Differential modulation of innate immune response by epinephrine and estradiol

2017 ◽  
Vol 30 (3) ◽  
Author(s):  
Sona Margaryan ◽  
Armenuhi Hyusyan ◽  
Anush Martirosyan ◽  
Shushan Sargsian ◽  
Gayane Manukyan
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Dependent Manner ◽  
Induced Expression ◽  
Short Term Exposure ◽  
Tnf Α ◽  
Vitro Effect ◽  
Dose Dependent

AbstractBackgroundAlthough it is widely accepted that catecholamines and estrogens influence immunity and have consequences for health, their effect on innate immunity (e.g. monocytes and neutrophils) is still not fully investigated.Materials and methodsOur study aimed to analyze the production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, monocyte chemoattractant protein (MCP)-1 and IL-8 by whole blood cells following short-term exposure to epinephrine (Epi) and 17β-estradiol (E2) in the presence or absence of lipopolysaccharide (LPS). We also evaluated the in vitro effect of these hormones on expression of β2 integrin (CD11b/CD18) and L-selectin (CD62L) by circulating neutrophils and monocytes in the blood of healthy subjects.ResultsEpi has shown a potential to modulate the production of pro-inflammatory mediators. Its exposure resulted in significantly increased production of IL-8 in a dose-dependent manner. On the contrary, a dose-dependent suppression of LPS-induced production of IL-1β, IL-8, and MCP-1 by Epi was observed. In neutrophils, a modest rise in CD11b expression was observed after Epi exposure. Simultaneously, Epi suppressed LPS-induced expression of CD11b and CD18. In monocytes, Epi suppressed LPS-induced expression of C11b. E2 inhibited LPS-induced TNF-α production and caused a significant decrease in CD62L expression in both cell populations. No significant changes were observed after double exposure of cells with Epi and E2.ConclusionsThus, our results show that Epi and E2 differentially modulate the innate immune response and have a dual effect on cytokine modulation. The findings suggest that the observed immunoregulatory role of Epi and E2 may influence the outcome in endotoxin responses and can be critical in the regulation of inflammatory responses.

scholarly journals The Threshold Effect: Lipopolysaccharide-Induced Inflammatory Responses in Primary Macrophages Are Differentially Regulated in an iRhom2-Dependent Manner

2021 ◽  
Vol 10 ◽  
Author(s):  
Joseph Skurski ◽  
Garima Dixit ◽  
Carl P. Blobel ◽  
Priya D. Issuree ◽  
Thorsten Maretzky
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Immune Cells ◽  
Regulatory Mechanism ◽  
Inflammatory Responses ◽  
Genetic Model ◽  
Innate Immune ◽  
High Dose ◽  
Dependent Manner ◽  
Low Levels

A well-controlled innate immune response is characterized by a rapid yet self-limiting inflammatory response. Although much is known about the range of inflammatory stimuli capable of triggering an innate immune response, the mechanisms which govern the degree of inflammation induced by inflammatory insults and the mechanisms in place to reset or maintain homeostasis are poorly understood. Tumor necrosis factor (TNF) is a potent early response pro-inflammatory cytokine produced by immune cells following a broad range of insults spanning autoimmunity and metabolic diseases to pathogenic infections. Previous studies have shown that a disintegrin and metalloproteinase (ADAM) 17 controls the release of soluble TNF and epidermal growth factor receptor signaling. Utilizing a genetic model of ADAM17 deficiency through the deletion of its regulator, the inactive rhomboid 2 (iRhom2), we show that loss of ADAM17 activity in innate immune cells leads to decreased expression of various cytokines in response to low levels of pathogen-associated molecular pattern (PAMP) stimulation but not at high-dose stimulation. In addition, TNF receptor (TNFR) 1/2-deficient bone marrow-derived macrophages yielded significantly reduced TNF expression following low levels of PAMP stimulation, suggesting that signaling through the TNFRs in immune cells drives a feed-forward regulatory mechanism wherein low levels of TNF allow sustained enhancement of TNF expression in an iRhom2/ADAM17-dependent manner. Thus, we demonstrate that inflammatory expression of TNF and IL1β is differentially regulated following high or low doses of PAMP stimulation, invoking the activation of a previously unknown regulatory mechanism of inflammation.

