The influenza-injured lung microenvironment promotes MRSA virulence, contributing to severe secondary bacterial pneumonia

Langouët-Astrié, Christophe; Oshima, Kêichi; McMurtry, Sarah A.; Yang, Yimu; Kwieciński, Jakub; LaRivière, Wells B.; Kavanaugh, J.S.; Zakharevich, Igor; Hansen, Kirk C.; Shi, Deling; Zhang, Fuming; Boguslawski, Kristina M.; Perelman, Sofya S.; Su, Gouwei; Torres, Victor J.; Liu, Jian; Horswill, Alexander R.; Schmidt, Eric P.

doi:10.1016/j.celrep.2022.111721

Cited by 13 publications

(6 citation statements)

References 99 publications

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“…The recent demonstrations that alveolar heparan sulfate can be actively shed into the airways during lung inflammation in ARDS patients (9), in an LPS-mediated experimental model of acute lung injury (9) and following influenza infection in mice (42) are in line with our observations. We observed increased GAG shedding upon heparinase treatment, but only in infected mice, indicating that it is an active process driven by pneumococcal pneumonia.…”

Section: Discussionsupporting

confidence: 90%

Enzymatic modulation of the pulmonary glycocalyx alters susceptibility toStreptococcus pneumoniae

Goekeri,

Linke,

Hoffmann

et al. 2024

Preprint

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The pulmonary epithelial glycocalyx is rich in glycosaminoglycans such as hyaluronan and heparan sulfate. Despite their presence, the precise role of these glycosaminoglycans in bacterial lung infections remains elusive. To address this, we intranasally inoculated mice with Streptococcus pneumoniae in the presence or absence of enzymes targeting pulmonary hyaluronan and heparan sulfate, followed by characterization of subsequent disease pathology, pulmonary inflammation, and lung barrier dysfunction. Enzymatic degradation of hyaluronan and heparan sulfate exacerbated pneumonia in mice, as evidenced by increased disease scores and alveolar neutrophil recruitment. However, targeting epithelial hyaluronan further exacerbated systemic disease, indicated by elevated splenic bacterial load and plasma levels of pro-inflammatory cytokines. In contrast, enzymatic cleavage of heparan sulfate resulted in increased bronchoalveolar bacterial burden, lung damage and pulmonary inflammation in mice infected with Streptococcus pneumoniae. Accordingly, heparinase-treated mice also exhibited disrupted lung barrier integrity as evidenced by higher alveolar edema scores and vascular protein leakage into the airways. This finding was corroborated in a human alveolus-on-a-chip platform, confirming that heparinase treatment also disrupts the human lung barrier. Notably, enzymatic pre-treatment with either hyaluronidase or heparinase also rendered human epithelial cells more sensitive to pneumococcal-induced barrier disruption, as determined by transepithelial electrical resistance measurements, consistent with our findings in murine pneumonia. Taken together, these findings demonstrate the importance of intact hyaluronan and heparan sulfate in controlling pneumococcal virulence, pulmonary inflammation, and epithelial barrier function.

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Section: Discussionsupporting

confidence: 90%

Enzymatic modulation of the pulmonary glycocalyx alters susceptibility toStreptococcus pneumoniae

Goekeri,

Linke,

Hoffmann

et al. 2024

Preprint

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show abstract

“…Given that S. aureus is one of the predominant causes of pneumonia, whole lung RNA‐sequencing data from mice with S. aureus primary pneumonia and controls were obtained from published studies and analysed 25 . Notably, significantly higher HDAC6 expression was observed in S. aureus ‐infected mice versus control mice (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

“…Given that S. aureus is one of the predominant causes of pneumonia, whole lung RNA-sequencing data from mice with S. aureus primary pneumonia and controls were obtained from published studies and analysed. 25 Notably, significantly higher HDAC6 expression was observed in S. aureus-infected mice versus control mice (Figure 1A). Similarly, western blotting (Figure 1B) and quantification (Figure 1C) showed that the level of HDAC6 in the S. aureusinfected bone marrow-derived macrophages (BMDMs) was higher than that in the control group and increased in a multiplicity of infection (MOI)-dependent manner.…”

