The type VI secretion system of Francisella tularensis – elucidation of its structure and assembly/disassembly control.
Type VI secretion systems (T6SSs) are virulence mechanisms used by many clinically relevant Gram-negative pathogens to establish eukaryotic host infections. How these sophisticated multicomponent systems are regulated and assembled is still not fully known. While most systems share a common set of so-called core components, several of these are lacking in the T6SS of Francisella tularensis (Ft). This highly virulent pathogen causes tularemia in humans and many animal species, and depend on its T6SS to invade and replicate within the host cell cytosol. With regard to Ft T6SS regulation, we have recently identified a critical, but yet not understood, role of the ClpB chaperone. The molecular details of these interactions within the model organism Francisella novicida as well as in the clinically important Ft subspecies, holarctica and tularensis, are under investigation. We are also investigating the composition and assembly of the Ft T6SS baseplate, the structure that connects the membrane complex with the syringe like tail complex, predicted to deliver toxins into host cells.
Development of a new tularemia vaccine
Francisella tularensis (Ft) is a highly virulent facultative intracellular bacterium that causes the severe disease tularemia in humans and many mammalian species. It can be disseminated by the aerosol route, has an extremely low infectious dose, and causes severe morbidity. Natural outbreaks of tularemia are occurring over the Northern hemisphere and a significant health problem, in particular in parts of Sweden and Finland. Here, more than 10,000 cases have been reported during the last 30 years; with a prominent increase during the last 10 years, e.g., > 1,000 cases in Sweden during autumn 2019. We have demonstrated that local incidences during years with outbreaks are very high, 400 - 1,000/100,000; numbers as high as those during influenza epidemics.
Thus, tularemia is a significant public health problem and protecting the population through vaccination would lead to considerable health gains. There is a live vaccine strain (LVS) empirically derived in the 1950’s, but it confers incomplete protection. We hypothesize that a more efficacious vaccine will be possible to develop, and our ongoing work is aimed to develop models that can identify the efficacy of new vaccines. We have so far generated a promising candidate vaccine, ∆clpB, which is highly attenuated and demonstrates better protective efficacy than does LVS. The overall aim of the ongoing work is to identify correlates of protection to validate the utility of this new vaccine, which in turn requires a comprehensive understanding of protective host immune responses.
The ongoing work Is based on state of the art in vitro methods and several co-culture models, including a human model, will be used to characterize the immune responses to F. tularensis. The work will be essential for the future licensing of an efficacious vaccine. The licensing of an efficacious vaccine will be important, since tularemia is a significant public health problem in areas in Sweden and Finland. Moreover, due to the low likelihood of re-exposure, tularemia offers a unique model for understanding the longevity of cellular immune response in general.