scholarly journals TRAF6 and TAK1 contribute to SAMHD1-mediated negative regulation of NF-κB signaling

2020 ◽  
Author(s):  
Constanza E. Espada ◽  
Corine St. Gelais ◽  
Serena Bonifati ◽  
Victoria V. Maksimova ◽  
Michael P. Cahill ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Negative Regulation ◽  
Innate Immune ◽  
Negative Regulator ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Tnf Α ◽  
Intracellular Dntp ◽  
Hiv 1

AbstractSterile alpha motif and HD-domain–containing protein 1 (SAMHD1) restricts HIV-1 replication by limiting the intracellular dNTP pool. SAMHD1 also suppresses the activation of NF-κB in response to viral infections and inflammatory stimuli. However, the mechanisms by which SAMHD1 negatively regulates this pathway remain unclear. Here we show that SAMHD1-mediated suppression of NF-κB activation is modulated by two key mediators of NF-κB signaling, tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and transforming growth factor-β-activated kinase-1 (TAK1). We compared NF-κB activation stimulated by interleukin (IL)-1β in monocytic THP-1 control and SAMHD1 knockout (KO) cells with and without partial TRAF6 knockdown (KD), or in cells treated with TAK1 inhibitors. Relative to control cells, IL-1β-treated SAMHD1 KO cells showed increased phosphorylation of the inhibitor of NF-κB (IκBα), an indication of pathway activation, and elevated levels of TNF-α mRNA. Moreover, SAMHD1 KO combined with TRAF6 KD or pharmacological TAK1 inhibition reduced IκBα phosphorylation and TNF-α mRNA to the level of control cells. SAMHD1 KO cells infected with single-cycle HIV-1 showed elevated infection and TNF-α mRNA levels compared to control cells, and the effects were significantly reduced by TRAF6 KD or TAK1 inhibition. We further demonstrated that overexpressed SAMHD1 inhibited TRAF6-stimulated NF-κB reporter activity in HEK293T cells in a dose-dependent manner. SAMHD1 contains a nuclear localization signal (NLS), but an NLS-defective SAMHD1 exhibited a suppressive effect similar to the wild-type protein. Our data suggest that the TRAF6-TAK1 axis contributes to SAMHD1-mediated suppression of NF-κB activation and HIV-1 infection.ImportanceCells respond to pathogen infection by activating a complex innate immune signaling pathway, which culminates in the activation of transcription factors and secretion of a family of functionally and genetically related cytokines. However, excessive immune activation may cause tissue damage and detrimental effects on the host. Therefore, in order to maintain host homeostasis, the innate immune response is tightly regulated during viral infection. We have reported SAMHD1 as a novel negative regulator of the innate immune response. Here, we provide new insights into SAMHD1-mediated negative regulation of the NF-κB pathway at the TRAF6-TAK1 checkpoint. We show that SAMHD1 inhibits TAK1 activation and TRAF6 signaling in response to proinflammatory stimuli. Interestingly, TRAF6 knockdown in SAMHD1-deficient cells significantly inhibited HIV-1 infection and activation of NF-κB induced by virus infection. Our research reveals a new negative regulatory mechanism by which SAMHD1 participates in the maintenance of cellular homeostasis during HIV-1 infection and inflammation.

scholarly journals microRNA-210 and microRNA-3570 Negatively Regulate NF-κB-Mediated Inflammatory Responses by Targeting RIPK2 in Teleost Fish

2021 ◽  
Vol 12 ◽  
Author(s):  
Hui Su ◽  
Renjie Chang ◽  
Weiwei Zheng ◽  
Yuena Sun ◽  
Tianjun Xu
Keyword(s):  
Immune Response ◽  
Signaling Pathway ◽  
Innate Immune Response ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Regulatory Role ◽  
Inflammatory Cytokine Production ◽  
Immune Genes ◽  
Lower Vertebrates ◽  
Antimicrobial Immunity

