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

Expression of intra- and extracellular granzymes in patients with typhoid fever.
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de Jong HK, Garcia-Laorden MI, Hoogendijk AJ, Parry CM, Maude RR, Dondorp AM, Faiz MA, van der Poll T, Wiersinga WJ,


de Jong HK, Garcia-Laorden MI, Hoogendijk AJ, Parry CM, Maude RR, Dondorp AM, Faiz MA, van der Poll T, Wiersinga WJ, (click to view)

de Jong HK, Garcia-Laorden MI, Hoogendijk AJ, Parry CM, Maude RR, Dondorp AM, Faiz MA, van der Poll T, Wiersinga WJ,

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PLoS neglected tropical diseases 2017 07 2711(7) e0005823 doi 10.1371/journal.pntd.0005823
Abstract
BACKGROUND
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 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 FINDINGS
We 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.

CONCLUSION
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.

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