TLR7 Contributes to the Rapid Progression but Not to the Overall Fatal Outcome of Secondary Pneumococcal Disease following Influenza A Virus Infection

Stegemann-Koniszewski, Sabine; Gereke, Marcus; Orrskog, Sofia; Lienenklaus, Stefan; Pasche, Bastian; Bader, Sophie R.; Gruber, Achim D.; Akira, Shizuo; Weiß, Siegfried; Henriques‐Normark, Birgitta; Bruder, Dunja; Gunzer, Matthias

doi:10.1159/000345112

Cited by 18 publications

(22 citation statements)

References 77 publications

(83 reference statements)

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“…A clear and distinct role for TLR7 in survival following IAV infection has so far been demonstrated only in mice expressing functional Mx1, unlike the commonly used laboratory mouse strains ( 36 ). We and others have rather found TLR7 to be involved in the fine-tuning of innate and adaptive anti-IAV responses ( 19 , 37 , 38 ), and in our model of respiratory IAV infection, there was no difference in morbidity and mortality between WT and TLR7-deficient hosts (see Fig. S6 in the supplemental material).…”

Section: Discussionsupporting

confidence: 54%

“…Nevertheless, we found the AECII response to IAV to be substantially blunted in the absence of TLR7. As both unchanged and clearly diminished IFN I production have been described in TLR7ko mice ( 19 , 39 ), it was surprising that TLR7 played such a central role in ensuring a robust early IFN response in our model. Most likely, the reduced levels of IFN I/III in the respiratory tract of TLR7ko mice to a large extent accounted for the blunted AECII response in these mice, especially since many of the regulated transcripts were ISG.…”

Section: Discussionmentioning

confidence: 66%

“…S1 in the supplemental material). Typically, inflammatory mediators and immune cell recruitment to the respiratory tract are induced by day 3 postinfection ( 19 ), and we analyzed transcriptional regulation in AECII and lung tissue at this time point. For AECII, two independent microarray experiments were conducted for each condition and the material for each independent experiment was pooled from five infected animals.…”

Section: Resultsmentioning

confidence: 99%

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Alveolar Type II Epithelial Cells Contribute to the Anti-Influenza A Virus Response in the Lung by Integrating Pathogen- and Microenvironment-Derived Signals

Stegemann-Koniszewski

Jeron

Gereke

et al. 2016

mBio

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Influenza A virus (IAV) periodically causes substantial morbidity and mortality in the human population. In the lower lung, the primary targets for IAV replication are type II alveolar epithelial cells (AECII), which are increasingly recognized for their immunological potential. So far, little is known about their reaction to IAV and their contribution to respiratory antiviral immunity in vivo. Therefore, we characterized the AECII response during early IAV infection by analyzing transcriptional regulation in cells sorted from the lungs of infected mice. We detected rapid and extensive regulation of gene expression in AECII following in vivo IAV infection. The comparison to transcriptional regulation in lung tissue revealed a strong contribution of AECII to the respiratory response. IAV infection triggered the expression of a plethora of antiviral factors and immune mediators in AECII with a high prevalence for interferon-stimulated genes. Functional pathway analyses revealed high activity in pathogen recognition, immune cell recruitment, and antigen presentation. Ultimately, our analyses of transcriptional regulation in AECII and lung tissue as well as interferon I/III levels and cell recruitment indicated AECII to integrate signals provided by direct pathogen recognition and surrounding cells. Ex vivo analysis of AECII proved a powerful tool to increase our understanding of their role in respiratory immune responses, and our results clearly show that AECII need to be considered a part of the surveillance and effector system of the lower respiratory tract.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 66%

Section: Resultsmentioning

confidence: 99%

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Alveolar Type II Epithelial Cells Contribute to the Anti-Influenza A Virus Response in the Lung by Integrating Pathogen- and Microenvironment-Derived Signals

Stegemann-Koniszewski

Jeron

Gereke

et al. 2016

mBio

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“…However, owing to a number of studies published over the last years, it is now largely understood that IAV infection also modulates the host’s immune system leaving it unable to mount an adequate anti-bacterial defense [ 92 , 93 ]. The proposed underlying mechanisms include the desensitization of alveolar macrophages [ 94 ], as well as the IFN-γ mediated suppression of their phagocytic function [ 95 , 96 ]. The recruitment and function of neutrophils, NK cells, and gamma-delta T cells have also been shown to be modulated during IAV infections [ 97 , 98 , 99 ].…”

