Granzyme A in Chikungunya and Other Arboviral Infections

Soares‐Schanoski, Alessandra; Le, Thuy T.; Kaiserman, Dion; Rowe, Caitlin; Prow, Natalie A.; Barboza, Diego Damasco; Santos, Cliomar Alves dos; Zanotto, Paolo M. A.; Magalhães, Kelly Grace; Aurelio, Luigi; Muller, David A.; Young, Paul R.; Zhao, Peishen; Bird, Phillip I.; Suhrbier, Andreas

doi:10.3389/fimmu.2019.03083

Cited by 33 publications

(61 citation statements)

References 114 publications

(167 reference statements)

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“…This result contradicts previous findings that showed that human inactive GzmA was not able to induce the production of inflammatory cytokines in human monocytes (17). In addition, it has been shown that the inflammatory activity of mouse GzmA in vivo is significantly affected when GzmA inactivated with an inhibitor is used (48). The reasons for this discrepancy are not clear yet and will require further investigation.…”

Section: Regulation Of Inflammatory Cytokine Network and Cytokine Stormcontrasting

confidence: 86%

“…Thus, it is not clear yet if PAR2 is activated by GzmA and the role of PAR2 in GzmAmediated cytokine induction. A recent study found that a PAR-2 inhibitor (I-343) inhibited foot swelling induced by in vivo administration of GzmA (48). This result suggests that PAR-2 could be directly or indirectly involved in some of the biological functions of GzmA, but its specific role in the regulation of GzmA-mediated inflammatory cytokine production will require further experimental validation.…”

Section: Endothelial Barrier Permeability: Any Role For Protease Actimentioning

confidence: 99%

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The Multifaceted Function of Granzymes in Sepsis: Some Facts and a Lot to Discover

et al. 2020

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Sepsis is a serious global health problem. In addition to a high incidence, this syndrome has a high mortality and is responsible for huge health expenditure. The pathophysiology of sepsis is very complex and it is not well-understood yet. However, it is widely accepted that the initial phase of sepsis is characterized by a hyperinflammatory response while the late phase is characterized by immunosuppression and immune anergy, increasing the risk of secondary infections. Granzymes (Gzms) are a family of serine proteases classified according to their cleavage specificity. Traditionally, it was assumed that all Gzms acted as cytotoxic proteases. However, recent evidence suggests that GzmB is the one with the greatest cytotoxic capacity, while the cytotoxicity of others such as GzmA and GzmK is not clear. Recent studies have found that GzmA, GzmB, GzmK, and GzmM act as pro-inflammatory mediators. Specially, solid evidences show that GzmA and GzmK function as extracellular proteases that regulate the inflammatory response irrespectively of its ability to induce cell death. Indeed, studies in animal models indicate that GzmA is involved in the cytokine release syndrome characteristic of sepsis. Moreover, the GZM family also could regulate other biological processes involved in sepsis pathophysiology like the coagulation cascade, platelet function, endothelial barrier permeability, and, in addition, could be involved in the immunosuppressive stage of sepsis. In this review, we provide a comprehensive overview on the contribution of these novel functions of Gzms to sepsis and the new therapeutic opportunities emerging from targeting these proteases for the treatment of this serious health problem.

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Section: Regulation Of Inflammatory Cytokine Network and Cytokine Stormcontrasting

confidence: 86%

Section: Endothelial Barrier Permeability: Any Role For Protease Actimentioning

confidence: 99%

The Multifaceted Function of Granzymes in Sepsis: Some Facts and a Lot to Discover

et al. 2020

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“…In addition, in our system, active or inactive GzmA did not potentiate the effect of LPS. Other studies employing inhibitors or enzymatically inactive mutants have also found that enzyme activity is required for the inflammatory action of mouse and human GzmA 16 , 50 . While the reasons for these apparently contradictory results are not known, it cannot be ruled out that both active and inactive forms of GzmA act as proinflammatory mediators in the plasma of septic patients.…”

Section: Discussionmentioning

confidence: 97%

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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“…Limitations include the inconsistent penetrance of overt liver lesions, as well as no elevation in bilirubin levels and high variability in elevated serum AST levels (although the latter does recapitulate the variability seen in human YFV infections). As illustrated herein, the model can be used to assess vaccine efficacy, but it may also find utility for other studies involving, for instance, fetal infection/development [ 48 , 49 ], immunopathology [ 50 ] and/or tropism [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

A Yellow Fever Virus 17D Infection and Disease Mouse Model Used to Evaluate a Chimeric Binjari-Yellow Fever Virus Vaccine

et al. 2020

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Despite the availability of an effective, live attenuated yellow fever virus (YFV) vaccine (YFV 17D), this flavivirus still causes up to ≈60,000 deaths annually. A number of new approaches are seeking to address vaccine supply issues and improve safety for the immunocompromised vaccine recipients. Herein we describe an adult female IFNAR-/- mouse model of YFV 17D infection and disease that recapitulates many features of infection and disease in humans. We used this model to evaluate a new YFV vaccine that is based on a recently described chimeric Binjari virus (BinJV) vaccine technology. BinJV is an insect-specific flavivirus and the chimeric YFV vaccine (BinJ/YFV-prME) was generated by replacing the prME genes of BinJV with the prME genes of YFV 17D. Such BinJV chimeras retain their ability to replicate to high titers in C6/36 mosquito cells (allowing vaccine production), but are unable to replicate in vertebrate cells. Vaccination with adjuvanted BinJ/YFV-prME induced neutralizing antibodies and protected mice against infection, weight loss and liver pathology after YFV 17D challenge.

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Granzyme A in Chikungunya and Other Arboviral Infections

Cited by 33 publications

References 114 publications

The Multifaceted Function of Granzymes in Sepsis: Some Facts and a Lot to Discover

The Multifaceted Function of Granzymes in Sepsis: Some Facts and a Lot to Discover

Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis

A Yellow Fever Virus 17D Infection and Disease Mouse Model Used to Evaluate a Chimeric Binjari-Yellow Fever Virus Vaccine

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