Neutrophil Recruitment and Participation in Severe Diseases Caused by Flavivirus Infection

Fontoura, Marina Alves; Rocha, Rebeca Fróes; Marques, Rafael Elias

doi:10.3390/life11070717

Cited by 3 publications

(3 citation statements)

References 168 publications

(189 reference statements)

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“…Both genes encode proteins essential for the adhesion, migration, and development of mature neutrophils (Yang et al 2005; Dwivedi and Greis 2017). Although the role of neutrophils in severe YFV infection remains unclear (Fontoura, Rocha, and Marques 2021), our findings suggest that these cells play an essential role in the pathogenesis of the disease.…”

Section: Resultsmentioning

confidence: 74%

Systems Immunology Approaches to Understanding Immune Responses in Acute Infection of Yellow Fever Patients

Gonçalves,

Costa,

Thomazella

et al. 2024

Preprint

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In the 2018 yellow fever (YF) outbreak in Brazil, we generated new transcriptomic data and combined it with clinical and immunological data to decode the pathogenesis of YF. Our analysis of 79 patients highlighted distinct gene expression patterns between acute YF infections, other viral infections, and the milder infection induced by the live-attenuated YF-17D vaccine. We identified a critical role for low-density, immature neutrophils in severe outcomes, marked by the downregulation of genes such as PADI4, CSF3R, and ICAM1 in deceased patients. These genes are essential for neutrophil migration and maturation, suggesting their pivotal role in disease progression. Furthermore, our study revealed a complex interaction among inflammation-related genes: increased expression of CXCL10 in the acute phase was accompanied by decreased expression of IL-1b and an increase in IL1R2, a decoy receptor that binds to IL-1 to inhibit its activity. The diminished expression of HLA class II genes suggests an impairment in antigen presentation. These insights underscore the delicate balance of immune responses in YF pathogenesis and provide a foundation for future therapeutic and diagnostic advancements in managing YF.

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Section: Resultsmentioning

confidence: 74%

Systems Immunology Approaches to Understanding Immune Responses in Acute Infection of Yellow Fever Patients

Gonçalves,

Costa,

Thomazella

et al. 2024

Preprint

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“…As in humans, CCL2 was the most prominent CC chemokine produced during infection ( Figure 1 C,D). While CXCL1 and CXCL8 (human) are mainly involved in neutrophil recruitment and activation, CCL2 is the main cytokine implicated in monocyte recruitment as well as TH1 polarization [ 47 , 48 , 49 ]. Put together, the concerted actions of these chemokines likely lead to a massive recruitment of leukocytes responsible of the ARDS observed in severe COVID-19 case [ 22 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Nsp2 Contributes to Inflammation by Activating NF-κB

Lacasse

Gudimard

Dubuc

et al. 2023

Viruses

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COVID-19 is associated with robust inflammation and partially impaired antiviral responses. The modulation of inflammatory gene expression by SARS-CoV-2 is not completely understood. In this study, we characterized the inflammatory and antiviral responses mounted during SARS-CoV-2 infection. K18-hACE2 mice were infected with a Wuhan-like strain of SARS-CoV-2, and the transcriptional and translational expression interferons (IFNs), cytokines, and chemokines were analyzed in mouse lung homogenates. Our results show that the infection of mice with SARS-CoV-2 induces the expression of several pro-inflammatory CC and CXC chemokines activated through NF-κB but weakly IL1β and IL18 whose expression are more characteristic of inflammasome formation. We also observed the downregulation of several inflammasome effectors. The modulation of innate response, following expressions of non-structural protein 2 (Nsp2) and SARS-CoV-2 infection, was assessed by measuring IFNβ expression and NF-κB modulation in human pulmonary cells. A robust activation of the NF-κB p65 subunit was induced following the infection of human cells with the corresponding NF-κB-driven inflammatory signature. We identified that Nsp2 expression induced the activation of the IFNβ promoter through its NF-κB regulatory domain as well as activation of p65 subunit phosphorylation. The present studies suggest that SARS-CoV-2 skews the antiviral response in favor of an NF-κB-driven inflammatory response, a hallmark of acute COVID-19 and for which Nsp2 should be considered an important contributor.

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“…1C and D). While CXCL1 and CXCL8 (human) are mainly involved in the neutrophil recruitment and activation, CCL2 is the main cytokine implicated in the monocyte recruitment as well as TH1 polarisation (39)(40)(41). Put together, concerted actions of these chemokines likely lead to a massive recruitment of leukocytes responsible of the acute respiratory distress syndrome (ARDS) observed in severe COVID-19 case (42).…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 type I Interferon modulation by nonstructural proteins 1 and 2

Flamand

Lacasse

Dubuc

et al. 2022

Preprint

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Since the beginning of the COVID-19 pandemic, enormous efforts were devoted to understanding how SARS-CoV-2 escapes the antiviral response. Yet, modulation of type I interferons (IFNs) by this virus is not completely understood. Using in vitro and in vivo approaches, we have characterized the type I IFN response during SARS-CoV-2 infection as well as immune evasion mechanisms. The transcriptional and translational expression of IFNs, cytokines and chemokines were measured in lung homogenates of Wuhan-like, Beta, and Delta SARS-CoV-2 K18-ACE2 transgenic mice. Using in vitro experiments, we measured SARS-CoV-2 and its non-structural proteins 1 and 2 (Nsp1-2) to modulate expression of IFNβ and interferon-stimulated genes (ISG). Our data show that infection of mice with Wuhan-like virus induces robust expression of Ifna and Ifnb1 mRNA and limited type I production. In contrast, Beta and Delta variant infected mice failed to activate and produce IFNα. Using in vitro systems, Ifnb gene translation inhibition was observed using an Nsp1 expression vector. Conversely, SARS-CoV-2 and its variants induce robust expression of NF-kB-driven genes such as those encoding CCL2 ans CXCL10 chemokines. We also identified Nsp2 as an activator of NF-kB that partially counteracts the inhibitory actions of Nsp1. In summary, our work indicates that SARS-CoV-2 skews the antiviral response in favor of an NF-kB-driven inflammatory response, a hallmark of acute COVID-19, and that Nsp2 is partly responsible for this effect.

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Neutrophil Recruitment and Participation in Severe Diseases Caused by Flavivirus Infection

Cited by 3 publications

References 168 publications

Systems Immunology Approaches to Understanding Immune Responses in Acute Infection of Yellow Fever Patients

Systems Immunology Approaches to Understanding Immune Responses in Acute Infection of Yellow Fever Patients

SARS-CoV-2 Nsp2 Contributes to Inflammation by Activating NF-κB

SARS-CoV-2 type I Interferon modulation by nonstructural proteins 1 and 2

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