Burkholderia pseudomalleiProteins Presented by Monocyte-Derived Dendritic Cells Stimulate Human Memory T CellsIn Vitro

Abstract

Melioidosis is a severe infectious disease caused by the saprophytic facultative intracellular pathogen Burkholderia pseudomallei. The disease is endemic in Southeast Asia and Northern Australia, and no effective vaccine exists. To describe human cell-mediated immune responses to B. pseudomallei and to identify candidate antigens for vaccine development, the ability of antigen-pulsed monocyte-derived dendritic cells (moDCs) to trigger autologous T-cell responses to B. pseudomallei and its products was tested. moDCs were prepared from healthy individuals exposed or not exposed to B. pseudomallei, based on serological evidence. These were pulsed with heat-killed B. pseudomallei or purified antigens, including ABC transporters (LolC, OppA, and PotF), Bsa type III secreted proteins (BipD and BopE), tandem repeat sequence-containing proteins (Rp1 and Rp2), flagellin, and heat shock proteins (Hsp60 and Hsp70), prior to being mixed with autologous T-cell populations. After pulsing of cells with either heat-killed B. pseudomallei, LolC, or Rp2, coculturing the antigen-pulsed moDCs with T cells elicited gamma interferon production from CD4 ؉ T cells from seropositive donors at levels greater than those for seronegative donors. These antigens also induced granzyme B (cytotoxic) responses from CD8 ؉ T cells. Activation of antigen-specific CD4 ؉ T cells required direct contact with moDCs and was therefore not dependent on soluble mediators. Rp peptide epitopes recognized by T cells in healthy individuals were identified. Our study provides valuable novel data on the induction of human cell-mediated immune responses to B. pseudomallei and its protein antigens that may be exploited in the rational development of vaccines to combat melioidosis.

Evaluation of a biodegradable microparticulate polymer as a carrier for Burkholderia pseudomallei subunit vaccines in a mouse model of melioidosis

“…However, there is a strong correlation between resolution of clinical melioidosis and T cell response Healey et al;Ketheesan et al;Ramsay et al;Tippayawat et al, 2011). After vaccinating T cell depleted mice with an auxotrophic mutant, Haque et al demonstrated protective responses to B. pseudomallei that were CD4 + , but not CD8 + cell, dependent (Haque et al).…”

“…This feature is advantageous for a melioidosis vaccine because there is a strong correlation between the resolution of clinical melioidosis and T cell responses Healey et al;Ketheesan et al;Ramsay et al;Tippayawat et al, 2011), and it is highly likely that cytotoxic T lymphocytes (CTLs) will play an important role in generating a protective immune response (Bondi and Goldberg, 2008;Haque et al, 2006b). CD8 + T cells and natural killer (NK) cells control various pathogens by secreting effector cytokines and cytotolytic granules containing perforin and various granzymes that together disrupt cell membranes and incite apoptotic death (Lauw et al, 2000;Orange and Ballas, 2006;Smith et al, 2009).…”

A Burkholderia pseudomallei Outer Membrane Vesicle Vaccine Provides Protection against Lethal Sepsis

“…Moving forward, it may be prudent to evaluate vaccines with Th1-promoting adjuvants or to use mouse strains that are better capable of eliciting Th1 immune responses, such as C57BL/6 (43). It may also be necessary to enrich the OMV cargo with virulence determinants specific to the intracellular stage of infection (44,45) or with antigens that induce strong T cell responses (46)(47)(48). A number of studies have shown that expression and delivery of homologous and heterologous antigens with OMVs are feasible (45,49,50).…”

Migration of Dendritic Cells Facilitates Systemic Dissemination of Burkholderia pseudomallei

“…Despite significant maturation and IL-12 production in bone marrow-derived DC (BMDC) from B. pseudomallei-susceptible BALB/c mice, bactericidal activity against intracellular B. pseudomallei was lower than observed for BMDC from B. pseudomallei-resistant C57BL/6 mice (15). (16,(19)(20)(21)(22).…”