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

Jong, Hanna K. de; García‐Laorden, M. Isabel; Hoogendijk, Arie J.; Parry, Christopher M.; Maude, Rapeephan R.; Dondorp, Arjen M.; Faiz, M. Abul; Poll, Tom van der; Wiersinga, W. Joost

doi:10.1371/journal.pntd.0005823

Cited by 19 publications

(22 citation statements)

References 21 publications

(44 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 41 - 43 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

Garzón-Tituaña¹,

Sierra-Monzón²,

Comas³

et al. 2021

Theranostics

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Aims: Peritonitis is one of the most common causes of sepsis, a serious syndrome characterized by a dysregulated systemic inflammatory response. Recent evidence suggests that Granzyme A (GzmA), a serine protease mainly expressed by NK and T cells, could act as a proinflammatory mediator and could play an important role in the pathogenesis of sepsis. This work aims to analyze the role and the therapeutic potential of GzmA in the pathogenesis of peritoneal sepsis. Methods: The level of extracellular GzmA as well as GzmA activity were analyzed in serum from healthy volunteers and patients with confirmed peritonitis and were correlated with the Sequential Organ Failure Assessment (SOFA) score. Peritonitis was induced in C57Bl/6 (WT) and GzmA -/- mice by cecal ligation and puncture (CLP). Mice were treated intraperitoneally with antibiotics alone or in combination serpinb6b, a specific GzmA inhibitor, for 5 days. Mouse survival was monitored during 14 days, levels of some proinflammatory cytokines were measured in serum and bacterial load and diversity was analyzed in blood and spleen at different times. Results: Clinically, 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 and GzmA did not affect bacterial replication in macrophages in vitro, indicating that GzmA has no role in bacterial control. Analysis of GzmA in lymphoid cells following CLP showed that it was mainly expressed by NK cells. 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. Conclusions: Our findings implicate GzmA as a key regulator of the inflammatory response during abdominal sepsis and provide solid evidences about its therapeutic potential for the treatment of this severe pathology.

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Section: Discussionsupporting

confidence: 88%

Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis

Garzón-Tituaña¹,

Sierra-Monzón²,

Comas³

et al. 2021

Theranostics

View full text Add to dashboard Cite

show abstract

“…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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“…Salmonella typhi causes typhoid fever, an acute, febrile, enteric disease, which continues to be important in many parts of the world. 91 Vivotif is another vaccine against gut pathogens and is administered by the oral route and is indicated for immunization against S. typhi for adults and children older than 6 years. This capsule vaccine should be administered in four doses to induce a broad immune response, mainly including serum IgG and IgA responses, mucosal antibodies, CD4 + T cells, and CD8 + cytotoxic T cells.…”

Section: Licensed Oral Vaccinesmentioning

confidence: 99%

Noninvasive vaccination against infectious diseases

Zheng

Díaz-Arévalo

Guan

et al. 2018

Human Vaccines & Immunotherapeutics

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The development of a successful vaccine, which should elicit a combination of humoral and cellular responses to control or prevent infections, is the first step in protecting against infectious diseases. A vaccine may protect against bacterial, fungal, parasitic, or viral infections in animal models, but to be effective in humans there are some issues that should be considered, such as the adjuvant, the route of vaccination, and the antigen-carrier system. While almost all licensed vaccines are injected such that inoculation is by far the most commonly used method, injection has several potential disadvantages, including pain, cross contamination, needlestick injury, under- or overdosing, and increased cost. It is also problematic for patients from rural areas of developing countries, who must travel to a hospital for vaccine administration. Noninvasive immunizations, including oral, intranasal, and transcutaneous administration of vaccines, can reduce or eliminate pain, reduce the cost of vaccinations, and increase their safety. Several preclinical and clinical studies as well as experience with licensed vaccines have demonstrated that noninvasive vaccine immunization activates cellular and humoral immunity, which protect against pathogen infections. Here we review the development of noninvasive immunization with vaccines based on live attenuated virus, recombinant adenovirus, inactivated virus, viral subunits, virus-like particles, DNA, RNA, and antigen expression in rice in preclinical and clinical studies. We predict that noninvasive vaccine administration will be more widely applied in the clinic in the near future.

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

Cited by 19 publications

References 21 publications

Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis

Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis

Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis

Noninvasive vaccination against infectious diseases

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