Evasion of Host Immunity by Virulent Salmonella: Implications for Vaccine Design

Abstract

Dendritic cells (DCs) are professional antigen presenting cells (APCs) capable of linking innate and adaptive immunity during infection. After recognition of pathogen-associated molecular patterns (PAMPs), DCs can engulf, process and present bacteria-derived antigens on MHC molecules to T cells. Because of the key role that DCs play on the initiation of innate and adaptive immunity, alterations in their function could render the host susceptible to bacterial dissemination. Consistent with this notion, is the observation that several pathogenic bacteria have evolved mechanisms to impair the DC capacity to prime naïve T cells. One of such bacteria is Salmonella enterica serovar Typhimurium, which causes a typhoid-like disease in mice and gastroenteritis in humans. Recent studies have shown that virulent Salmonella can use intestinal DCs to spread inside the host, evading T cell priming. The avoidance of T cell recognition by Salmonella is in large part achieved by the activity of gene products encoded on Salmonella Pathogenicity Islands -1 and - 2. The understanding of some of the remarkable molecular virulence mechanisms displayed by Salmonella has contributed to the design of new vaccines capable of inducing protective immunity against this pathogen in mouse models. Here we describe recent data underscoring the virulence mechanisms used by Salmonella to exploit DC function and discuss strategies based on this new knowledge aimed at the design of new efficient and safe vaccines against this pathogen.

IgG keeps virulent Salmonella from evading dendritic cell uptake

“…In support of this observation are recent studies describing how only partial extracellular engagement of FcγRIII or FcγRI in the surface of an antigen‐presenting cell is enough to trigger a strong intracellular degradative pathway, which renders host cells able to fuse early/late endosomes with lysosomal compartments 66 . Hence, this observation unifies our findings and suggests that superficial IgGs, being present in ICs, could be engaging FcγRIII in the surface of the DCs and triggering a strong degradative pathway that promotes the fusion of already internalized Salmonella ‐ICs (engulfed without the assistance of FcγRs) with lysosomes 24,45 . Interestingly, the degradation of ST‐IgG within DCs was characterized as a function of PI3K 24 .…”

“…This leads to reduced availability of the intracellular bacterial‐derived antigens necessary to produce T‐cell‐activating antigen‐loaded MHCs 43,44 . IgG‐opsonization of the pathogen before infection restores the capacity of DCs to prime antigen‐specific naive T cells 23,24,45 . However, little is known about how IgG‐opsonization could enhance bacterial degradation/antigen presentation.…”

“…43,44 IgG-opsonization of the pathogen before infection restores the capacity of DCs to prime antigen-specific naive T cells. 23,24,45 However, little is known about how IgG-opsonization could enhance bacterial degradation/antigen presentation. In a previous report, we have shown that for restoration of antigen presentation by DCs in the context of an infection with ST-IgG, the superficial expression of FccRIII (CD16) 24 is required so it is likely that this receptor could also be counteracting the evasion of phagocytosis displayed by S. Typhimurium in these cells.…”

Carbon monoxide decreases endosome–lysosome fusion and inhibits soluble antigen presentation by dendritic cells to T cells.

“…Here, we provide evidence that the interference in the fusion between late endosomes and lysosomes can be the cause for reduced presentation on class MHC‐II molecules. In agreement with these data, it has been previously shown that the accumulation of pathogens in Rab7 + vesicles decreases late phagosome‐to‐lysosome fusion, thus reducing the efficiency of antigen presentation and that decreased destination of pathogens to Lamp1 + compartments drastically decrease antigen presentation in both class I and class II MHCs because lysosomes have the full repertoire for MHCs and peptide mounting during endo/lysosomal trafficking mainly occurs in these late acidic vesicles .…”

New technologies in developing recombinant attenuated Salmonella vaccine vectors

“…Salmonella has evolved many mechanisms to contend with adverse environments imposed by the host and to suppress or modulate induction of immune responses mainly by SPI-2 effectors [176]. Although many mechanisms still need to be elucidated, much progress has been made to facilitate attenuated vaccine development.…”