Section: Hdac6 Is Upregulated In S Aureus Pneumoniamentioning

confidence: 94%

HDAC6 inhibitor promotes reactive oxygen species‐meditated clearance of Staphylococcus aureus in macrophage

Yimiti,

Fei,

Yang

et al. 2024

Clin Exp Pharma Physio

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Staphylococcus aureus (S. aureus) pneumonia has become an increasingly important public health problem. Recent evidence suggests that epigenetic modifications are critical in the host immune defence against pathogen infection. In this study, we found that S. aureus infection induces the expression of histone deacetylase 6 (HDAC6) in a dose‐dependent manner. Furthermore, by using a S. aureus pneumonia mouse model, we showed that the HDAC6 inhibitor, tubastatin A, demonstrates a protective effect in S. aureus pneumonia, decreasing the mortality and destruction of lung architecture, reducing the bacterial burden in the lungs and inhibiting inflammatory responses. Mechanistic studies in primary bone marrow‐derived macrophages demonstrated that the HDAC6 inhibitors, tubastatin A and tubacin, reduced the intracellular bacterial load by promoting bacterial clearance rather than regulating phagocytosis. Finally, N‐acetyl‐L‐ cysteine, a widely used reactive oxygen species (ROS) scavenger, antagonized ROS production and significantly inhibited tubastatin A‐induced S. aureus clearance. These findings demonstrate that HDAC6 inhibitors promote the bactericidal activity of macrophages by inducing ROS, an important host factor for S. aureus clearance and production. Our study identified HDAC6 as a suitable epigenetic modification target for preventing S. aureus infection, and tubastatin A as a useful compound in treating S. aureus pneumonia.

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“…Due to the methodological challenges inherent in our primary epithelial cell ALI culture setup, we were unable to distinctly differentiate between bacterial adherence and invasion in vitro. Instead, we utilized a super-infection mouse model to evaluate both the adherence of S. aureus and its invasion into the lung tissue 61 , as well as bacterial CFU in the spleen as an indicator of systemic bacterial dissemination 62 . In order to establish an in vivo correlation with the observed loss of the epithelial barrier function in our in vitro super-infection model (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Airway epithelial CD47 plays a critical role in inducing influenza virus-mediated bacterial super-infection

Moon,

Han,

Jang

et al. 2024

Nat Commun

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Respiratory viral infection increases host susceptibility to secondary bacterial infections, yet the precise dynamics within airway epithelia remain elusive. Here, we elucidate the pivotal role of CD47 in the airway epithelium during bacterial super-infection. We demonstrated that upon influenza virus infection, CD47 expression was upregulated and localized on the apical surface of ciliated cells within primary human nasal or bronchial epithelial cells. This induced CD47 exposure provided attachment sites for Staphylococcus aureus, thereby compromising the epithelial barrier integrity. Through bacterial adhesion assays and in vitro pull-down assays, we identified fibronectin-binding proteins (FnBP) of S. aureus as a key component that binds to CD47. Furthermore, we found that ciliated cell-specific CD47 deficiency or neutralizing antibody-mediated CD47 inactivation enhanced in vivo survival rates. These findings suggest that interfering with the interaction between airway epithelial CD47 and pathogenic bacterial FnBP holds promise for alleviating the adverse effects of super-infection.

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The influenza-injured lung microenvironment promotes MRSA virulence, contributing to severe secondary bacterial pneumonia

Cited by 13 publications

References 99 publications

Enzymatic modulation of the pulmonary glycocalyx alters susceptibility toStreptococcus pneumoniae

Enzymatic modulation of the pulmonary glycocalyx alters susceptibility toStreptococcus pneumoniae

HDAC6 inhibitor promotes reactive oxygen species‐meditated clearance of Staphylococcus aureus in macrophage

Airway epithelial CD47 plays a critical role in inducing influenza virus-mediated bacterial super-infection

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