Abstract
BACKGROUND:
Cell-surface mucins are expressed in apical epithelial cells of the respiratory tract, and contribute a crucial part of the innate immune system. Despite anti-inflammatory or antiviral functions being revealed for certain cell-surface mucins such as MUC1, the roles of other mucins are still poorly understood, especially in viral infections.
METHODS:
To further identify mucins significant in influenza infection, we screened the expression of mucins in human nasal epithelial cells infected by H3N2 influenza A virus.
RESULTS:
We found that the expression of MUC15 was significantly upregulated upon infection, and specific only to active infection. While MUC15 did not interact with virus particles or reduce viral replication directly, positive correlations were observed between MUC15 and inflammatory factors in response to viral infection. Given that the upregulation of MUC15 was only triggered late into infection when immune factors (including cytokines, chemokines, EGFR and phosphorylated ERK) started to peak and plateau, MUC15 may potentially serve an immunomodulatory function later during influenza viral infection.
CONCLUSIONS:
Our study revealed that MUC15 was one of the few cell-surface mucins induced during influenza infection. While MUC15 did not interact directly with influenza virus, we showed that its increase coincides with the peak of immune activation and thus MUC15 may serve an immunomodulatory role during influenza infection.
Cell-surface mucins are expressed in apical epithelial cells of the respiratory tract, and contribute a crucial part of the innate immune system. Despite anti-inflammatory or antiviral functions being revealed for certain cell-surface mucins such as MUC1, the roles of other mucins are still poorly understood, especially in viral infections.
METHODS:
To further identify mucins significant in influenza infection, we screened the expression of mucins in human nasal epithelial cells infected by H3N2 influenza A virus.
RESULTS:
We found that the expression of MUC15 was significantly upregulated upon infection, and specific only to active infection. While MUC15 did not interact with virus particles or reduce viral replication directly, positive correlations were observed between MUC15 and inflammatory factors in response to viral infection. Given that the upregulation of MUC15 was only triggered late into infection when immune factors (including cytokines, chemokines, EGFR and phosphorylated ERK) started to peak and plateau, MUC15 may potentially serve an immunomodulatory function later during influenza viral infection.
CONCLUSIONS:
Our study revealed that MUC15 was one of the few cell-surface mucins induced during influenza infection. While MUC15 did not interact directly with influenza virus, we showed that its increase coincides with the peak of immune activation and thus MUC15 may serve an immunomodulatory role during influenza infection.
Background
Airway
epithelium is the central component of the defense against respiratory
pathogens through the combined functions of physical barrier and the
regulation of both innate and adaptive immunity [1].
In the healthy state, integrated cell-cell junctions, the airway mucus
layer and the beating cilia act as the physical barrier by clearance of
particulates such as pathogens and preventing them from entry into
submucosa. The airway mucus is a viscoelastic gel with a complicated
composition including antimicrobial substances, cytokines and
antioxidant proteins [2] where mucins also play the role of the structural framework.
To date, 22 types of mucin proteins have been discovered in humans [3]. The mucins can be further divided into two groups according to their subcellular localization: secreted mucins and membrane-tethered mucins. Secreted mucins, such as MUC5AC and MUC5B, are large glycoproteins mainly produced by goblet cells and submucosal glands [4]. Conversely, membrane-tethered mucins, also known as cell-surface mucins, are encoded by MUC1, MUC3A/B, MUC4, MUC11, MUC12, MUC13, MUC15, MUC16, MUC17, MUC18, MUC20, MUC21 or MUC22; and consist of transmembrane domains that anchor themselves to the plasma membrane, and some of them may shed their extracellular fragments into the airway tract cavity [3].
There are two distinctive mucus layers [5, 6]. The apical layer is rich in the two well-known secreted mucins, MUC5AC and MUC5B; and this layer is stickier so that particulates in the airway tract cavity could cling to it and then be trapped. The lower layer, also called periciliary layer (PCL), is “watery” or less viscoelastic, and thus allows cilia to beat with less resistance. In this layer, most membrane-tethered mucins such as MUC1, MUC4 and MUC16 localize on microvilli, cilia or goblet cells. These tethered mucins are found to trap smaller adenoassociated virus. Therefore, unlike their secreted counterparts, cell surface mucins likely function as a selective barrier rather than a non-specific one [6, 7].
