Innate Immune Recognition: Implications for the Interaction of Francisella tularensis with the Host Immune System

Abstract

The intracellular bacterial pathogen Francisella tularensis causes serious infectious disease in humans and animals. Moreover, F. tularensis, a highly infectious pathogen, poses a major concern for the public as a bacterium classified under Category A of bioterrorism agents. Unfortunately, research has so far failed to develop effective vaccines, due in part to the fact that the pathogenesis of intracellular bacteria is not fully understood and in part to gaps in our understanding of innate immune recognition processes leading to the induction of adaptive immune response. Recent evidence supports the concept that immune response to external stimuli in the form of bacteria is guided by the primary interaction of the bacterium with the host cell. Based on data from different Francisella models, we present here the basic paradigms of the emerging innate immune recognition concept. According to this concept, the type of cell and its receptor(s) that initially interact with the target constitute the first signaling window; the signals produced in the course of primary interaction of the target with a reacting cell act in a paracrine manner; and the innate immune recognition process as a whole consists in a series of signaling windows modulating adaptive immune response. Finally, the host, in the strict sense, is the interacting cell.

Contributions of TolC Orthologs to Francisella tularensis Schu S4 Multidrug Resistance, Modulation of Host Cell Responses, and Virulence

“…Once in the cytosol, F. tularensis replicates robustly, eventually triggering host cell death, which contributes to bacterial release, dissemination, and infection of additional host cells (9). Early during infection, F. tularensis actively downmodulates the host's proinflammatory responses (12)(13)(14)(15)(16)(17). In addition, F. tularensis actively dampens host programmed cell death responses during infection, presumably to preserve intracellular replicative niches (18)(19)(20)(21)(22)(23)(24).…”

A novel vaccine platform using glucan particles for induction of protective responses againstFrancisella tularensisand other pathogens

“…In contrast, LVS, having been used in many thousands of humans under Investigational New Drug status, seems to be effective for the prevention of respiratory tularaemia in humans , but has safety concerns associated with its use, and thus the LVS strain has yet to be approved by regulatory bodies. We hypothesized that subunit vaccines are most attractive due to their defined nature and thus good safety profiles, but that we needed to deliver promising candidate antigens in a manner that induced both humoral and cellular immune responses to achieve protection, as only a balanced humoral and cellular immune memory response, supported by innate immune mechanisms, protects against tularaemia (reviewed by Roberts et al and Krokova et al ). We therefore decided to employ the GP vaccine delivery platform described above to address this challenge .…”

“…This allowed us to identify seven proteins of interest: IgIC, FTT0071, FTT0289, FTT0438, FTT0814, FTT0890 and FTT1043. As IglC has been previously reported to induce partial protection in animals (reviewed by Roberts et al and Krokova et al ) this was also included, even though the IglC GP vaccine induced poor immune responses. However, consistent with our selection rationale, it did not perform well later, and was subsequently dropped.…”

Desarrollo y utilidad de las técnicas de ELISA y quimioluminiscencia para el diagnóstico de la tularemia humana

“…Además de los receptores TLRs, el mecanismo por el que los fagocitos reconocen a las bacterias está compuesto por diferentes receptores en función de las condiciones de opsonización de la bacteria 26,27 . Dentro de estos receptores, aquellos que participan en la fagocitosis no opsónica son menos conocidos, aunque se puede destacar el papel de los receptores de manosa de los macrófagos (un tipo de receptores de Lectina tipo C).…”

“…Dentro de estos receptores, aquellos que participan en la fagocitosis no opsónica son menos conocidos, aunque se puede destacar el papel de los receptores de manosa de los macrófagos (un tipo de receptores de Lectina tipo C). Por su parte, los receptores que intervienen en la fagocitosis opsónica son: receptores del sistema del complemento, concretamente CR3 (CD11b/CD18) en macrófagos y CR4 (CD11c/CD18) en células dendríticas, receptores scavenger A (SRA), receptores FC gamma (FCγR) y nucleolina 26,27 .…”