Abstract
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
Highlights
The facultative intracellular bacterium, Francisella tularensis, is highly virulent and the etiological agent of tularemia, a potentially lethal disease in humans and many other mammals [1]
The results demonstrate that rats immunized with Live vaccine strain- (LVS) or ∆clpB/∆wbtC were partly protected against a challenge with SCHU S4 and that LVS conferred more efficacious protection than ∆clpB/∆wbtC
Investigations of vaccine-mediated protective mechanisms against F. tularensis require relevant animal models and this is even more so for tularemia vaccines than for studies of other vaccines, since human efficacy studies are unlikely to be of sufficient power in view of the relative rarity of the disease
Summary
The facultative intracellular bacterium, Francisella tularensis, is highly virulent and the etiological agent of tularemia, a potentially lethal disease in humans and many other mammals [1]. F. tularensis is classified as a Category A Select Agent, thereby being a potential biological weapon, since it can spread via aerosols, is extremely infectious, and cause disease with high morbidity. Natural outbreaks of tularemia may occur in many countries of the Northern hemisphere and are common and cause significant health problems in parts of Scandinavia, Eastern Europe, and Turkey, but rather uncommon elsewhere in the world. Subspecies tularensis (type A) and holarctica (type B) both cause human disease. Pathogens 2020, 9, 338 and only the former may give rise to potentially lethal disease, infection caused by subspecies holarctica, despite its lower virulence, may be serious. No licensed tularemia vaccine is available in the US or in Western Europe.
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