Pathogen infection can cause the production of inflammatory cytokines, which are key mediators that cause the host’s innate immune response. Therefore, proper regulation of immune genes associated with inflammation is essential for immune response. Among them, microRNAs (miRNAs) as gene regulator have been widely reported to be involved in the innate immune response of mammals. However, the regulatory network in which miRNAs are involved in the development of inflammation is largely unknown in lower vertebrates. Here, we identified two miRNAs from miiuy croaker (Miichthys miiuy), miR-210 and miR-3570, which play a negative regulatory role in host antibacterial immunity. We found that the expressions of miR-210 and miR-3570 were significantly upregulated under the stimulation of Gram-negative bacterium vibrio harveyi and LPS (lipopolysaccharide). Induced miR-210 and miR-3570 inhibit inflammatory cytokine production by targeting RIPK2, thereby avoiding excessive inflammation. In particular, we found that miR-210 and miR-3570 negatively regulate antimicrobial immunity by regulating the RIPK2-mediated NF-κB signaling pathway. The collective results indicated that both miRNAs are used as negative feedback regulators to regulate RIPK2-mediated NF-κB signaling pathway and thus play a regulatory role in bacteria-induced inflammatory response.

scholarly journals The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression

Oncogene ◽  
2020 ◽  
Vol 39 (44) ◽  
pp. 6841-6855 ◽  
Author(s):  
Christina Jessen ◽  
Julia K. C. Kreß ◽  
Apoorva Baluapuri ◽  
Anita Hufnagel ◽  
Werner Schmitz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Immune Response ◽  
Transcription Factor ◽  
Prostaglandin E2 ◽  
Innate Immune Response ◽  
Stress Responses ◽  
Melanoma Cells ◽  
Innate Immune ◽  
Dependent Manner

AbstractThe transcription factor NRF2 is the major mediator of oxidative stress responses and is closely connected to therapy resistance in tumors harboring activating mutations in the NRF2 pathway. In melanoma, such mutations are rare, and it is unclear to what extent melanomas rely on NRF2. Here we show that NRF2 suppresses the activity of the melanocyte lineage marker MITF in melanoma, thereby reducing the expression of pigmentation markers. Intriguingly, we furthermore identified NRF2 as key regulator of immune-modulating genes, linking oxidative stress with the induction of cyclooxygenase 2 (COX2) in an ATF4-dependent manner. COX2 is critical for the secretion of prostaglandin E2 and was strongly induced by H2O2 or TNFα only in presence of NRF2. Induction of MITF and depletion of COX2 and PGE2 were also observed in NRF2-deleted melanoma cells in vivo. Furthermore, genes corresponding to the innate immune response such as RSAD2 and IFIH1 were strongly elevated in absence of NRF2 and coincided with immune evasion parameters in human melanoma datasets. Even in vitro, NRF2 activation or prostaglandin E2 supplementation blunted the induction of the innate immune response in melanoma cells. Transcriptome analyses from lung adenocarcinomas indicate that the observed link between NRF2 and the innate immune response is not restricted to melanoma.

Transient membrane recruitment of IRAK-1 in response to LPS and IL-1β requires TNF R1

2008 ◽  
Vol 295 (2) ◽  
pp. C313-C323 ◽  
Author(s):  
Angelia Lockett ◽  
Mark G. Goebl ◽  
Maureen A. Harrington
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Plasma Membrane ◽  
Innate Immune Response ◽  
Cellular Response ◽  
Interleukin 1 ◽  
Innate Immune ◽  
Variable Response ◽  
Membrane Recruitment ◽  
Tnf Α

