Author response: Dengue vascular leakage is augmented by mast cell degranulation mediated by immunoglobulin Fcγ receptors

Syenina, Ayesa; Jagaraj, Cyril J; Aman, Siti A B; Sridharan, Aishwarya; John, Ashley L. St.

doi:10.7554/elife.05291.008

Cited by 4 publications

(3 citation statements)

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“…Apart from direct infection by the DENV, monocyte infection is further facilitated in acute dengue, by ADE (Chareonsirisuthigul et al, 2007;Syenina et al, 2015;Katzelnick et al, 2017). Internalization of antigen-antibody complexes is known to further suppress antiviral responses Tsai et al, 2014;Wang et al, 2017).…”

Section: Monocyte/macrophage Responses In Severe Denguementioning

confidence: 99%

“…Mast cells are shown to be permissive to infection by the DENV, which is enhanced in the presence of DENV-specific antibodies Syenina et al, 2015). Many proteases and inflammatory mediators produced by mast cells such as chymases, tryptases, platelet activating factor (PAF) and vascular endothelial growth factor (VEGF) have been implicated in vascular leak and disease pathogenesis (Furuta et al, 2012;Jeewandara et al, 2015;Kamaladasa et al, 2016;Tissera et al, 2017;Inokuchi et al, 2018;Malavige et al, 2018).…”

Section: Mast Cells In Denguementioning

confidence: 99%

“…Initial infection with a particular DENV serotype is known as a primary infection, while subsequent infection with any other serotype is known as a secondary dengue infection (WHO, 2011). Secondary dengue infection is thought to be one of the most important risk factors for development of severe disease, in part due to antibody dependent enhancement (ADE) in which poorly neutralizing, highly cross-reactive antibodies enhance infection in FcγR-expressing cells (Chareonsirisuthigul et al, 2007;Chau et al, 2008;Guzman et al, 2013;Syenina et al, 2015;Katzelnick et al, 2017). However, not all secondary dengue infections result in symptomatic infection or DHF and only 15% of secondary dengue infections progress to DHF (Wang et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Dysfunctional Innate Immune Responses and Severe Dengue

Malavige

Jeewandara

Ogg

2020

Front. Cell. Infect. Microbiol.

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Although infection with the dengue virus (DENV) causes severe dengue, it causes a mild self-limiting illness in the majority of individuals. There is emerging evidence that an aberrant immune response in the initial stages of infection lead to severe disease. Many inflammatory cytokines, chemokines, and lipid mediators are significantly higher in patients with severe dengue compared to those who develop mild infection, during febrile phase of illness. Monocytes, mast cells, and many other cells of the immune system, when infected with the DENV, especially in the presence of poorly neutralizing antibodies, leads to production of pro-inflammatory cytokines and inhibition of interferon signaling pathways. In addition, production of immunosuppressive cytokines such as IL-10 further leads to inhibition of cellular antiviral responses. This dysregulated and aberrant immune response leads to reduced clearance of the virus, and severe dengue by inducing a vascular leak and excessive inflammation due to high levels of inflammatory cytokines. Individuals with comorbid illnesses could be prone to more severe dengue due to low grade endotoxemia, gut microbial dysbiosis and an altered phenotype of innate immune cells. The immunosuppressive and inflammatory lipid mediators and altered phenotype of monocytes are likely to further act on T cells and B cells leading to an impaired adaptive immune response to the virus. Therefore, in order to identify therapeutic targets for treatment of dengue, it would be important to further characterize these mechanisms in order for early intervention. In this review, we discuss the differences in the innate immune responses in those who progress to develop severe dengue, compared to those with milder disease in order to understand the mechanisms that lead to severe dengue.

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Section: Monocyte/macrophage Responses In Severe Denguementioning

confidence: 99%

Section: Mast Cells In Denguementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dysfunctional Innate Immune Responses and Severe Dengue

Malavige

Jeewandara

Ogg

2020

Front. Cell. Infect. Microbiol.

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Divergent Mast Cell Responses Modulate Antiviral Immunity During Influenza Virus Infection

Murphy-Schafer

Paust

2021

Front. Cell. Infect. Microbiol.

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Influenza A virus (IAV) is a respiratory pathogen that infects millions of people each year. Both seasonal and pandemic strains of IAV are capable of causing severe respiratory disease with a high risk of respiratory failure and opportunistic secondary infection. A strong inflammatory cytokine response is a hallmark of severe IAV infection. The widespread tissue damage and edema in the lung during severe influenza is largely attributed to an overexuberant production of inflammatory cytokines and cell killing by resident and infiltrating leukocytes. Mast cells (MCs) are a sentinel hematopoietic cell type situated at mucosal sites, including the lung. Poised to react immediately upon detecting infection, MCs produce a vast array of immune modulating molecules, including inflammatory cytokines, chemokines, and proteases. As such, MCs have been implicated as a source of the immunopathology observed in severe influenza. However, a growing body of evidence indicates that MCs play an essential role not only in inducing an inflammatory response but in suppressing inflammation as well. MC-derived immune suppressive cytokines are essential to the resolution of a number of viral infections and other immune insults. Absence of MCs prolongs infection, exacerbates tissue damage, and contributes to dissemination of the pathogen to other tissues. Production of cytokines such as IL-10 and IL-6 by MCs is essential for mitigating the inflammation and tissue damage caused by innate and adaptive immune cells alike. The two opposing functions of MCs—one pro-inflammatory and one anti-inflammatory—distinguish MCs as master regulators of immunity at the site of infection. Amongst the first cells to respond to infection or injury, MCs persist for the duration of the infection, modulating the recruitment, activation, and eventual suppression of other immune cells. In this review, we will discuss the immune modulatory roles of MCs over the course of viral infection and propose that the immune suppressive mediators produced by MCs are vital to minimizing immunopathology during influenza infection.

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Mast Cell and Eosinophil Activation Are Associated With COVID-19 and TLR-Mediated Viral Inflammation: Implications for an Anti-Siglec-8 Antibody

et al. 2021

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Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection represents a global health crisis. Immune cell activation via pattern recognition receptors has been implicated as a driver of the hyperinflammatory response seen in COVID-19. However, our understanding of the specific immune responses to SARS-CoV-2 remains limited. Mast cells (MCs) and eosinophils are innate immune cells that play pathogenic roles in many inflammatory responses. Here we report MC-derived proteases and eosinophil-associated mediators are elevated in COVID-19 patient sera and lung tissues. Stimulation of viral-sensing toll-like receptors in vitro and administration of synthetic viral RNA in vivo induced features of hyperinflammation, including cytokine elevation, immune cell airway infiltration, and MC-protease production—effects suppressed by an anti-Siglec-8 monoclonal antibody which selectively inhibits MCs and depletes eosinophils. Similarly, anti-Siglec-8 treatment reduced disease severity and airway inflammation in a respiratory viral infection model. These results suggest that MC and eosinophil activation are associated with COVID-19 inflammation and anti-Siglec-8 antibodies are a potential therapeutic approach for attenuating excessive inflammation during viral infections.

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Author response: Dengue vascular leakage is augmented by mast cell degranulation mediated by immunoglobulin Fcγ receptors

Cited by 4 publications

References 0 publications

Dysfunctional Innate Immune Responses and Severe Dengue

Dysfunctional Innate Immune Responses and Severe Dengue

Divergent Mast Cell Responses Modulate Antiviral Immunity During Influenza Virus Infection

Mast Cell and Eosinophil Activation Are Associated With COVID-19 and TLR-Mediated Viral Inflammation: Implications for an Anti-Siglec-8 Antibody

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