Section: Discussion and Future Perspectivesmentioning

confidence: 99%

Modeling Influenza Virus Infection: A Roadmap for Influenza Research

Boianelli

Nguyen

Ebensen

et al. 2015

Viruses

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142

135

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Influenza A virus (IAV) infection represents a global threat causing seasonal outbreaks and pandemics. Additionally, secondary bacterial infections, caused mainly by Streptococcus pneumoniae, are one of the main complications and responsible for the enhanced morbidity and mortality associated with IAV infections. In spite of the significant advances in our knowledge of IAV infections, holistic comprehension of the interplay between IAV and the host immune response (IR) remains largely fragmented. During the last decade, mathematical modeling has been instrumental to explain and quantify IAV dynamics. In this paper, we review not only the state of the art of mathematical models of IAV infection but also the methodologies exploited for parameter estimation. We focus on the adaptive IR control of IAV infection and the possible mechanisms that could promote a secondary bacterial coinfection. To exemplify IAV dynamics and identifiability issues, a mathematical model to explain the interactions between adaptive IR and IAV infection is considered. Furthermore, in this paper we propose a roadmap for future influenza research. The development of a mathematical modeling framework with a secondary bacterial coinfection, immunosenescence, host genetic factors and responsiveness to vaccination will be pivotal to advance IAV infection understanding and treatment optimization.

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“…Influenza is commonly associated with a high risk of complications in children, the elderly, and adults with certain conditions such as asthma, diabetes, morbid obesity, and pregnancy (Barker and Mullooly 1980; Barker and Mullooly 1982; Singleton et al 2004; Jain et al 2009). Only recently has it been recognized that the majority of deaths following influenza infection result from ensuing bacterial superinfection, most commonly caused by Streptococcus pneumoniae (Kash et al 2011; Li et al 2012; Weeks-Gorospe et al 2012; Marzano et al 2013; Stegemann-Koniszewski et al 2013). In addition to pneumonia, this secondary bacterial infection can lead to disseminated infections, such as meningitis and septicemia (Cartwright 2002).…”

Section: Introductionmentioning

confidence: 99%

Desialylation of airway epithelial cells during influenza virus infection enhances pneumococcal adhesion via galectin binding

Niță-Lazăr

Banerjee

Feng

et al. 2015

Molecular Immunology

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The continued threat of worldwide influenza pandemics, together with the yearly emergence of antigenically drifted influenza A virus (IAV) strains, underscore the urgent need to elucidate not only the mechanisms of influenza virulence, but also those mechanisms that predispose influenza patients to increased susceptibility to subsequent infection with Streptococcus pneumoniae. Glycans displayed on the surface of epithelia that are exposed to the external environment play important roles in microbial recognition, adhesion, and invasion. It is well established that the IAV hemagglutinin and pneumococcal adhesins enable their attachment to the host epithelia. Reciprocally, the recognition of microbial glycans by host carbohydrate-binding proteins (lectins) can initiate innate immune responses, but their relevance in influenza or pneumococcal infections is poorly understood. Galectins are evolutionarily conserved lectins characterized by affinity for β-galactosides and a unique sequence motif, with critical regulatory roles in development and immune homeostasis. In this study, we examined the possibility that galectins expressed in the airway epithelial cells might play a significant role in viral or pneumococcal adhesion to airway epithelial cells. Our results in a mouse model for influenza and pneumococcal infection revealed that the murine lung expresses a diverse galectin repertoire, from which selected galectins, including galectin 1 (Gal1) and galectin 3 (Gal3), are released to the bronchoalveolar space. Further, the results showed that influenza and subsequent S. pneumoniae infections significantly alter the glycosylation patterns of the airway epithelial surface and modulate galectin expression. In vitro studies on the human airway epithelial cell line A549 were consistent with the observations made in the mouse model, and further revealed that both Gal1 and Gal3 bind strongly to IAV and S. pneumoniae, and that exposure of the cells to viral neuraminidase or influenza infection increased galectin-mediated S. pneumoniae adhesion to the cell surface. Our results suggest that upon influenza infection, pneumococcal adhesion to the airway epithelial surface is enhanced by an interplay among the host galectins and viral and pneumococcal neuraminidases. The observed enhancement of pneumococcal adhesion may be a contributing factor to the observed hypersusceptibility to pneumonia of influenza patients.

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TLR7 Contributes to the Rapid Progression but Not to the Overall Fatal Outcome of Secondary Pneumococcal Disease following Influenza A Virus Infection

Cited by 18 publications

References 77 publications

Alveolar Type II Epithelial Cells Contribute to the Anti-Influenza A Virus Response in the Lung by Integrating Pathogen- and Microenvironment-Derived Signals

Alveolar Type II Epithelial Cells Contribute to the Anti-Influenza A Virus Response in the Lung by Integrating Pathogen- and Microenvironment-Derived Signals

Modeling Influenza Virus Infection: A Roadmap for Influenza Research

Desialylation of airway epithelial cells during influenza virus infection enhances pneumococcal adhesion via galectin binding

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