STAT1 Is Required for Suppression of Type 17 Immunity during Influenza and Bacterial Superinfection

Lee, Benjamin; Gopal, Radha; Manni, Michelle L.; McHugh, Kevin J.; Mandalapu, Sivanarayana; Robinson, Keven M.; Alcorn, John F.

doi:10.4049/immunohorizons.1700030

Cited by 38 publications

(38 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have previously shown that influenza-associated IFNβ attenuated host bacterial defense due to suppression of Type 17 immunity ( 13 , 14 ). Also, we recently identified that Type 17 immunity is rescued in the absence of STAT1 signaling during influenza-bacterial super-infection ( 17 ). In this study, we examined the effects of MRSA challenge on day 6 of influenza infection in WT and Stat2 − /− mice.…”

Section: Resultsmentioning

confidence: 99%

“…Further, we have also shown increased bacterial control in Ifnar −/− mice during super-infection, suggesting that influenza-induced type I IFN is a critical mediator of antibacterial immune suppression ( 13 ). Also, we have recently shown increased Type 17 immunity in STAT1 −/− mice during super-infection ( 17 ). Therefore, we hypothesized that STAT2 deficiency would rescue suppression of Type 17 responses during influenza infection.…”

Section: Discussionmentioning

confidence: 96%

“…These data suggest that influenza-induced STAT1 and STAT2 signaling is critical to mediating susceptibility to secondary bacterial pneumonia. We have recently shown that STAT1 is involved in increasing bacterial burden through suppression of the Type 17 immune response during influenza-bacterial super-infection ( 17 ). However, little is known regarding the specific role of STAT2 in super-infection.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

STAT2 Signaling Regulates Macrophage Phenotype During Influenza and Bacterial Super-Infection

et al. 2018

Self Cite

View full text Add to dashboard Cite

Influenza is a common respiratory virus that infects between 5 and 20% of the US population and results in 30,000 deaths annually. A primary cause of influenza-associated death is secondary bacterial pneumonia. We have previously shown that influenza induces type I interferon (IFN)-mediated inhibition of Type 17 immune responses, resulting in exacerbation of bacterial burden during influenza and Staphylococcus aureus super-infection. In this study, we investigated the role of STAT2 signaling during influenza and influenza-bacterial super-infection in mice. Influenza-infected STAT2−/− mice had increased morbidity, viral burden, and inflammation when compared to wild-type mice. Despite an exaggerated inflammatory response to influenza infection, we found increased bacterial control and survival in STAT2 deficient mice during influenza-MRSA super-infection compared to controls. Further, we found that increased bacterial clearance during influenza-MRSA super-infection is not due to rescue of Type 17 immunity. Absence of STAT2 was associated with increased accumulation of M1, M2 and M1/M2 co-expressing macrophages during influenza-bacterial super-infection. Neutralization of IFNγ (M1) and/or Arginase 1 (M2) impaired bacterial clearance in Stat2−/− mice during super-infection, demonstrating that pulmonary macrophages expressing a mixed M1/M2 phenotype promote bacterial control during influenza-bacterial super-infection. Together, these results suggest that the STAT2 signaling is involved in suppressing macrophage activation and bacterial control during influenza-bacterial super-infection. Further, these studies reveal novel mechanistic insight into the roles of macrophage subpopulations in pulmonary host defense.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

STAT2 Signaling Regulates Macrophage Phenotype During Influenza and Bacterial Super-Infection

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…Lee, et al . 19 reported that STAT1 signaling played a detrimental role in influenza infection by controlling the magnitude of type 17 immune activation. GBP1 , an interferon-inducible protein, was reported to inhibit the replication of influenza virus by contributing to the host immune response 20 .…”

Section: Discussionmentioning

confidence: 99%

Sex-specific patterns of gene expression following influenza vaccination

Wen

Guo

et al. 2018

Sci Rep

View full text Add to dashboard Cite

Sex-based variations in the immune response to the influenza vaccines was reported, however, the genetic basis responsible for the sex variations in the immune response toward the influenza vaccines remains unclear. Here, the genes responsible for sex-specific responses after vaccination with trivalent inactivated influenza virus were identified. These genes were enriched in virus response pathways, especially interferon signaling. A list of genes showing different responses to the vaccine between females and males were obtained next. Our results demonstrated that females generate stronger immune responses to seasonal influenza vaccines within 24 hours than males. However, most of these genes with variability between sexes had the opposite expression levels after three days, suggesting that males retained the immune responses longer than female. To summary, our study identified genes responsible for the sex variations toward influenza vaccination. Our findings might provide insights into the development of the sex-dependent influenza vaccines.

show abstract

“…This proposal is often based on the function of the STAT1 transcription factor that is essential for each type of IFN signaling pathway. For example, STAT1 deficiencies, similar to IFNR deficiencies, in transgenic mouse models results in a marked increase in susceptibility to viral infection (3)(4)(5)(6), including respiratory viral infection (7,8). The central role of STAT1 in antiviral defense is further highlighted by observations that viruses often selectively target STAT1 function to subvert the immune response (9).…”

mentioning

confidence: 99%

Respiratory Enterovirus (like Parainfluenza Virus) Can Cause Chronic Lung Disease if Protection by Airway Epithelial STAT1 Is Lost

Zhang

Mao

Keeler

et al. 2019

The Journal of Immunology

View full text Add to dashboard Cite

Epithelial barrier cells are proposed to be critical for host defense, and airway epithelial cell capacity for IFN signal transduction is presumed to protect against respiratory viral infection. However, it has been difficult to fully test these concepts given the absence of tools to analyze IFN signaling specific to airway epithelial cells in vivo. To address these issues, we generated a new line of transgenic mice with Cre-driver genes (Foxj1 and Scgb1a1) for a floxed-Stat1 allele (designated Foxj1-Scgb1a1-Cre-Stat1f/f mice) to target the master IFN signal regulator STAT1 in airway epithelial cells and tested these mice for control of infection because of mouse parainfluenza (Sendai) virus and human enterovirus D68 (EV-D68). Indeed, both types of infections showed increases in viral titers and severity of acute illness in Foxj1-Scgb1a1-Cre-Stat1f/f mice and conventional Stat1−/− mice compared with wild-type mice. In concert, the chronic lung disease that develops after Sendai virus infection was also increased in Foxj1-Scgb1a1-Cre-Stat1f/f and Stat1–/– mice, marked by airway and adjacent parenchymal immune cell infiltration and mucus production for at least 7 wk postinfection. Unexpectedly, relatively mild EV-D68 infection also progressed to chronic lung disease in Foxj1-Scgb1a1-Cre-Stat1f/f and Stat1−/− mice but was limited (like viral replication) to airways. The results thereby provide proof-of-concept for a critical role of barrier epithelial cells in protection from acute illness and chronic disease after viral infection and suggest a specific role for airway epithelial cells given the limitation of EV-D68 replication and acute and chronic manifestations of disease primarily to airway tissue.

show abstract

STAT1 Is Required for Suppression of Type 17 Immunity during Influenza and Bacterial Superinfection

Cited by 38 publications

References 32 publications

STAT2 Signaling Regulates Macrophage Phenotype During Influenza and Bacterial Super-Infection

STAT2 Signaling Regulates Macrophage Phenotype During Influenza and Bacterial Super-Infection

Sex-specific patterns of gene expression following influenza vaccination

Respiratory Enterovirus (like Parainfluenza Virus) Can Cause Chronic Lung Disease if Protection by Airway Epithelial STAT1 Is Lost

Contact Info

Product

Resources

About