Mechanisms used by virulent Salmonella to impair dendritic cell function and evade adaptive immunity

Abstract

Innate and adaptive immunity are inter-related by dendritic cells (DCs), which directly recognize bacteria through the binding of pathogen-associated molecular patterns (PAMPs) to specialized receptors on their surface. After capturing and degrading bacteria, DCs present their antigens as small peptides bound to MHC molecules and prime naive bacteria-specific T cells. In response to PAMP recognition DCs undergo maturation, which is a phenotypic change that increases their immunogenicity and promotes the activation of naive T cells. As a result, a specific immune response that targets bacteria-derived antigens is initiated. Therefore, the characterization of DC-bacteria interactions is important to understand the mechanisms used by virulent bacteria to avoid adaptive immunity. Furthermore, any impairment of DC function might contribute to bacterial survival and dissemination inside the host. An example of a bacterial pathogen capable of interfering with DC function is Salmonella enterica serovar Typhimurium (S. Typhimurium). Virulent strains of this bacterium are able to differentially modulate the entrance to DCs, avoid lysosomal degradation and prevent antigen presentation on MHC molecules. These features of virulent S. Typhimurium are controlled by virulence proteins, which are encoded by pathogenicity islands. Modulation of DC functions by these gene products is supported by several studies showing that pathogenesis might depend on this attribute of virulent S. Typhimurium. Here we discuss some of the recent data reported by the literature showing that several virulence proteins from Salmonella are required to modulate DC function and the activation of host adaptive immunity.

Figure 1

Lamina propria invasion and inflammatory immune response during Salmonella enterica Typhimurium infection. (a) Once Salmonella arrives at the lamina propria (LP), it can traverse cell intestinal layers and cause cytokine secretion and immune cells recruitment. Intestinal dendritic cells (DCs) can sample the pathogen, so enhancing the inflammatory environment by Toll-like receptor (TLR) activation after pathogen-associated molecular pattern (PAMP) recognition. Different types of cells, such as granulocytes and macrophages, can reach the site of infection increasing both the infiltrate and the acute gastroenteritis. (b) Salmonella pathogenicity island 1 (SPI-1) -derived proteins responsible for epithelial cell invasion during LP infection. After Salmonella recognize epithelial cell surface, SPI-1-encoded proteins are expressed and injected into host cells. Virulence effectors such as SipA, SopE, SopE2 and SopB are responsible for reorganizing actin cytoskeleton, promoting bacterial engulfment. Other SPI-1-secreted factors, such as SptP, decrease this process avoiding host cell death by excessive intracellular bacterial load. Proteins, such as flagellin and PrgJ can also be translocated into the host cell cytosol where they activate nucleotide oligomerization domain-like receptor (NLR)-containing inflammasomes to promote the secretion of inflammatory cytokines, including interleukin-1β (IL-1β) and IL-18.

Figure 2

Fcγ receptor-mediated enhancement of T-cell priming by dendritic cells (DCs) after recognition and degradation of Salmonella-derived antigens. (a) After IgG opsonization, Salmonella can be recognized by FcγRIII expressed on the surface of DCs. Then, these cells are able to present bacterial-derived antigens MHC-I and MHC-II to CD8⁺ and CD4⁺ T cells, respectively. IgG opsonization can restore antigen presentation by DCs infected with Salmonella. (b) IgG-opsonized Salmonella engages FcγRIII on the surface of the DCs, triggering an intracellular class III phosphatidyl inositol 3 kniase (PI3K) -dependent degradation pathway, which enhances fusion of the Salmonella-containing vacuoles (SCV) with lysosomes (Lamp1⁺). SCV-containing IgG-coated bacteria are created after internalization of elevated numbers of Salmonella complexes in an FcγRs/class I PI3K/Actin/Class I and Class II and dynamin-independent mechanism. Internalization is driven by an unidentified receptor, which could recognize bacterial surface molecules unblocked by IgG-opsonization. Once inside the SCV, Salmonella still remain able to secrete Salmonella pathogenicity island 2 (SPI-2) -derived virulence determinants. As a result of IgG opsonization, antigen capture, degradation and presentation by DCs are significantly enhanced.