Virus-Triggered ATP Release Limits Viral Replication through Facilitating IFN-β Production in a P2X7-Dependent Manner

Zhang, Chengfei; He, Hongwang; Wang, Li; Zhang, Na; Huang, Hui; Xiong, Qingqing; Yan, Yan; Wu, Nannan; Ren, Hua; Han, Hongyu; Liu, Mingyao; Qian, Min; Du, Bing

doi:10.4049/jimmunol.1700187

Cited by 70 publications

(59 citation statements)

References 35 publications

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“…We therefore turned our attention to the nucleotide ATP, which had been shown to induce shedding of human CD23 (45), and also of mouse CD23 and CD27 from lymphocytes (46). Elevated levels of eATP has been identified as part of the innate and adaptive immune response to viral infections (47–49) and also contributes to vaccine-induced responses by the oil-in-water squalene based adjuvant MF59 (50). By co-incubation of PBMCs with ATP we could demonstrate decreased surface expression of CD27 on isotype switched B cells (p=0.031) and CD23 on B cells (p=0.016) in vitro (Figure 6C).…”

Section: Resultsmentioning

confidence: 99%

The generation of plasma cells and CD27⁻IgD⁻B cells during Hantavirus infection are associated with distinct pathological findings

Kerkman

Dernstedt

Tadala

et al. 2019

Preprint

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Human hantavirus infections can cause hemorrhagic fever with renal syndrome (HFRS), major signs of the disease being thrombocytopenia and transient kidney dysfunction. By a comprehensive and longitudinal study of circulating B cells, we demonstrate that these two pathologies associate with distinct effects on the humoral immune system during HFRS. Low thrombocyte counts strongly associated with an abnormal frequency of plasmablasts in circulation, whereas kidney dysfunction was indicative of an accumulation of CD27 -B cells and plasmablasts. Finally, we provide evidence that high levels of extracellular ATP in circulation during HFRS correlates with shedding of surface CD27 on B cells via a metallomatrix proteinase-8-mediated mechanism. Since extracellular ATP is known to regulate kidney function, our study reveals a link between kidney dysfunction and the generation of CD27 -IgD -B cells, and a potential molecular target for treatment of the symptomatic phase of HFRS. Dobrava, Seol and Puumala (PUUV) strains, where PUUV is endemic to Scandinavia. To date, no efficacious treatment or vaccination regimen exists to protect against severe hantavirus infections.Well controlled human studies have shown that hantavirus infections cause aberrant activation of both innate and adaptive immunity (5)(6)(7)(8). A potent antiviral IgG-response is associated with protection from severe disease during both HPS and HFRS (9-12) and passive transfer of serum antibodies could reduce case fatality rate in a small cohort of HPS patients (13). These findings clearly demonstrate that activation of the humoral immune system and subsequent elicitation of antiviral antibodies play a central role in the control of viremia and/or pathogenesis during hantavirus infections.A recent study of HPS demonstrated that very high levels of plasmablasts (PBs) and CD27 -IgD -B cells were detected in circulation of patients (14). The rapid and extensive PB-response is similar to that reported during acute dengue virus infection and contrasts to the comparably moderate levels of PBs that are found in circulation during influenza infection or after influenza vaccination (15). An expansion of the CD27 -IgD -B cell subset has previously been shown for numerous inflammatory and infectious diseases, as well as during ageing and cancer (16-21), yet their functional role in humoral immunity remains undetermined. The CD27 -IgD -B cells resemble memory B cells, have isotype switched and hypermutated B cell receptors and therefore likely originate from T cell-dependent germinal center reactions in secondary lymphoid organs (16, 20). In systemic lupus erythematosus (SLE), an expanded population of CD27 -IgD -B cells was associated with the manifestation of nephritis in patients (16). This suggests that their detection in blood may be linked to reduced kidney function, but the cause for their expansion remains to be determined.During HFRS-causing hantavirus infections, reduced kidney function occurs independently of the induced thrombocytopenia (22, 23). We therefor...

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Section: Resultsmentioning

confidence: 99%

The generation of plasma cells and CD27⁻IgD⁻B cells during Hantavirus infection are associated with distinct pathological findings

Kerkman

Dernstedt

Tadala

et al. 2019

Preprint

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“…Zhang et al have demonstrated that enhancement in the c-ATP can reverse this process. This occurs by the facilitation of IFN secretion through P38/JNK/ATF-2 signaling pathway (7). Therefore, ATP-depleted cells are more susceptible to this effect of COVID-19.…”

Section: Evaluation Of the Hypothesismentioning

confidence: 99%

The powerful immune system against powerful COVID-19: A hypothesis

2020

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On March 11, 2020, the World Health Organization declared the coronavirus outbreak a pandemic. Since December 2019, the world has experienced an outbreak of coronavirus disease 2019 (COVID-19). Epidemiology, risk factors, and clinical characteristics of patients with COVID-19 have been reported but the factors affecting the immune system against COVID-19 have not been well described. In this article, we provide a novel hypothesis to describe how an increase in cellular adenosine triphosphate (c-ATP) can potentially improve the efficiency of innate and adaptive immune systems to either prevent and fight off COVID-19.

