Spleen Tyrosine Kinase (Syk) Mediates IL-1β Induction by Primary Human Monocytes during Antibody-enhanced Dengue Virus Infection

Callaway, Justin B.; Smith, Scott A.; McKinnon, Karen P.; Silva, Aravinda M. de; Crowe, James E.; Ting, Jenny P.Y.

doi:10.1074/jbc.m115.664136

Cited by 40 publications

(45 citation statements)

References 91 publications

(60 reference statements)

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“…The FcγRIIa cytoplasmic tail has been shown to be essential for ADE of dengue virus entry and the involvement of Syk cascade in ADE entry has been reported [38–40]. Our data indicate that the cytoplasmic tail of FcγRIIa is crucial for the ADE of EBOV infection and that Src family PTK-dependent signaling is important to enhance viral uptake into cellular vesicles during ADE-mediated entry of EBOV.…”

Section: Discussionsupporting

confidence: 66%

“…Another difference found between VSV-EBOV GP and authentic EBOV was that while the Syk inhibitor did not affect EBOV ADE, non-ADE infection was significantly enhanced in the presence of this inhibitor, an effect not observed for VSV-EBOV GP. This might be due to the effect on post-entry mechanisms such as antiviral cellular responses, as proposed by a recent study demonstrating that dengue virus-antibody complexes decreased type-I interferon-stimulated gene expression triggered by the FcγR-mediated signaling pathway through Syk, leading to enhanced replication of the virus [39,40]. Since such an antiviral response could be different between VSV- and EBOV-infected cells, it is possible that the Syk inhibitor specifically affected the replication of EBOV, but not VSV, RNA genomes.…”

Section: Discussionmentioning

confidence: 99%

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Fcγ-receptor IIa-mediated Src Signaling Pathway Is Essential for the Antibody-Dependent Enhancement of Ebola Virus Infection

et al. 2016

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Antibody-dependent enhancement (ADE) of Ebola virus (EBOV) infection has been demonstrated in vitro, raising concerns about the detrimental potential of some anti-EBOV antibodies. ADE has been described for many viruses and mostly depends on the cross-linking of virus-antibody complexes to cell surface Fc receptors, leading to enhanced infection. However, little is known about the molecular mechanisms underlying this phenomenon. Here we show that Fcγ-receptor IIa (FcγRIIa)-mediated intracellular signaling through Src family protein tyrosine kinases (PTKs) is required for ADE of EBOV infection. We found that deletion of the FcγRIIa cytoplasmic tail abolished EBOV ADE due to decreased virus uptake into cellular endosomes. Furthermore, EBOV ADE, but not non-ADE infection, was significantly reduced by inhibition of the Src family protein PTK pathway, which was also found to be important to promote phagocytosis/macropinocytosis for viral uptake into endosomes. We further confirmed a significant increase of the Src phosphorylation mediated by ADE. These data suggest that antibody-EBOV complexes bound to the cell surface FcγRIIa activate the Src signaling pathway that leads to enhanced viral entry into cells, providing a novel perspective for the general understanding of ADE of virus infection.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Fcγ-receptor IIa-mediated Src Signaling Pathway Is Essential for the Antibody-Dependent Enhancement of Ebola Virus Infection

et al. 2016

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“…For example, the interleukin IL-1β plays a crucial role in the cytokine storm during dengue infection (5,6). It is an extremely potent cytokine that is regulated and induced by dengue-infected macrophages and monocytes (6)(7)(8). Further, most dengue virus-infected patients present with fever, which is the most common symptom caused by the endogenous pyrogen molecule (EP).…”

Section: Introductionmentioning

confidence: 99%

“…It is also demonstrated that platelets from dengue-infected patients contribute to increased vascular permeability during infection by the synthesis and release of IL-1β (13). Spleen Tyrosine Kinase (Syk) augments IL-1β induction during antibody-enhanced dengue virus infection in primary human monocytes, however caspase-1 and NLRP3 are required for the maturation of pro-IL-1β during antibody-dependent enhancement (7). Altogether, these observations indicated that inflammasome activation might play a critical role in the pathogenesis of DENV infection.…”

