Diabetes alters immune response patterns to acute melioidosis in humans.

Barbara Kronsteiner,Panjaporn Chaichana,Direk Limmathurotsakul,Manutsanun Sumonwiriya,Kemajitra Jenjaroen,Suchintana Chumseng,Prapit Teparrukkul,Fazle Rabbi Chowdhury,Nicholas P.J Day,Paul Klenerman,Susanna J Dunachie

doi:10.1002/eji.201848037

Abstract

Diabetes mellitus (DM) is a serious global health problem currently affecting over 450 million people worldwide. Defining its interaction with major global infections is an international public health priority. Melioidosis is caused by Burkholderia pseudomallei, an exemplar pathogen for studying intracellular bacterial infection in the context of DM due to the 12‐fold increased risk in this group. We characterized immune correlates of survival in peripheral blood of acute melioidosis patients with and without DM and highlight different immune response patterns. We demonstrate the importance of circulating NK cells and show that CX3CR1 expression on lymphocytes is a novel correlate of survival from acute melioidosis. Furthermore, excessive serum levels of IL‐15 and IL‐18BP contribute to poor outcome independent of DM comorbidity. CD8+ T cells and granzyme B expression in NK cells are important for survival of non‐DM patients, whereas high antibody titers against B. pseudomallei and double‐negative T cells are linked to survival of DM patients. Recall responses support a role of γδ T‐cell‐derived IFN‐γ in the establishment of protective immunity in the DM group. Defining the hallmarks of protection in people with DM is crucial for the design of new therapies and vaccines targeting this rapidly expanding risk group.

Highlights

Diabetes is a serious global health problem currently affecting over 450 million people worldwide [1] and causing an enormous economic burden [2]
We have demonstrated that acute melioidosis patients irrespective of diabetes mellitus (DM) status rely on NK cells for survival with CX3CR1 and granzyme B · indirect hemagglutination assay (IHA) (GzmB) being important in non-DM patients only
We demonstrate that acute melioidosis patients rely on NK cells for survival and excessive levels of proinflammatory cytokines IL-15 and biologically inactive IL-18 contribute to poor outcome independent of diabetes comorbidity (Fig. 6)

Summary

Introduction

Diabetes is a serious global health problem currently affecting over 450 million people worldwide [1] and causing an enormous economic burden [2]. An increased risk of infection and poorer outcomes in type 2 diabetes (T2D) is seen for intracellular pathogens, with a threefold increased risk of developing tuberculosis (TB) [3], and increased risk of death or treatment failure in TB [4]. The highest risk association by far (12-fold) for an infectious disease and diabetes is seen for melioidosis [9, 10], a neglected tropical disease caused by the Gram-negative facultative intracellular bacterium Burkholderia pseudomallei (BP). This soil-dwelling pathogen is prevalent in Southeast Asia and Northern Australia, and is a major cause of mortality in these regions [11]. Aside from diabetes mellitus (DM), melioidosis is associated with other risk factors including chronic renal and lung disease, alcohol consumption, and increasing age [13], posing a challenge for vaccine design and immunomodulatory therapeutics targeting these at-risk groups

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