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“…Previous studies have found that extracellular ATP reduces the replication of several viruses through activation of P2X7 receptors, which specifically bind ATP 38, 39 . Less is known about the role of ADP in cellular signaling or its effects on viral infection and replication.…”

Section: Resultsmentioning

confidence: 99%

Rotavirus Induces Intercellular Calcium Waves through ADP Signaling

Chang-Graham

Perry

Engevik

et al. 2020

Preprint

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26Rotavirus causes severe diarrheal disease in children worldwide. A hallmark of rotavirus 27 infection is an increase in cytosolic calcium in infected small intestine epithelial cells. However, 28 the underlying mechanism(s) of rotavirus-cell signaling remains incompletely characterized. Here 29 we show that rotavirus-infected cells produce paracrine signals that manifest as intercellular 30 calcium waves (ICWs); which are observed in both cell lines and human intestinal enteroids 31 (HIEs). Rotavirus ICWs are caused by the release of extracellular adenosine diphosphate (ADP) 32 that activates P2Y1 purinergic receptors on neighboring cells and are blocked by P2Y1 33 antagonists or CRISPR/Cas9 knockout of P2Y1. This paracrine purinergic signal is critical for 34 rotavirus replication and diarrhea. Blocking the ICW signal reduces rotavirus replication; inhibits 35 rotavirus-induced serotonin release and fluid secretion; and reduces diarrhea severity in neonatal 36 mice. This is the first evidence that viruses exploit intercellular calcium waves to amplify diarrheal 37 signaling; a finding which have broad implications for gastrointestinal physiology. signaling molecules during RV infection, including enterotoxin NSP4, prostaglandins (PGE2), and 57 nitric oxide (NO) 7,15-17 . In this model, enterotoxin NSP4 can bind to neighboring, uninfected 58 enterocytes to activate Ca 2+ -activated chloride channels and cause secretory diarrhea 18,19 , and 59 PGE2 and NO may further activate fluid secretion processes 20,21 . Dysregulation of neighboring 60 enteroendocrine cells triggers the Ca 2+ -dependent release of serotonin, which stimulates the 61 enteric nervous system both to activate vomiting centers in the central nervous system and to 62 activate secretory reflex pathways in the gastrointestinal (GI) tract 5,22 . Thus, this model of RV-63 induced diarrhea addresses how limited infection at the middle-to-upper villi may cause 64 widespread dysregulation of host physiology and life-threatening disease. 65Herein we demonstrate that RV-infected cells signal to uninfected cells via an extracellular 66 purinergic signaling pathway. This newly identified pathway is a dominant driver of observed RV 67 disease processes, including replication, upregulation of PGE2-and NO-producing enzymes, 68 serotonin secretion, fluid secretion, and diarrhea in a neonatal mouse model. Our findings provide 69 new insights into the mechanism(s) of viral diarrhea and gastrointestinal physiology. 70 Results 71 Low multiplicity infection reveals intercellular calcium waves 72Previous studies have shown that RV significantly increases cytosolic Ca 2+ during infection 73 and disrupts host Ca 2+ -dependent processes to cause disease [23][24][25] . We used African Green 74 monkey kidney MA104 cells stably expressing the genetically-encoded calcium indicator (GECI) 75GCaMP5G or GCaMP6s to observe changes in cytosolic Ca 2+ during RV infection using live-cell 76 time-lapse epifluorescence imaging. We did not observe differences in response using either...

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Virus-Triggered ATP Release Limits Viral Replication through Facilitating IFN-β Production in a P2X7-Dependent Manner

Cited by 70 publications

References 35 publications

The generation of plasma cells and CD27⁻IgD⁻B cells during Hantavirus infection are associated with distinct pathological findings

The generation of plasma cells and CD27⁻IgD⁻B cells during Hantavirus infection are associated with distinct pathological findings

The powerful immune system against powerful COVID-19: A hypothesis

Rotavirus Induces Intercellular Calcium Waves through ADP Signaling

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Virus-Triggered ATP Release Limits Viral Replication through Facilitating IFN-β Production in a P2X7-Dependent Manner

Cited by 70 publications

References 35 publications

The generation of plasma cells and CD27−IgD−B cells during Hantavirus infection are associated with distinct pathological findings

The generation of plasma cells and CD27−IgD−B cells during Hantavirus infection are associated with distinct pathological findings

The powerful immune system against powerful COVID-19: A hypothesis

Rotavirus Induces Intercellular Calcium Waves through ADP Signaling

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Product

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The generation of plasma cells and CD27⁻IgD⁻B cells during Hantavirus infection are associated with distinct pathological findings

The generation of plasma cells and CD27⁻IgD⁻B cells during Hantavirus infection are associated with distinct pathological findings