Interrelationship between Dendritic Cell Trafficking and Francisella tularensis Dissemination following Airway Infection

Abstract

Francisella tularensis, the etiological agent of the inhalation tularemia, multiplies in a variety of cultured mammalian cells. Nevertheless, evidence for its in vivo intracellular residence is less conclusive. Dendritic cells (DC) that are adapted for engulfing bacteria and migration towards lymphatic organs could serve as potential targets for bacterial residence and trafficking. Here, we focus on the in vivo interactions of F. tularensis with DC following airway infection of mice. Lethal airway infection of mice with the live vaccine strain (LVS) results in trafficking of a CD11bhigh/CD11cmed/autofluorescencelow DC subset from the respiratory tract to the draining mediastinal lymph node (MdLN). Simultaneously, a rapid, massive bacterial colonization of the MdLN occurs, characterized by large bacterial foci formation. Analysis of bacteria in the MdLN revealed a major population of extracellular bacteria, which co-exists with a substantial fraction of intracellular bacteria. The intracellular bacteria are viable and reside in cells sorted for DC marker expression. Moreover, in vivo vital staining experiments indicate that most of these intracellular bacteria (∼75%) reside in cells that have migrated from the airways to the MdLN after infection. The correlation between DC and bacteria accumulation in the MdLN was further demonstrated by manipulating DC migration to the MdLN through two independent pathways. Impairment of DC migration to the MdLN, either by a sphingosine-1-phosphate receptor agonist (FTY720) or by the D prostanoid receptor 1 agonist (BW245C), resulted in reduced bacterial colonization of MdLN. Moreover, BW245C treatment delayed the onset of morbidity and the time to death of the infected mice. Taken together, these results suggest that DC can serve as an inhabitation niche for F. tularensis in the early stages of infection, and that DC trafficking plays a role in pathogen dissemination. This underscores the therapeutic potential of DC migration impairing drugs in tularemia treatment.

Migration of Dendritic Cells Facilitates Systemic Dissemination of Burkholderia pseudomallei

“…Cytoskeleton rearrangement is impaired in DC infected with Y. pestis, rendering them unable to adhere to surfaces and migrate toward CCL19 (23). Alternatively, other intracellular pathogens, such as Listeria monocytogenes, Francisella tularensis, and Streptococcus pneumoniae, use DC migration as a "Trojan horse" to facilitate dissemination (24)(25)(26). Blocking of DC migration or depletion of DC correlated with enhanced capacity to restrict systemic dissemination, significantly reduced bacterial loads, and improved resistance to F. tularensis and S. pneumoniae infection (25,26).…”

“…Alternatively, other intracellular pathogens, such as Listeria monocytogenes, Francisella tularensis, and Streptococcus pneumoniae, use DC migration as a "Trojan horse" to facilitate dissemination (24)(25)(26). Blocking of DC migration or depletion of DC correlated with enhanced capacity to restrict systemic dissemination, significantly reduced bacterial loads, and improved resistance to F. tularensis and S. pneumoniae infection (25,26). DC migration has also been shown to facilitate the rapid dissemination of Bacillus anthracis spores from the lungs to the thoracic lymph nodes (using transgenic mice developed to specifically express green fluorescent protein [GFP] in DC only (27,28).…”

The Presence of CD14 Overcomes Evasion of Innate Immune Responses by VirulentFrancisella tularensisin Human Dendritic Cells In Vitro and Pulmonary Cells In Vivo

“…Alveolar macrophages and airway DC are the primary targets of Francisella infection following inhalation of the bacterium during the first few days of infection, and these cells have both functional and phenotypic properties that are similar to those of human dendritic cells derived from peripheral blood (5,11,12,28,29,36,56). Therefore, as observed above in human dendritic cells (Fig.…”

In VivoMechanisms Involved in Enhanced Protection Utilizing an Fc Receptor-Targeted Mucosal Vaccine Platform in a Bacterial Vaccine and Challenge Model

“…ϩ DCs were found to be recruited in areas of high CCL-19 and CCL-21 chemokine concentrations (29,30). Whether the levels of these chemokines are increased significantly in the lungs of IC-immunized mice over mice administered with iFT alone, essentially recruiting mature DCs from peripheral sites, remains to be addressed.…”