TNF overproduction impairs epithelial staphylococcal response in hyper IgE syndrome

Myles, Ian A.; Anderson, Erik D.; Earland, Noah; Zarember, Kol A.; Sastalla, Inka; Williams, Kelli W.; Gough, Portia; Moore, Ian N.; Ganesan, Sundar; Fowler, Cynthia; Laurence, Arian; Garofalo, Mary; Kuhns, Douglas B.; Kieh, Mark D.; Saleem, Arhum; Welch, Pamela A.; Darnell, Dirk; Gallin, John I.; Freeman, Alexandra F.; Holland, Steven M.; Datta, Sandip K.

doi:10.1172/jci121486

Cited by 27 publications

(30 citation statements)

References 49 publications

(54 reference statements)

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“…However, overproduction of these cytokines has detrimental effects on the host, including systemic inflammation and severe tissue damage (42,43). In this study, Etanercept increased survival of TCR -/mice infected by P. aeruginosa, suggesting that the overproduction of TNF in the absence of  T cells contributes to increased mortality.…”

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confidence: 53%

Mice Lacking γδ T Cells Exhibit Impaired Clearance of Pseudomonas aeruginosa Lung Infection and Excessive Production of Inflammatory Cytokines

et al. 2020

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Pseudomonas aeruginosa is an opportunistic pathogen that causes chronic and life-threatening infections in immunocompromised patients. A better understanding of the role that innate immunity plays in the control of P. aeruginosa infection is crucial for therapeutic development. Specifically, the role of unconventional immune cells like γδ T cells in the clearance of P. aeruginosa lung infection is not yet well characterized. In this study, the role of γδ T cells was examined in an acute mouse model of P. aeruginosa lung infection. In the absence of γδ T cells, mice displayed impaired bacterial clearance and decreased survival, outcomes which were associated with delayed neutrophil recruitment and impaired recruitment of other immune cells (macrophages, T cells, natural killer cells, and natural killer T [NKT] cells) into the airways. Despite reduced NKT cell recruitment in the airways of mice lacking γδ T cells, NKT cell-deficient mice exhibited wild-type level control of P. aeruginosa infection. Proinflammatory cytokines were also altered in γδ T cell-deficient mice, with increased production of interleukin-1β, interleukin-6, and tumor necrosis factor. γδ T cells did not appear to contribute significantly to the production of interleukin-17A or the chemokines CXCL1 and CXCL2. Importantly, host survival could be improved by inhibiting tumor necrosis factor signaling with the soluble receptor construct etanercept in γδ cell-deficient mice. These findings demonstrate that γδ T cells play a protective role in coordinating the host response to P. aeruginosa lung infection, both in contributing to early immune cell recruitment and by limiting inflammation.

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confidence: 53%

Mice Lacking γδ T Cells Exhibit Impaired Clearance of Pseudomonas aeruginosa Lung Infection and Excessive Production of Inflammatory Cytokines

et al. 2020

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“…Viable bacterial colonies were only detectable in the pulmonary tissue of neutropenic mice inoculated with CNS (Figure 4). In contrast, known pathogens such as the methicillin resistant S. aureus (MRSA) isolate USA300-LAC have demonstrated marked pathology in pulmonary and systemic models in wild type mice (Gaidamakova et al, 2012; Myles et al, 2018b).…”

Section: Resultsmentioning

confidence: 99%

Differing Virulence of Healthy Skin Commensals in Mouse Models of Infection

Myles

Moore

Castillo

et al. 2019

Front. Cell. Infect. Microbiol.

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Introduction: As therapies for atopic dermatitis (AD) based on live biotherapeutic products (LBP) are developed, the potential displacement of biotherapeutic strains, and species to mucosal sites where they are not naturally found is of investigative interest. However, formal assessment of the toxicity potential of healthy skin commensal organisms has not been reported in the literature. Our previous research indicates that topical application of live Roseomonas mucosa to treat AD was associated with clinical benefit on the skin, but the effects of exposure via inhalation, eye inoculation, and ingestion were unknown.Methods: Herein we report our findings from mice inoculated with commensal strains of R. mucosa, coagulase negative Staphylococci (CNS), and Pseudomonas aeruginosa. Bacterial isolates were collected under clinical trial NCT03018275, however these results do not represent an interventional clinical trial.Results: Our tested R. mucosa isolates did not display significant infection or inflammation. However, neutropenic mice inoculated with CNS had infection without major inflammation in pulmonary models. In contrast, systemic infection generated hepatic and splenic pathology for P. aeruginosa and CNS, which was worsened by the presence of neutropenia.Discussion: Our results suggest that LBP derived from bacteria without significant infectivity histories, such as R. mucosa, may represent safer options than known pathobionts like P. aeruginosa and Staphylococcus spp. Overall, these results suggest that topically applied LBP from select skin commensals are likely to present safe therapeutic options and reinforce our prior clinical findings.

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“…For example, S. aureus colonization is frequently associated with atopic dermatitis and psoriasis, skin diseases that feature epidermal barrier dysfunction 65–68 , and S. aureus may actually contribute to skin inflammation in these patients 69 . Recurrent S. aureus SSTI is also a hallmark of autosomal dominant hyper IgE syndrome (AD-HIES) 70 and it has recently been shown that the impaired epithelial response to infection in these patients results from overproduction of the pro-inflammatory cytokine TNFα 71 . TNFα also contributes to the severity of atopic dermatitis, though TNF blockade by anti-TNF biologicals has thus far failed to improve outcomes in these patients 72 .…”

Section: Discussionmentioning

confidence: 99%

GPER activation protects against epithelial barrier disruption by Staphylococcus aureus α-toxin

Triplett

Pokhrel

Castleman

et al. 2019

Sci Rep

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Sex bias in innate defense against Staphylococcus aureus skin and soft tissue infection (SSTI) is dependent on both estrogen production by the host and S. aureus secretion of the virulence factor, α-hemolysin (Hla). The impact of estrogen signaling on the immune system is most often studied in terms of the nuclear estrogen receptors ERα and ERβ. However, the potential contribution of the G protein-coupled estrogen receptor (GPER) to innate defense against infectious disease, particularly with respect to skin infection, has not been addressed. Using a murine model of SSTI, we found that GPER activation with the highly selective agonist G-1 limits S. aureus SSTI and Hla-mediated pathogenesis, effects that were absent in GPER knockout mice. Specifically, G-1 reduced Hla-mediated skin lesion formation and pro-inflammatory cytokine production, while increasing bacterial clearance. In vitro, G-1 reduced surface expression of the Hla receptor, ADAM10, in a human keratinocyte cell line and increased resistance to Hla-mediated permeability barrier disruption. This novel role for GPER activation in skin innate defense against infectious disease suggests that G-1 may have clinical utility in patients with epithelial permeability barrier dysfunction or who are otherwise at increased risk of S. aureus infection, including those with atopic dermatitis or cancer.

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TNF overproduction impairs epithelial staphylococcal response in hyper IgE syndrome

Cited by 27 publications

References 49 publications

Mice Lacking γδ T Cells Exhibit Impaired Clearance of Pseudomonas aeruginosa Lung Infection and Excessive Production of Inflammatory Cytokines

Mice Lacking γδ T Cells Exhibit Impaired Clearance of Pseudomonas aeruginosa Lung Infection and Excessive Production of Inflammatory Cytokines

Differing Virulence of Healthy Skin Commensals in Mouse Models of Infection

GPER activation protects against epithelial barrier disruption by Staphylococcus aureus α-toxin

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