BpOmpW Antigen Stimulates the Necessary Protective T-Cell Responses Against Melioidosis.

Julen Tomás-Cortázar,Eve Mcmahon,Siobhán Mcclean,Susanna J Dunachie,Maitiú Ó Murchú,Daniel Altmann,Patpong Rongkard,Alfonso Blanco,Conor Quinn,Catherine J Reynolds,Niamh Corcoran,Mahavir Singh,Rosemary J Boyton,Severine Giltaire,Juan Anguita,Lorenzo Bossi,Johan Arnold,David K Butler

doi:10.3389/fimmu.2021.767359

Abstract

Melioidosis is a potentially fatal bacterial disease caused by Burkholderia pseudomallei and is estimated to cause 89,000 deaths per year in endemic areas of Southeast Asia and Northern Australia. People with diabetes mellitus are most at risk of melioidosis, with a 12-fold increased susceptibility for severe disease. Interferon gamma (IFN-γ) responses from CD4 and CD8 T cells, but also from natural killer (NK) and natural killer T (NKT) cells, are necessary to eliminate the pathogen. We previously reported that immunization with B. pseudomallei OmpW (BpOmpW antigen) protected mice from lethal B. pseudomallei challenge for up to 81 days. Elucidating the immune correlates of protection of the protective BpOmpW vaccine is an essential step prior to clinical trials. Thus, we immunized either non-insulin-resistant C57BL/6J mice or an insulin-resistant C57BL/6J mouse model of type 2 diabetes (T2D) with a single dose of BpOmpW. BpOmpW induced strong antibody responses, stimulated effector CD4+ and CD8+ T cells and CD4+ CD25+ Foxp3+ regulatory T cells, and produced higher IFN-γ responses in CD4+, CD8+, NK, and NKT cells in non-insulin-resistant mice. The T-cell responses of insulin-resistant mice to BpOmpW were comparable to those of non-insulin-resistant mice. In addition, as a precursor to its evaluation in human studies, humanized HLA-DR and HLA-DQ (human leukocyte antigen DR and DQ isotypes, respectively) transgenic mice elicited IFN-γ recall responses in an enzyme-linked immune absorbent spot (ELISpot)-based study. Moreover, human donor peripheral blood mononuclear cells (PBMCs) exposed to BpOmpW for 7 days showed T-cell proliferation. Finally, plasma from melioidosis survivors with diabetes recognized our BpOmpW vaccine antigen. Overall, the range of approaches used strongly indicated that BpOmpW elicits the necessary immune responses to combat melioidosis and bring this vaccine closer to clinical trials.

Highlights

Melioidosis is a potentially fatal tropical infection caused by the Gram-negative facultative intracellular bacillus Burkholderia pseudomallei
Given that T-cell effector functions, especially Interferon gamma (IFN-g) responses, correlate with survival in acute melioidosis patients [16], we examined the T-cell responses associated with BpOmpW immunization
Activation of BpOmpW-re-stimulated splenocytes was demonstrated by a significant decrease in CD45RB expression (p < 0.0001; Figure 1B), while the levels of CD25 and CD44 were significantly increased in response to BpOmpW re-exposure in both CD4+ and CD8+ T cells when compared to splenocytes from Sigma Adjuvant System (SAS) control mice (p < 0.0001; Figures 1C–F)

Summary

Introduction

Melioidosis is a potentially fatal tropical infection caused by the Gram-negative facultative intracellular bacillus Burkholderia pseudomallei. Melioidosis is endemic in Southeast Asia and Northern Australia, but increasingly emerging throughout the tropics. The case fatality rates vary from 35% to 42% in Thailand [6] to 26% recorded in Australia [7]. Individuals with diabetes mellitus (DM) have a 12-fold increased susceptibility to melioidosis and experience more severe disease [5]. DM affects over 450 million people worldwide [8], of which 90% are considered to have type 2 diabetes (T2D) [9], and more than 50% of these individuals live in melioidosis endemic regions in Southeast Asia and Northern Australia [1]. There is no licensed vaccine available to protect people in endemic regions from melioidosis, including those with T2D

Methods

Results

Conclusion