The transcription factor NF-κB is an essential regulator of the innate immune response that functions as the first line of defense against infections. Activation of the innate immune response by bacterial lipopolysaccharide (LPS) triggers production of tumor necrosis factor-α (TNF-α) followed by interleukin-1 (IL-1). The IL-1 receptor associated kinase-1 (IRAK-1) is an integral component of the LPS, TNF-α, and IL-1 signaling pathways that regulate NF-κB. Thus we hypothesized that IRAK-1 coordinates cellular NF-κB responses to LPS, TNF-α, and IL-1. In contrast to TNF-α where IRAK-1 subcellular localization does not change, treatment with LPS or IL-1 leads to a loss in cytoplasmic IRAK-1 with a coordinate increase in plasma membrane associated modified IRAK-1. In fibroblasts lacking the type 1 TNF-α receptor (TNF R1), IRAK-1 turnover is altered and modification of IRAK-1 in the plasma membrane is decreased in response to LPS and IL-1, respectively. When NF-κB controlled gene expression is measured, fibroblasts lacking TNF R1 are hyperresponsive to LPS, whereas a more variable response to IL-1 is seen. Further analysis of the LPS response revealed that plasma membrane-associated IRAK-1 is found in Toll 4, IL-1, and TNF R1-containing complexes. The data presented herein suggest a model whereby the TNF R1-IRAK-1 interaction integrates the cellular response to LPS, TNF-α, and IL-1, culminating in a cell poised to activate TNF-α-dependent NF-κB controlled gene expression. In the absence of TNF R1-dependent events, exposure to LPS or IL-1 leads to hyperactivation of the inflammatory response.

scholarly journals TRAF6 and TAK1 contribute to SAMHD1-mediated negative regulation of NF-κB signaling

2020 ◽  
Author(s):  
Constanza E. Espada ◽  
Corine St. Gelais ◽  
Serena Bonifati ◽  
Victoria V. Maksimova ◽  
Michael P. Cahill ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Transforming Growth Factor ◽  
Negative Regulation ◽  
Innate Immune ◽  
Negative Regulator ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Intracellular Dntp ◽  
Hiv 1

Sterile alpha motif and HD-domain-containing protein 1 (SAMHD1) restricts HIV-1 replication by limiting the intracellular dNTP pool. SAMHD1 also suppresses the activation of NF-κB in response to viral infections and inflammatory stimuli. However, the mechanisms by which SAMHD1 negatively regulates this pathway remain unclear. Here we show that SAMHD1-mediated suppression of NF-κB activation is modulated by two key mediators of NF-κB signaling, tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and transforming growth factor-ß-activated kinase-1 (TAK1). We compared NF-κB activation stimulated by interleukin (IL)-1ß in monocytic THP-1 control and SAMHD1 knockout (KO) cells with and without partial TRAF6 knockdown (KD), or in cells treated with TAK1 inhibitors. Relative to control cells, IL-1ß-treated SAMHD1 KO cells showed increased phosphorylation of the inhibitor of NF-κB (IκBα), an indication of pathway activation, and elevated levels of TNF-α mRNA. Moreover, SAMHD1 KO combined with TRAF6 KD or pharmacological TAK1 inhibition reduced IκBα phosphorylation and TNF-α mRNA to the level of control cells. SAMHD1 KO cells infected with single-cycle HIV-1 showed elevated infection and TNF-α mRNA levels compared to control cells, and the effects were significantly reduced by TRAF6 KD or TAK1 inhibition. We further demonstrated that overexpressed SAMHD1 inhibited TRAF6-stimulated NF-κB reporter activity in HEK293T cells in a dose-dependent manner. SAMHD1 contains a nuclear localization signal (NLS), but an NLS-defective SAMHD1 exhibited a suppressive effect similar to the wild-type protein. Our data suggest that the TRAF6-TAK1 axis contributes to SAMHD1-mediated suppression of NF-κB activation and HIV-1 infection. Importance Cells respond to pathogen infection by activating a complex innate immune signaling pathway, which culminates in the activation of transcription factors and secretion of a family of functionally and genetically related cytokines. However, excessive immune activation may cause tissue damage and detrimental effects on the host. Therefore, in order to maintain host homeostasis, the innate immune response is tightly regulated during viral infection. We have reported SAMHD1 as a novel negative regulator of the innate immune response. Here, we provide new insights into SAMHD1-mediated negative regulation of the NF-κB pathway at the TRAF6-TAK1 checkpoint. We show that SAMHD1 inhibits TAK1 activation and TRAF6 signaling in response to proinflammatory stimuli. Interestingly, TRAF6 knockdown in SAMHD1-deficient cells significantly inhibited HIV-1 infection and activation of NF-κB induced by virus infection. Our research reveals a new negative regulatory mechanism by which SAMHD1 participates in the maintenance of cellular homeostasis during HIV-1 infection and inflammation.