Furthermore, cell-surface mucin may function as immunomodulatory factors during invasion of pathogens and allergens, working in concert with other components of the immune system to exert a suitable immune response. Among the cell surface mucins, MUC1 is the most studied cell-surface mucin and its anti-inflammatory role initiated by bacterial and viral infection has been well established. MUC1 is upregulated by respiratory virus-induced cytokines such as TNFα and IL8. However, MUC1 can then diminish the levels of these inflammatory factors by suppressing Toll-like receptor (TLR) pathway as a feedback loop [8,9,10,11]. Recently, it was reported that MUC1 defends against influenza virus by directly interacting with the viral particles and eliminating viral entry into respiratory epithelial cells [12]. These results implied that cell-surface mucins might regulate the immune response in airway epithelial cells during bacterial or viral infection so as to reduce inflammation’s harmful effect on the host.
However, despite the many studies on MUC1, the role of other cell-surface mucins in the airway during viral infection has not been well illustrated and demonstrated. Considering that MUC1 plays a role in microbial infection, it is therefore interesting to investigate the expression of other cell-surface mucins in an airway infection model. We have previously established a human nasal epithelial cells (hNECs) model for influenza infection and the study of airway host factors [13,14,15]. Using this hNECs model, we investigated the expression and potential functions of these mucins in influenza A virus infection, which can potentially help identify other mucins that are significant in influenza infection as targets for diagnostic or treatment purposes.
Discussion..
Another interesting finding was that the upregulation of MUC15 expression only occurred during active infection of the nasal epithelial cells, rather than by UV-inactivated virus or viral mimics like poly (I:C). This indicated that increased MUC15 might be induced by the virus as a defense mechanism against host inflammatory responses. Future work can therefore focus on the interaction between the influenza NS1 protein and MUC15, and as a possible diagnosticbiomarker for severe influenza infections. ..
To date, 22 types of mucin proteins have been discovered in humans [3]. The mucins can be further divided into two groups according to their subcellular localization: secreted mucins and membrane-tethered mucins. Secreted mucins, such as MUC5AC and MUC5B, are large glycoproteins mainly produced by goblet cells and submucosal glands [4]. Conversely, membrane-tethered mucins, also known as cell-surface mucins, are encoded by MUC1, MUC3A/B, MUC4, MUC11, MUC12, MUC13, MUC15, MUC16, MUC17, MUC18, MUC20, MUC21 or MUC22; and consist of transmembrane domains that anchor themselves to the plasma membrane, and some of them may shed their extracellular fragments into the airway tract cavity [3].
There are two distinctive mucus layers [5, 6]. The apical layer is rich in the two well-known secreted mucins, MUC5AC and MUC5B; and this layer is stickier so that particulates in the airway tract cavity could cling to it and then be trapped. The lower layer, also called periciliary layer (PCL), is “watery” or less viscoelastic, and thus allows cilia to beat with less resistance. In this layer, most membrane-tethered mucins such as MUC1, MUC4 and MUC16 localize on microvilli, cilia or goblet cells. These tethered mucins are found to trap smaller adenoassociated virus. Therefore, unlike their secreted counterparts, cell surface mucins likely function as a selective barrier rather than a non-specific one [6, 7].
Furthermore, cell-surface mucin may function as immunomodulatory factors during invasion of pathogens and allergens, working in concert with other components of the immune system to exert a suitable immune response. Among the cell surface mucins, MUC1 is the most studied cell-surface mucin and its anti-inflammatory role initiated by bacterial and viral infection has been well established. MUC1 is upregulated by respiratory virus-induced cytokines such as TNFα and IL8. However, MUC1 can then diminish the levels of these inflammatory factors by suppressing Toll-like receptor (TLR) pathway as a feedback loop [8,9,10,11]. Recently, it was reported that MUC1 defends against influenza virus by directly interacting with the viral particles and eliminating viral entry into respiratory epithelial cells [12]. These results implied that cell-surface mucins might regulate the immune response in airway epithelial cells during bacterial or viral infection so as to reduce inflammation’s harmful effect on the host.
However, despite the many studies on MUC1, the role of other cell-surface mucins in the airway during viral infection has not been well illustrated and demonstrated. Considering that MUC1 plays a role in microbial infection, it is therefore interesting to investigate the expression of other cell-surface mucins in an airway infection model. We have previously established a human nasal epithelial cells (hNECs) model for influenza infection and the study of airway host factors [13,14,15]. Using this hNECs model, we investigated the expression and potential functions of these mucins in influenza A virus infection, which can potentially help identify other mucins that are significant in influenza infection as targets for diagnostic or treatment purposes.
Discussion..
Another interesting finding was that the upregulation of MUC15 expression only occurred during active infection of the nasal epithelial cells, rather than by UV-inactivated virus or viral mimics like poly (I:C). This indicated that increased MUC15 might be induced by the virus as a defense mechanism against host inflammatory responses. Future work can therefore focus on the interaction between the influenza NS1 protein and MUC15, and as a possible diagnosticbiomarker for severe influenza infections. ..
Inga kommentarer:
Skicka en kommentar