat Co-Culture System. Pathogens 2020, 9, 338.

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