The Zinc Finger Protein Gfi1 Controls TLR4-Mediated Inflammatory Response by Directly Antagonizing NF-κB Transcription Factor

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 469-469
Author(s):  
Ehssan Sharif-Askari ◽  
Hui Zeng ◽  
Lothar Vassen ◽  
Christian Kosan ◽  
Cyrus Khandanpour ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Direct Interaction ◽  
Innate Immune ◽  
Dependent Manner ◽  
Negative Regulators ◽  
Tlr Signaling ◽  
Tnf Α ◽  
Dose Dependent ◽  
Lps Treatment ◽  
Stimulation Of

Abstract Inflammatory responses are complex and comprise multiple mediators including cytokines such as TNF-alpha (TNF-α) and IL-1beta. These cytokines are synthesized and secreted in response to signaling by plasma membrane receptors of the Toll-like receptor (TLR) family. A central downstream element of TLR-dependent signaling is the transcription factor NF-kappaB (NF-κB), which plays a pivotal role in controlling the proper sequence of events during an inflammatory response. In unstimulated cells, NF-κB is bound to inhibitory IkappaB (IκB) proteins and remains sequestered in the cytoplasm. Stimulation of TLRs triggers a signaling cascade that leads to phosphorylation and proteasomal degradation of IκB, resulting in the translocation of NF-κB to the nucleus, where it acts as a transcriptional activator of target genes. To keep the innate immune system under control, the TLR signaling cascade is under a tight control of many positive and negative regulators. We have previously shown that the transcription factor Growth Factor Independence 1 (Gfi1) represents a novel factor limiting the inflammatory immune response including TNF-α. Gfi1-deficient (Gfi1−/−) mice show a very strong systemic response to the TLR4 ligand and endotoxin LPS and die rapidly within 36 h with symptoms of septic shock. Here, we investigated the molecular mechanism of this exaggerated TNF-α production in the absence of Gfi1. It is known that endotoxin stimulation results in the activation of the transcription factor NF-κB through TLR4, leading to TNF-α production. This activation also resulted in rapid and de novo expression of Gfi1 in the nucleus in a time- and dose-dependent manner. The expression of Gfi1 was not due to feedback regulation from secreted TNF, since TNF-deficient macrophages were also able to upregulate Gfi1 mRNA following LPS stimulation. As expected, LPS stimulation of Gfi1−/− macrophages resulted in significantly higher levels of TNF-α mRNA, and secreted TNF-α cytokine. Strikingly and in contrast to most known negative regulators of TLRs, Gfi1 did not affect the activity or the expression levels of the cytoplasmic components of TLR signaling pathway. Additionally, NF-κB phosphorylation and nuclear translocation post- LPS treatment were intact in both Gfi1−/− and Gfi1+/+ macrophages. Immunoprecipitation analysis from cells endogenously expressing Gfi1 and NF-κB or over-expressing these two proteins post transfection, clearly revealed a direct interaction between Gfi1 and the p65 subunit of NF-κB. Immunofluorescence staining of macrophages post-LPS treatment confirmed direct interaction of these two proteins in the nucleus at the endogenous level. Gfi1 represses transcription by binding to DNA recognition sequences in target gene promoters. Thus, aiming to investigate the effect of Gfi1 expression on NF-κB nuclear signaling, we found that LPS treatment enhances NF-κB DNA binding activity in Gfi1−/− macrophages as compared to Gfi1+/+ cells. Furthermore, over expression of Gfi1 protein resulted in negative regulation of NF-κB mediated gene activation in a dose-dependent manner. Chromatin immune precipitation with anti-p65 antibodies from LPS stimulated Gfi1+/+ and Gfi1−/− macrophages revealed enhanced NF-κB promoter occupancy at the TNF gene in Gfi1−/− macrophages as compared to Gfi1+/+ cells. In conclusion, our findings reveal a novel function for Gfi1 in the innate immune response by directly antagonizing NF-κB function. This molecular perceptive of TNF-α regulation during inflammation may provide an attractive strategy for therapeutic intervention in chronic inflammatory diseases and certain cancers.

