Increased intra- and extracellular granzyme expression in patients with tuberculosis

García‐Laorden, M. Isabel; Blok, Dana C.; Kager, Liesbeth M.; Hoogendijk, Arie J.; Mierlo, Gerard J. van; Lede, Ivar O.; Rahman, Waliur; Afroz, Rumana; Ghose, Aniruddha; Visser, Caroline E.; Zahed, Abu Shahed Md; Husain, Anwar; Alam, Khan Mashrequl; Barua, Pravat Chandra; Hassan, Mahtabuddin; Hossain, Ahmed; Tayab, Abu; Day, Nick; Dondorp, Arjen M.; Vos, Alex F. de; Poll, Tom van der

doi:10.1016/j.tube.2015.05.016

Cited by 12 publications

(19 citation statements)

References 27 publications

(39 reference statements)

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“…This suggestion is further supported by our results showing increased levels of extracellular GzmA in serum from patients with abdominal sepsis. Similar findings have been reported in other septic patients with human bacteraemia, tuberculosis and typhoid fever where high serum levels of GzmA have been detected (de Jong et al, 2017;Garcia-Laorden et al, 2015;Lauw et al, 2000) suggesting that this protease may have extracellular effects during other infectious diseases. But how does this protease regulate inflammation from the extracellular milieu?…”

Section: Discussionsupporting

confidence: 88%

Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis

Arias

Pardo

Garzón

et al. 2020

Preprint

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Sepsis is a serious syndrome characterised by a dysregulated systemic inflammatory response. Here we have analysed the role and the therapeutic potential of Granzyme A (GzmA) in the pathogenesis of peritoneal sepsis using the Cecal Ligation and Puncture (CLP) polymicrobial sepsis model and samples from humans undergoing abdominal sepsis.Elevated GzmA was observed in serum from patients with abdominal sepsis suggesting that GzmA plays an important role in this pathology. In the CLP model GzmA deficient mice, or WT mice treated with an extracellular GzmA inhibitor, showed increased survival, which correlated with a reduction in proinflammatory markers in both serum and peritoneal lavage fluid. GzmA deficiency did not influence bacterial load in blood and spleen indicating that GzmA has no role in bacterial control.Mechanistically, we found that extracellular active GzmA acts as a proinflammatory mediator in macrophages by inducing the TLR4-dependent expression of IL-6 and TNFα.Our findings implicate GzmA as a key regulator of the inflammatory response during abdominal sepsis, and suggest that it could be targeted for treatment of this severe pathology.

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Section: Discussionsupporting

confidence: 88%

Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis

Arias

Pardo

Garzón

et al. 2020

Preprint

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“…The expression of granzyme A, B and K in different lymphocyte populations in PBMCs, as well as the serum levels of granzyme A and B in patients with active PTB and healthy individuals, have been reported (12). TB patients had a slightly increased expression of granzyme B in CD8 + T cells, CD4 + T cells, but not in D56 + T cells, NK cells compared to controls (no statistical significance) (12,22). Our study showed a similar result that a slight increase in the expression of granzyme B in CD8 + T cells from TB patients compared with the healthy controls, but there is no statistical significance.…”

Section: Discussionmentioning

confidence: 99%

“…Granzymes are a family of serine proteases found in granules of cytotoxic lymphocytes. In humans, five different granzymes (A, B, H, K, and M) have been identified, of which the expression are generally restricted to cells of the lymphoid lineage (12). Granzyme A and granzyme B are the predominant and well-studied of all the granzymes (13).…”

Section: Introductionmentioning

confidence: 99%

Decreased expression of perforin in CD8+ T lymphocytes in patients with Mycobacterium tuberculosis infection and its potential value as a marker for efficacy of treatment

et al. 2017

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“…Lymphocytes were gated in the forward scatter versus side scatter dot plot. Cells were selected as CD3 + or CD56 + , or as CD3 + CD4 + (CD4 + T cells), CD3 + CD8 + (CD8 + T cells), CD3 + CD56 + (CD56 + T cells) and CD3 − CD56 + (NK cells), and expression of granzymes was analyzed in these populations as described previously [ 14 ]. The results are expressed as percentage of cells of the specific lymphocyte population expressing the corresponding granzyme and as the median fluorescence intensity (MFI).…”

Section: Methodsmentioning

confidence: 99%

“…Elevated levels of granzyme B are a characteristic feature of various chronic inflammatory diseases and are thought to reflect a state of hyper-inflammation [ 10 , 12 ]. Furthermore, it has been shown that granzymes are elevated in patients with malaria, endotoxemia, sepsis and tuberculosis [ 8 , 12 – 14 ]. However, the expression of intra- and extracellular granzymes in patients with S .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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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.

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Increased intra- and extracellular granzyme expression in patients with tuberculosis

Cited by 12 publications

References 27 publications

Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis

Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis

Decreased expression of perforin in CD8+ T lymphocytes in patients with Mycobacterium tuberculosis infection and its potential value as a marker for efficacy of treatment

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

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