The Interaction between Respiratory Pathogens and Mucus

Abstract

The interaction between respiratory pathogens and their hosts is complex and incompletely understood. This is particularly true when pathogens encounter the mucus layer covering the respiratory tract. The mucus layer provides an essential first host barrier to inhaled pathogens that can prevent pathogen invasion and subsequent infection. Respiratory mucus has numerous functions and interactions, both with the host and with pathogens. This review summarizes the current understanding of respiratory mucus and its interactions with the respiratory pathogens Pseudomonas aeruginosa, respiratory syncytial virus and influenza viruses, with particular focus on influenza virus transmissibility and host-range specificity. Based on current findings we propose that respiratory mucus represents an understudied host-restriction factor for influenza virus.

Figure 1. The ‘gel on brush’ model of respiratory mucus and the structure of mucins

(A). The gel on brush model of respiratory mucus describes mucus existing in two discreet layers, a more viscous gel layer on top and a periciliary layer (PCL) below. The gel layer contains the secreted mucins MUC5AC and MUC5B whilst the PCL contains the membrane-tethered mucins MUC1, MUC4 and MUC16. The reduced viscosity of the PCL in comparison to the gel layer facilitates the beating of cilia and mucociliary clearance. (B). Generic structure of a membrane-bound mucin. (C). Generic structure of a secreted mucin.

Figure 2. Pseudomonas aeruginosa colonization of the cystic fibrosis lung

(A) Pseudomonas aeruginosa (PA) binds preferentially to the sialyl-Lewis^x carbohydrate moieties (blue dots) present on mucins via the flagellar cap. The PA toxin pyocyanin (red dots) stimulates mucus hypersecretion by goblet cells (dashed arrow) and induces the production and release of the pro-inflammatory cytokines tumor necrosis factor alpha (TNFα) and interleukins 6 (IL-6) and 8 (IL-8) (solid arrow). (B). TNFα, IL-6 and IL-8 lead to inflammation and upregulate the sialyl-Lewis^x biosynthesis glycosyltransferases core 2/core 4 beta-1,6-N-acetylglucosaminyltransferase (C2/4GnT) and α2,3-sialyltransferase IV (ST3Gal-IV) via the phosphoinositol-specific phospholipase C (PI-PLC) pathway (grey arrow), leading to an increase in sialyl-Lewis^x content and increased PA binding. (C). PA is commonly found in a biofilm in the CF lung. In this setting, PA aggregate, lose their motility and switch to anaerobic respiration, facilitaing resistance to cells of the immune system and to multiple front-tier antibiotics. (D). The structure of sialyl-Lewis^x (C₃₁H₅₂N₂O₂₃). Image was obtained from PubChem, CID number 643990.

Figure 3. Influenza viruses, neuraminidase, respiratory mucus, viral transmissibility and host range

Neuraminidase (NA), one of the surface glycoproteins on influenza virus, cleaves sialic acids to prevent the virus becoming trapped in the heavily sialydated mucins in respiratory mucus, thus facilitating infection of the underlying cells (represented here by shading on the cell monolayer). (A). The antiviral drug oseltamivir inhibits the enzymatic activity of NA, which inhibits the viral penetration of mucus, decreasing the infectivity of the virus for the cells underlying the mucus layer. Viruses with low NA enzymatic activity are also inhibited by mucus. Conversely, addition of exogenous NA facilitates viral penetration of mucus and thus increases viral infectivity. (B). Compared to human mucus, swine mucus appears to be less inhibitory to influenza viruses with low neuraminidase activity for reasons not fully understood. (C). Influenza viruses that express NA proteins with low enzymatic activity do not transmit by aerosol droplets efficiently in the ferret model of transmission, despite being shed from infected animals and transmitted to direct contact animals. The mechanism behind this is not fully understood.