scholarly journals Dimethyl itaconate inhibits TNF-α induced NF-κB signaling pathway in human epithelial cells

2020 ◽  
Author(s):  
Yalei Zhang ◽  
Xiaobing Deng ◽  
Hao Liang ◽  
Annan Guo ◽  
Kenan Li ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Cysteine Residue ◽  
Luciferase Assay ◽  
Dependent Manner ◽  
Nuclear Entry ◽  
Tnf Α ◽  
Novel Strategy ◽  
Dose Dependent ◽  
Dimethyl Itaconate

Abstract Background: Dimethyl itaconate (DMI), a membrane-permeable derivative of itaconate, was found to moderate IL-17-IκBζ-induced skin pathology including psoriasis in mouse experiments . TNF-α induced NF-κB pathway, which controls a variety of immune and inflammatory responses, was also proven to play a crucial role as mediator in psoriasis. However, whether DMI interacts with the TNF-α induced NF-κB pathway remains unclear. Results: Here we show that DMI inhibits TNF-α induced NF-κB transcriptional activities in dose-dependent manner in several human cell lines using dual luciferase assay and blocks the NF-κB nuclear entry. Moreover, DMI potently inhibits IKKβ dependent phosphorylation and degradation of IκBα in TNF-α induced activation of NF-κB pathway. We also demonstrate that DMI covalently binds to cysteine residue in IKKβ, a key regulator in NF-κB pathway, to suppress IKKβ activation and inhibit the canonical NF-κB pathway. Conclusion Our study presents a new mechanism for DMI as an anti-inflammatory agent that may have therapeutic potentials in treating NF-κB related human inflammatory diseases. Our results also suggest that itaconate produced by endogenous IRG1 may regulate NF-κB at post translation modification level, and the IRG1-itaconate-NF-κB axis could be targeted as a novel strategy for the treatment of IRG1-NF-κB mediated diseases.

scholarly journals A Chemokine-Degrading Extracellular Protease Made by Group A Streptococcus Alters Pathogenesis by Enhancing Evasion of the Innate Immune Response

2008 ◽  
Vol 76 (3) ◽  
pp. 978-985 ◽  
Author(s):  
Paul Sumby ◽  
Shizhen Zhang ◽  
Adeline R. Whitney ◽  
Fabiana Falugi ◽  
Guido Grandi ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Group A Streptococcus ◽  
Cell Envelope ◽  
Innate Immune ◽  
Infection Model ◽  
Dependent Manner ◽  
Wild Type ◽  
Group A

ABSTRACT Circumvention of the host innate immune response is critical for bacterial pathogens to infect and cause disease. Here we demonstrate that the group A Streptococcus (GAS; Streptococcus pyogenes) protease SpyCEP (S. pyogenes cell envelope protease) cleaves granulocyte chemotactic protein 2 (GCP-2) and growth-related oncogene alpha (GROα), two potent chemokines made abundantly in human tonsils. Cleavage of GCP-2 and GROα by SpyCEP abrogated their abilities to prime neutrophils for activation, detrimentally altering the innate immune response. SpyCEP expression is negatively regulated by the signal transduction system CovR/S. Purified recombinant CovR bound the spyCEP gene promoter region in vitro, indicating direct regulation. Immunoreactive SpyCEP protein was present in the culture supernatants of covR/S mutant GAS strains but not in supernatants from wild-type strains. However, wild-type GAS strains do express SpyCEP, where it is localized to the cell wall. Strain MGAS2221, an organism representative of the highly virulent and globally disseminated M1T1 GAS clone, differed significantly from its isogenic spyCEP mutant derivative strain in a mouse soft tissue infection model. Interestingly, and in contrast to previous studies, the isogenic mutant strain generated lesions of larger size than those formed following infection with the parent strain. The data indicate that SpyCEP contributes to GAS virulence in a strain- and disease-dependent manner.

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