Coagulation Factor X Activates Innate Immunity to Human Species C Adenovirus

Doronin, Konstantin; Flatt, Justin W.; Paolo, Nelson C. Di; Khare, Reeti; Kalyuzhniy, Oleksandr; Acchione, Mauro; Sumida, John P.; Ohto, Umeharu; Shimizu, Toshiyuki; Akashi-Takamura, Sachiko; Miyake, Kensuke; MacDonald, James W.; Bammler, Theo K.; Beyer, Richard P.; Farin, Frederico M.; Stewart, Phoebe L.; Shayakhmetov, Dmitry M.

doi:10.1126/science.1226625

Cited by 142 publications

(194 citation statements)

References 29 publications

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“…Another biological process involving FX concerns viral infections through its binding to the surface of herpes simplex virus-1 or human species C adenovirus. Whether such interactions promote the activation of the innate immune response 10,11 or, in contrast, facilitate adenovirus and adenovirus-associated viruses infection 12 is still a matter of debate. In any case, in view of this multiplicity of FX biological functions, further understanding of the regulatory mechanisms that control FX circulatory levels is clearly required.…”

Section: Introductionmentioning

confidence: 99%

Macrophage receptor SR-AI is crucial to maintain normal plasma levels of coagulation factor X

Muczynski

Bazaa

Loubière

et al. 2016

Blood

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Key Points• SR-AI is the major receptor of FX at the macrophage surface.• Macrophages use SR-AI to control FX circulatory levels.Beside its classical role in the coagulation cascade, coagulation factor X (FX) is involved in several major biological processes including inflammation and enhancement of virusinduced immune responses. We recently reported that the long circulatory half-life of FX is linked to its interaction with liver-resident macrophages. Importantly, we now observed that macrophages, but not undifferentiated monocytes, support this interaction. Using cell biology approaches with primary and THP1-derived macrophages as well as transfected cells, we further identified the scavenger receptor type A member I (SR-AI) to be a macrophage-specific receptor for FX. This result was confirmed using SR-AI-deficient mice, which exhibit reduced circulating levels of FX in vivo and loss of FX-macrophage interactions in vitro. Binding studies using purified proteins revealed that FX binds specifically (half-maximal binding, 3 mg/mL) to the extracellular domain of SR-AI. Altogether, we demonstrate that macrophages regulate FX plasma levels in an SR-AI-dependent manner. (Blood. 2016;127(6):778-786)

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Section: Introductionmentioning

confidence: 99%

Macrophage receptor SR-AI is crucial to maintain normal plasma levels of coagulation factor X

Muczynski

Bazaa

Loubière

et al. 2016

Blood

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“…Coagulation factor X (Stuart Prower factor) is one of the vitamin K-dependent serine proteases of the coagulation cascade, which plays a pivotal role in the homeostasis phenomenon as the first enzyme in the common pathway of fibrin formation (1,2). The FX gene is 22 kb long and is located at 13q34-ter, 2.8 kb downstream of the F7 gene.…”

Section: Introductionmentioning

confidence: 99%

“…FX is a vitamin K-dependent liver-produced serine protease, which serves an important role in the normal coagulation mechanism. Following activation by FIXa and its cofactor or by FVIIa and tissue factor, FXa catalyses the conversion of prothrombin to thrombin (1). Factor X deficiency (FXD) is a hereditary coagulation disorder, which is characterized by clinical manifestations including hematoma, epistaxis, menorrhagia, ecchymosis, and central nervous system (CNS) or gastrointestinal bleeding (depending on the zygosity) (2,3).…”

Section: Introductionmentioning

confidence: 99%

“…Homeostasis is caused by the interaction between platelets, coagulation factors, and anticoagulant proteins in blood vessels (1). Coagulation factor X (Stuart Prower factor) is one of the vitamin K-dependent serine proteases of the coagulation cascade, which plays a pivotal role in the homeostasis phenomenon as the first enzyme in the common pathway of fibrin formation (1,2).…”

Section: Introductionmentioning

confidence: 99%

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Subarachnoid Hemorrhage in Congenital Factor X Deficiency: A Case Study and Literature Review

