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

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. © 2017 de jong et al.