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

Abstract

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.

Galectins regulate the inflammatory response in airway epithelial cells exposed to microbial neuraminidase by modulating the expression of SOCS1 and RIG1

“…When the replication process is terminated, the NA facilitates the release of progeny virions that infect neighboring cells (Fukuyama and Kawaoka 2011; Luo 2012). Moreover, viral neuraminidase contributes to the increase of bacterial adhesion and dissemination by cleaving the respiratory epithelial cell sialic acids (Feng et al 2013; Nita-Lazar et al 2015). …”

“…We have previously shown both in vitro and in vivo that the expression and secretion of galectins, particularly galectin-1 (Gal1) and galectin-3 (Gal3), are modulated during IAV infection, and that the viral neuraminidase unmasks galactosy moieties in the airway epithelia (Nita-Lazar et al 2015). The increased levels of galectins remaining in the bronchoalveolar space upon recovery from influenza further contribute to the increased binding of Gal3 and enhancement of pneumococcal adhesion by cross-linking the bacteria to the cell surface (Nita-Lazar et al 2015).…”

“…The increased levels of galectins remaining in the bronchoalveolar space upon recovery from influenza further contribute to the increased binding of Gal3 and enhancement of pneumococcal adhesion by cross-linking the bacteria to the cell surface (Nita-Lazar et al 2015). Thus, we proposed that the activity of the influenza and pneumococcal neuraminidases, which unmask galactosyl moieties on the airway epithelial cell surface, and act synergistically with the increased Gal3 and Gal1 concentrations in the bronchoalveolar space to promote galectin binding and additional pneumococcal adhesion as shown in our previous study, could also regulate the cytokine/chemokine expression and release by the airway epithelial cells and lead to the typical cytokine storm.…”

Pneumococcal Neuraminidase A (NanA) Promotes Biofilm Formation and Synergizes with Influenza A Virus in Nasal Colonization and Middle Ear Infection

“…In addition, IAV neuraminidase activity has been shown to interact synergistically with S. pneumoniae. Indeed, pneumococcal adherence in vitro and pulmonary infection in vivo are increased during coinfection with IAV (17)(18)(19). This effect is reliant, at least in part, on the activity of the viral neuraminidase, as IAV neuraminidase inhibitors have been shown to protect against pneumococcal pneumonia in mice independently of their effect on viral replication (17).…”

Multi-Omics Studies towards Novel Modulators of Influenza A Virus–Host Interaction

“…Interestingly, 41 of the 199 druggable cellular factors were shown to be implicated in IAV infection (Table S2) [10,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,...…”