Discordance in the Effects ofYersinia pestison the Dendritic Cell Functions Manifested by Induction of Maturation and Paralysis of Migration

Abstract

The encounter between invading microorganisms and dendritic cells (DC) triggers a series of events which include uptake and degradation of the microorganism, induction of a maturation process, and enhancement of DC migration to the draining lymph nodes. Various pathogens have developed strategies to counteract these events as a measure to evade the host defense. In the present study we found that interaction of the Yersinia pestis EV76 strain with DC has no effect on cell viability and is characterized by compliance with effective maturation, which is manifested by surface display of major histocompatibility complex class II, of costimulatory markers, and of the chemokine receptor CCR7. This is in contrast to maturation inhibition and cell death induction exerted by the related species Yersinia enterocolitica WA O:8. Y. pestis interactions with DC were found, however, to impair functions related to cytoskeleton rearrangement. DC pulsed with Y. pestis failed to adhere to solid surfaces and to migrate toward the chemokine CCL19 in an in vitro transmembrane assay. Both effects were dependent on the presence of the pCD1 virulence plasmid and on a bacterial growth shift to 37°C prior to infection. Moreover, while instillation of a pCD1-cured Y. pestis strain into mouse airways triggered effective transport of alveolar DC to the mediastinal lymph node, instillation of Y. pestis harboring the plasmid failed to do so. Taken together, these results suggest that virulence plasmid-dependent impairment of DC migration is the major mechanism utilized by Y. pestis to subvert DC function.Dendritic cells (DC) play a key role at the interface of innate and adaptive immunity (1,36,49). Interactions between DC and bacterial pathogens are therefore important in determining the outcomes of the infectious processes.DC reside in peripheral epithelial tissues in an immature state, where they serve as sentinels for invading microorganisms. Contact with the microorganism triggers a series of programmed events which begin by pathogen internalization and a concomitant stimulation of pattern recognition receptors such as Toll-like receptors, which subsequently leads to conversion of the immature DC into mature DC. Maturation is marked by a reduction in phagocytic ability, an increase in surface expression of major histocompatibility complex (MHC) class II and costimulatory molecules, and production of proinflammatory cytokines. This occurs together with degradation of the pathogen within the phagosome and presentation of microbial antigens on MHC molecules. Maturation is also characterized by changes in the repertoire of chemokine receptor expression, including the up-regulation of CCR7, which facilitates migration to the local lymph node (20,59). This in turn allows DC to activate T cells in an MHC-specific manner and thus initiate an immune response, before undergoing apoptosis in the lymph node. (8,44).In spite of the differences in pathogenesis, certain mechanisms for evading the host innate immunity are shared by all three Yersinia sp...

Modulation of dendritic cell differentiation and function by YopJ of Yersinia pestis

“…While less is known about YopJ's effect on DC, YopP in Y. enterocolitica infection of fully differentiated DC has been implicated in mediating apoptosis (in murine DC), suppressing cytokine production, antigen presentation and immunostimulatory capacity [14,17,18]. In Y. pestis, YopJ appears to have less of a negative effect on the survival and immune function of differentiated murine DC, but rather has a marked effect on DC migration [19]. Our findings suggest that YopJ can also inhibit DC immunogenicity upstream of the mature DC, namely by disrupting signaling pathways during progenitor to DC differentiation.…”

“…An important caveat is that our studies were not designed to rigorously characterize YopJ-mediated apoptosis. Interestingly, however, it has been recently suggested that YopJmediated killing of DC is a much less prominent feature of Y. pestis than seen for Y. enterocolitica [19] or Y. pseudotuberculosis [9].…”

“…(e.g. Y. enterocolitica) also can impair DC function and induce DC apoptosis (in mice) [14,17,18], and it has been recently shown that Y. pestis inhibits cellular migration in fully differentiated murine DC [19].…”

TLR2 Utilization ofBorreliaDoes Not Induce p38- and IFN-β Autocrine Loop-Dependent Expression of CD38, Resulting in Poor Migration and Weak IL-12 Secretion of Dendritic Cells

“…CCR7 has long been thought to be the dominant mediator of DC migration. However, a study by Velan et al (36) showed that DCs pulsed with Yersinia pestis showed decreased migration toward CCL19 in an in vitro and an in vivo assay but still showed upregulated CCR7 expression. In a study on the role of CD47 in DC migration, CD47 2/2 DCs showed normal CCR7 expression but impaired migration to CCL19 in an vitro assay (37).…”

Gr1+Cells Control Growth of YopM-NegativeYersinia pestisduring Systemic Plague

“…There is evidence that Y. pestis selectively engages Ms, DCs, and PMNs for Yop injection through the T3SS (34), and the migration of DCs to draining lymph nodes is inhibited when the infecting Y. pestis strain contains the virulence plasmid carrying genes encoding Yops (63). We monitored the numbers of three major subgroups of DCs in mice infected by the parent or YopM Ϫ Y. pestis.…”