Section: Introductionmentioning

confidence: 99%

Dengue Virus Serotype 2 and Its Non-Structural Proteins 2A and 2B Activate NLRP3 Inflammasome

et al. 2020

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Dengue is the most prevalent and rapidly transmitted mosquito-borne viral disease of humans. One of the fundamental innate immune responses to viral infections includes the processing and release of pro-inflammatory cytokines such as interleukin (IL-1β and IL-18) through the activation of inflammasome. Dengue virus stimulates the Nod-like receptor (NLRP3-specific inflammasome), however, the specific mechanism(s) by which dengue virus activates the NLRP3 inflammasome is unknown. In this study, we investigated the activation of the NLRP3 inflammasome in endothelial cells (HMEC-1) following dengue virus infection. Our results showed that dengue infection as well as the NS2A and NS2B protein expression increase the NLRP3 inflammasome activation, and further apoptosis-associated speck-like protein containing caspase recruitment domain (ASC) oligomerization, and IL-1β secretion through caspase-1 activation. Specifically, we have demonstrated that NS2A and NS2B, two proteins of dengue virus that behave as putative viroporins, were sufficient to stimulate the NLRP3 inflammasome complex in lipopolysaccharide (LPS)-primed endothelial cells. In summary, our observations provide insight into the dengue-induced inflammatory response mechanism and highlight the importance of DENV-2 NS2A and NS2B proteins in activation of the NLRP3 inflammasome during dengue virus infection.

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“…Macrophages are the first cells to encounter pathogens and respond by secreting various cytokines such as IL-1, IL-6 and IL-10 (Xing et al, 2008). The pro-inflammatory cytokine IL-1β is a part of the IL-1 family and its presence correlated with some disease states such as influenza and dengue (Xing et al, 2008;Callaway et al, 2015). IL-6 is also a pro-inflammatory cytokine and is multifunctional in the innate immune response (Schaper and Rose-John, 2015).…”

Section: Discussionmentioning

confidence: 99%

ALV-J strain SCAU-HN06 induces innate immune responses in chicken primary monocyte-derived macrophages

et al. 2017

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Avian leucosis virus subgroup J (ALV-J) can cause lifelong infection and can escape from the host immune defenses in chickens. Since macrophages act as the important defense line against invading pathogens in host innate immunity, we investigated the function and innate immune responses of chicken primary monocyte-derived macrophages (MDM) after ALV-J infection in this study. Our results indicated that ALV-J was stably maintained in MDM cells but that the viral growth rate was significantly lower than that in DF-1 cells. We also found that ALV-J infection significantly increased nitric oxide (NO) production, but had no effect on MDM phagocytic capacity. Interestingly, infection with ALV-J rapidly promoted the expression levels of Myxovirus resistance 1 (Mx) (3 h, 6 h), ISG12 (6 h), and interleukin-1β (IL-1β) (3 h, 12 h) at an early infection stage, whereas it sharply decreased the expression of Mx (24 h, 36 h), ISG12 (36 h), and made little change on IL-1β (24 h, 36 h) production at a late infection stage in MDM cells. Moreover, the protein levels of interferon-β (IFN-β) and interleukin-6 (IL-6) had sharply increased in infected MDM cells from 3 to 36 h post infection (hpi) of ALV-J. And, the protein level of interleukin-10 (IL-10) was dramatically decreased at 36 hpi in MDM cells infected with ALV-J. These results demonstrate that ALV-J can induce host innate immune responses and we hypothesize that macrophages play an important role in host innate immune attack and ALV-J immune escape.

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Spleen Tyrosine Kinase (Syk) Mediates IL-1β Induction by Primary Human Monocytes during Antibody-enhanced Dengue Virus Infection

Cited by 40 publications

References 91 publications

Fcγ-receptor IIa-mediated Src Signaling Pathway Is Essential for the Antibody-Dependent Enhancement of Ebola Virus Infection

Fcγ-receptor IIa-mediated Src Signaling Pathway Is Essential for the Antibody-Dependent Enhancement of Ebola Virus Infection

Dengue Virus Serotype 2 and Its Non-Structural Proteins 2A and 2B Activate NLRP3 Inflammasome

ALV-J strain SCAU-HN06 induces innate immune responses in chicken primary monocyte-derived macrophages

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