Expression of intra- and extracellular granzymes in patients with typhoid fever.

Hanna K De Jong,Rapeephan R Maude,Mohammed Abul Faiz,Christopher M Parry,Arie J Hoogendijk,Tom Van Der Poll,Willem Joost Wiersinga,Maria Isabel Garcia-Laorden,Arjen M Dondorp

doi:10.1371/journal.pntd.0005823

Abstract

BackgroundTyphoid fever, caused by the intracellular pathogen Salmonella (S.) enterica serovar Typhi, remains a major cause of morbidity and mortality worldwide. Granzymes are serine proteases promoting cytotoxic lymphocytes mediated eradication of intracellular pathogens via the induction of cell death and which can also play a role in inflammation. We aimed to characterize the expression of extracellular and intracellular granzymes in patients with typhoid fever and whether the extracellular levels of granzyme correlated with IFN-γ release.Methods and principal findingsWe analyzed soluble protein levels of extracellular granzyme A and B in healthy volunteers and patients with confirmed S. Typhi infection on admission and day of discharge, and investigated whether this correlated with interferon (IFN)-γ release, a cytokine significantly expressed in typhoid fever. The intracellular expression of granzyme A, B and K in subsets of lymphocytic cells was determined using flow cytometry. Patients demonstrated a marked increase of extracellular granzyme A and B in acute phase plasma and a correlation of both granzymes with IFN-γ release. In patients, lower plasma levels of granzyme B, but not granzyme A, were found at day of discharge compared to admission, indicating an association of granzyme B with stage of disease. Peripheral blood mononuclear cells of typhoid fever patients had a higher percentage of lymphocytic cells expressing intracellular granzyme A and granzyme B, but not granzyme K, compared to controls.ConclusionThe marked increase observed in extra- and intracellular levels of granzyme expression in patients with typhoid fever, and the correlation with stage of disease, suggests a role for granzymes in the host response to this disease.

Highlights

Typhoid fever, caused by the intracellular and human-specific Gram-negative bacterium Salmonella (S.) enterica serovar Typhi, remains an important cause of illness and death in many parts of the world
The marked increase observed in extra- and intracellular levels of granzyme expression in patients with typhoid fever, and the correlation with stage of disease, suggests a role for granzymes in the host response to this disease
While the total white blood cell count (WBC) did not differ between patients and controls, there was a significant shift towards a higher neutrophil and lower lymphocyte count in typhoid fever patients, which is a characteristic clinical feature for this disease [17]

Summary

Introduction

Typhoid fever, caused by the intracellular and human-specific Gram-negative bacterium Salmonella (S.) enterica serovar Typhi, remains an important cause of illness and death in many parts of the world. Typhi-infected cells by specific CD8+ T cells is executed through a Fas-independent, but granule-dependent mechanism, which suggests a role for granzymes in the containment of S. The classic role of granzymes is to promote cytotoxic lymphocytes-mediated eradication of infected, neoplastic, or foreign cells via the induction of cell death. Typhoid fever, caused by the intracellular pathogen Salmonella (S.) enterica serovar Typhi, remains a major cause of morbidity and mortality worldwide. Granzymes are serine proteases promoting cytotoxic lymphocytes mediated eradication of intracellular pathogens via the induction of cell death and which can play a role in inflammation. We aimed to characterize the expression of extracellular and intracellular granzymes in patients with typhoid fever and whether the extracellular levels of granzyme correlated with IFN-γ release

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