Mohammadi

Torab

Aghakhani

et al. 2016

Iran Red Crescent Med J

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Background: Inborn factor X deficiency (FXD) is a very rare (1: 500,000) hereditary coagulation disorder, which is characterized by clinical manifestations including hematoma, epistaxis, menorrhagia, ecchymosis, and central nervous system (CNS) or gastrointestinal (GI) bleeding (depending on the zygosity). In homozygote patients, the risk of spontaneous intracranial hemorrhage (ICH) is high. Objectives: The aim of this investigation was to study and long-term follow-up of the patients with FXD and ICH. In addition, we investigated their frequent bleeding symptoms throughout their life and the results were compared with results of other studies. Patients and Methods: This study investigated 2 cases with spontaneous intracranial hemorrhage in patients with severe congenital (factor X) FX deficiency including a 3-year-old boy and a 1-month-old female neonate. The world literature was explored through the PubMed Medline and Scopus using appropriate and pertinent key words. Results: The Patients referred to the hematology department due to the neurological complications such as vomiting, unconsciousness, prolonged nasal bleeding for recent 12 hours. They had no familial history of spontaneous CNS bleeding. The blood coagulation test analysis indicated a prolonged activated partial thromboplastin time (APTT) and also revealed a prolonged prothrombin time (PT) and the low levels of coagulation factor X implicating severe congenital FX deficiency. They followed up by our hematologists to prevent intracranial hemorrhage. Discussions: As one ICH patient whose PT and aPTT suggest a coagulation disorder secondary to vitamin K deficiency or coagulation factor deficiency, unresponsiveness to vitamin K therapy should be useful to take FX deficiency into consideration.

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“…Factor IX (FIX) has also been reported to aid the transduction of hepatocytes, although it remains unclear which viral protein is responsible, and complement-4-binding protein (C4BP) binds to the fiber knob (16,18). Importantly, viral binding to blood factors rapidly induces innate immune activation to the vector, resulting in systemic inflammatory responses in patients (18,19). We hypothesized that the local viral concentration at tumor sites could be increased by: (i) targeting of mutants to pancreatic tumors and (ii) decreasing binding to erythrocytes and blood factors.…”

Section: Introductionmentioning

confidence: 99%

The Novel Oncolytic Adenoviral Mutant Ad5-3Δ-A20T Retargeted to αvβ6 Integrins Efficiently Eliminates Pancreatic Cancer Cells

Man

Davies

Coughlan

et al. 2018

Molecular Cancer Therapeutics

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Metastatic pancreatic ductal adenocarcinomas (PDAC) are incurable due to the rapid development of resistance to all current therapeutics. Oncolytic adenoviral mutants have emerged as a promising new strategy that negates such resistance. In contrast to normal tissue, the majority of PDACs express the avb6 integrin receptor. To exploit this feature, we modified our previously reported oncolytic adenovirus, AdDD, to selectively target avb6 integrins to facilitate systemic delivery. Structural modifications to AdDD include the expression of the small but potent avb6-binding peptide, A20FMDV2, and ablation of binding to the native coxsackie and adenovirus receptor (CAR) within the fiber knob region. The resultant mutant, Ad5-3D-A20T, infected and killed avb6 integrin-expressing cells more effectively than the parental wild-type (Ad5wt) virus and AdDD. Viral uptake through avb6 integrins rather than native viral receptors (CAR, avb3 and avb5 integrins) promoted viral propagation and spread. Superior efficacy of Ad5-3D-A20T compared with Ad5wt was demonstrated in 3D organotypic cocultures, and similar potency between the two viruses was observed in Suit-2 in vivo models. Importantly, Ad5-3D-A20T infected pancreatic stellate cells at low levels, which may further facilitate viral spread and cancer cell elimination either as a single agent or in combination with the chemotherapy drug, gemcitabine. We demonstrate that Ad5-3D-A20T is highly selective for avb6 integrin-expressing pancreatic cancer cells, and with further development, this new and exciting strategy can potentially be extended to improve the systemic delivery of adenoviruses to pancreatic cancer patients. Mol Cancer Ther; 17(2); 575-87. Ó2018 AACR.

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Coagulation Factor X Activates Innate Immunity to Human Species C Adenovirus

Cited by 142 publications

References 29 publications

Macrophage receptor SR-AI is crucial to maintain normal plasma levels of coagulation factor X

Macrophage receptor SR-AI is crucial to maintain normal plasma levels of coagulation factor X

Subarachnoid Hemorrhage in Congenital Factor X Deficiency: A Case Study and Literature Review

The Novel Oncolytic Adenoviral Mutant Ad5-3Δ-A20T Retargeted to αvβ6 Integrins Efficiently Eliminates Pancreatic Cancer Cells

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