de Jong Hanna K, Garcia-Laorden Maria Isabel, Hoogendijk Arie J, Parry Christopher M, Maude Rapeephan R, Dondorp Arjen M, Faiz Mohammed Abul, van der Poll Tom, Wiersinga Willem Joost
Department of Internal Medicine, Division of Infectious Diseases and Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, the Netherlands.
Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
PLoS Negl Trop Dis. 2017 Jul 27;11(7):e0005823. doi: 10.1371/journal.pntd.0005823. eCollection 2017 Jul.
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.
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.
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.
由细胞内病原体肠炎沙门氏菌血清型伤寒杆菌引起的伤寒热，仍然是全球发病和死亡的主要原因。颗粒酶是丝氨酸蛋白酶，可通过诱导细胞死亡促进细胞毒性淋巴细胞介导的细胞内病原体清除，并且在炎症中也可发挥作用。我们旨在表征伤寒热患者细胞外和细胞内颗粒酶的表达情况，以及颗粒酶的细胞外水平是否与干扰素-γ释放相关。
我们分析了健康志愿者以及确诊为伤寒杆菌感染的患者入院时和出院当天细胞外颗粒酶A和B的可溶性蛋白水平，并研究了这是否与干扰素（IFN）-γ释放相关，干扰素-γ是伤寒热中显著表达的一种细胞因子。使用流式细胞术测定淋巴细胞亚群中颗粒酶A、B和K的细胞内表达。患者急性期血浆中细胞外颗粒酶A和B显著增加，且两种颗粒酶均与干扰素-γ释放相关。与入院时相比，患者出院当天血浆中颗粒酶B水平降低，但颗粒酶A水平未降低，这表明颗粒酶B与疾病阶段相关。与对照组相比，伤寒热患者外周血单核细胞中表达细胞内颗粒酶A和颗粒酶B但不表达颗粒酶K的淋巴细胞百分比更高。
伤寒热患者细胞外和细胞内颗粒酶表达水平显著增加，且与疾病阶段相关，这表明颗粒酶在宿主对该疾病的反应中发挥作用。
