Protease-activated receptor 4 protects mice from Coxsackievirus B3 and H1N1 influenza A virus infection

Tatsumi, Kohei; Schmedes, Clare M.; Houston, E. Reaves; Butler, Emily; Mackman, Nigel; Antoniak, Silvio

doi:10.1016/j.cellimm.2019.103949

Cited by 24 publications

(39 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To investigate if PAR1 affects mortality after IAV infection, all mouse strains were infected with an IAV dose (0.02 HAU) that leads to ~ 20% mortality in control mice. 15,31,33 Mice with a global deficiency of PAR1 did not exhibit a change in weight loss but exhibited a significant increase in mortality after IAV infection compared with infected control mice ( Figure 7A Figure 7C-J). Similarly, mice expressing mutant versions of PAR1 (R41Q or R46Q) exhibited similar weight loss and survival after IAV infection compared with control mice (Figure 7K,L).…”

Section: Effect Of Par1 On Survival After Iav Infectionmentioning

confidence: 99%

“…Total white blood cell (WBC), neutrophil, lymphocyte, and monocyte numbers were determined with a Hemavet 950 (Drew Scientific). 15,31,33 To obtain cytospins from BALF cells, 50 µl of resuspended BALF cells was spun onto poly-D-lysine-coated microscope slides (Thermo Fisher Scientific) using a StatSpin CytoFuge (HemoCue America). Cells were stained with Wright-Giemsa stain (Fisher Scientific).…”

Section: Measurement Of Cell Countsmentioning

confidence: 99%

“…Activation of these receptors leads to a variety of cellular responses 9 . Importantly, there is crosstalk between PARs and TLRs 10‐15 . Polyinosinic:polycytidylic acid (poly I:C) is a dsRNA mimetic that is used to activate TLR3.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

PAR1 regulation of CXCL1 expression and neutrophil recruitment to the lung in mice infected with influenza A virus

Antoniak

Tatsumi²,

Schmedes³

et al. 2021

Journal of Thrombosis and Haemostasis

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Effect Of Par1 On Survival After Iav Infectionmentioning

confidence: 99%

Section: Measurement Of Cell Countsmentioning

confidence: 99%

See 1 more Smart Citation

PAR1 regulation of CXCL1 expression and neutrophil recruitment to the lung in mice infected with influenza A virus

Antoniak

Tatsumi²,

Schmedes³

et al. 2021

Journal of Thrombosis and Haemostasis

Self Cite

View full text Add to dashboard Cite

show abstract

“…PAR-4 antagonism by treatment with pepducin p4pal-10 protected mice from death in H1N1 and H3N2 infection (Lê et al, 2015). A recent study observed more lung injury and lethality by a more pronounced cytokine immune response in the lung of PAR-4-deficient mice infected with IAV H1N1 (Tatsumi et al, 2019). An additional approach to stop coagulation in IAV infection is the direct inhibition of thrombin by anti-thrombin III (AT, serine protease inhibitor).…”

Section: P Otential Ther Apeuti C Targ E Ts or Tre Atments In Acutementioning

confidence: 99%

Endothelial–platelet interactions in influenza‐induced pneumonia: A potential therapeutic target

Rommel

Milde

Eberle

et al. 2019

Anat Histol Embryol

View full text Add to dashboard Cite

Every year, influenza viruses spread around the world, infecting the respiratory systems of countless humans and animals, causing illness and even death. Severe influenza infection is associated with pulmonary epithelial damage and endothelial dysfunction leading to acute lung injury (ALI). There is evidence that an aggressive cytokine storm and cell damage in lung capillaries as well as endothelial/platelet interactions contribute to vascular leakage, pro‐thrombotic milieu and infiltration of immune effector cells. To date, treatments for ALI caused by influenza are limited to antiviral drugs, active ventilation or further symptomatic treatments. In this review, we summarize the mechanisms of influenza‐mediated pathogenesis, permissive animal models and histopathological changes of lung tissue in both mice and men and compare it with histological and electron microscopic data from our own group. We highlight the molecular and cellular interactions between pulmonary endothelium and platelets in homeostasis and influenza‐induced pathogenesis. Finally, we discuss novel therapeutic targets on platelets/endothelial interaction to reduce or resolve ALI.

show abstract

“…However, several inducible phenotypes have been reported in PAR4-deficient mice, and PAR4 activation has been shown to have some ‘favourable’ biological effects that may be overcome by long-term pharmacological inhibition of the receptor. For example, PAR4 activation in mice has been shown to protect mice from Coxsackievirus B3 and H1N1 influenza A virus infection [62,63] and to limit bacterial growth in Streptococcus-induced pneumonia [63]. It is proposed that inhibiting PAR4 could lead to loss of protection against certain infections.…”

Section: What Are the Major Issues To Consider For Par4 Inhibitors?mentioning

confidence: 99%

Using PAR4 Inhibition as an Anti-Thrombotic Approach: Why, How, and When?

Li¹,

Tarlac²,

Hamilton³

2019

IJMS

View full text Add to dashboard Cite

Protease-activated receptors (PARs) are a family of four GPCRs with a variety of cellular functions, yet the only advanced clinical endeavours to target these receptors for therapeutic gain to date relates to the impairment of platelet function for anti-thrombotic therapy. The only approved PAR antagonist is the PAR1 inhibitor, vorapaxar—the sole anti-platelet drug against a new target approved in the past 20 years. However, there are two PARs on human platelets, PAR1 and PAR4, and more recent efforts have focused on the development of the first PAR4 antagonists, with first-in-class agents recently beginning clinical trial. Here, we review the rationale for this approach, outline the various modes of PAR4 inhibition, and speculate on the specific therapeutic potential of targeting PAR4 for the prevention of thrombotic conditions.

show abstract

Protease-activated receptor 4 protects mice from Coxsackievirus B3 and H1N1 influenza A virus infection

Cited by 24 publications

References 60 publications

PAR1 regulation of CXCL1 expression and neutrophil recruitment to the lung in mice infected with influenza A virus

PAR1 regulation of CXCL1 expression and neutrophil recruitment to the lung in mice infected with influenza A virus

Endothelial–platelet interactions in influenza‐induced pneumonia: A potential therapeutic target

Using PAR4 Inhibition as an Anti-Thrombotic Approach: Why, How, and When?

Contact Info

Product

Resources

About