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Host Mucin Is Subverted by Pseudomonas Aeruginosa During bioRxiv preprint doi: https://doi.org/10.1101/675538; this version posted June 20, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Host mucin is subverted by Pseudomonas aeruginosa during infection to 2 provide free glycans required for successful colonization 3 4 5 Casandra L Hoffman1 and Alejandro Aballay1* 6 7 8 9 1 Molecular Microbiology and Immunology Department, Oregon Health and Sciences 10 University, Portland, OR, United States of America 11 12 13 * Corresponding author 14 E-mail: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/675538; this version posted June 20, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 15 Abstract 16 The mucosal barrier, found lining epithelial cells, serves multiple functions in a range of animals. 17 The major structural components of mucus are mucins, which are heavily glycosylated proteins 18 that are either membrane bound or secreted by the epithelial cells. Mucins are key components of 19 the innate immune system, as they are involved in the clearance of pathogens from the airways 20 and intestines, and their expression is typically upregulated upon epithelial cell exposure to a 21 variety of pathogens. In this study, we identified the mucin MUL-1 as an innate immune factor 22 that appears to be utilized by P. aeruginosa to colonize hosts. We found that while the 23 expression of several mucins, including MUL-1, increased upon P. aeruginosa infection of the 24 nematode Caenorhabditis elegans, silencing of or deletion of mul-1 resulted in enhanced 25 survival and reduced bacterial accumulation. P. aeruginosa required host sialidase CTSA-1.1 to 26 use mucin-derived glycans to colonize the host, while sialidase-encoding bacteria required host 27 MUL-1 but not CTSA-1.1 to cause a lethal infection. This role of mucins and free glycans in 28 host-pathogen interaction appears to be conserved from C. elegans to humans, as P. aeruginosa 29 binding to human lung epithelial cells was also enhanced in the presence of free glycans, and 30 free glycans reversed the binding defect of P. aeruginosa to human lung cells lacking the mucin 31 MUC1. 32 2 bioRxiv preprint doi: https://doi.org/10.1101/675538; this version posted June 20, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 33 Author Summary 34 The gastrointestinal, respiratory, reproductive, and urinary tracts, are large surfaces exposed to 35 the exterior environment and thus, these mucosal epithelial tissues serve as primary routes of 36 infection. One of the first lines of defense present at these barriers is mucus, which is a highly 37 viscous material formed by mucin glycoproteins. Mucins serve various functions, but 38 importantly they aid in the clearance of pathogens and debris from epithelial barriers and serve 39 as innate immune effectors. In this study, we describe the ability of Pseudomonas aeruginosa to 40 utilize mucin-derived glycans to colonize the intestine and ultimately cause death in 41 Caenorhabditis elegans. We also show conserved mechanisms of P. aeruginosa virulence traits, 42 by demonstrating that free glycans alter the ability of the bacteria to bind to human lung alveolar 43 epithelial cells. Over the course of host-pathogen evolution, pathogens seem to have evolved to 44 use mucins for their own advantage, and thus one of the biggest questions is which party benefits 45 from pathogen-mucin binding. By gaining a better understanding of pathogen-mucin 46 interactions, we can better protect against pathogen infection. 47 3 bioRxiv preprint doi: https://doi.org/10.1101/675538; this version posted June 20, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 48 Introduction. 49 The mucus layer found lining mucosal epithelial cells is a crucial first barrier against microbial 50 infections. The main structural components of the protective barrier of mucus are mucins, which 51 are high molecular weight proteins, heavily glycosylated at serine and threonine residues (1-4). 52 Mucins are secreted in large quantities by mucosal epithelial cells and both membrane-tethered 53 and secreted mucins are found on the apical surface of all mucosal epithelium. Mucins aid in the 54 formation of highly viscous, aqueous solutions that protect epithelial cells from physical damage, 55 dehydration, and infection (1,2,5). 56 Epithelial barriers have evolved multiple mechanisms to respond to environmental cues, 57 including those associated with pathogen exposure. At basal levels and in response to microbes, 58 epithelial cells secrete defensive compounds, including mucins, defensins, lysozymes, and other 59 antimicrobial compounds. Together, these compounds can form a physical barrier, have direct 60 antimicrobial activity, and aid in pathogen clearance. Mucins are able to perform all of these 61 activities. In addition to forming an impervious gel, mucus traps microbes, aids in the clearance 62 of microbes, forms a physical barrier, and provides a matrix for a rich array of antimicrobial 63 molecules (6,7). 64 Despite the various defensive properties of mucins, some bacterial pathogens are able to 65 colonize mucosal epithelial barriers (6,7) . Microbes must first penetrate the mucosal barrier to 66 either attach to epithelial cells or release toxins that disrupt the epithelial barrier (7). One of the 67 low-affinity binding mechanisms used by microbes is mediated by hydrophobic interactions with 68 lectins and glycosylated receptors. Bacterial adhesins can bind to oligosaccharides present on 69 mucins to mediate adhesion (8,9). One of the largest questions that remains to be answered is 70 whether the bacterial-mucin binding event favors the bacteria or the host. It would appear that 71 increased mucin secretion during infection would categorize mucins as a component of host 72 defenses, but the coevolution of pathogens and hosts may allow for a range of roles for mucins 73 for both parties. Some components of mucins may facilitate bacterial colonization of the host, 74 including oligosaccharides that act as adhesion sites for bacteria and individual monosaccharides 75 from mucins that can be accessed as energy sources by bacteria with mucolytic activity (10). 76 Finally, mucus components can influence the virulence characteristics of pathogenic bacteria, 77 such as virulence factor expression, adhesion, motility, proliferation, and/or growth (11-15). 4 bioRxiv preprint doi: https://doi.org/10.1101/675538; this version posted June 20, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 78 Alterations in mucin expression or glycosylation patterns have been linked to various 79 pathologies and diseases, including cystic fibrosis, chronic obstructive pulmonary disease, 80 cancers, and inflammatory bowel disease (1). These diseases, that are linked to changes in mucin 81 expression, glycosylation patterns, and alterations in mucus levels, are associated with higher 82 rates of infection with opportunistic pathogens (2,16,17). Increases in mucus levels often result 83 in a more highly viscous material that is not readily cleared from the mucosal barrier. Decreases 84 in mucus levels remove the protective barrier, which allows pathogens to have direct access to 85 epithelial cells. Many of the diseases linked to alterations in mucus levels have no known cure, 86 and the primary mode of treatment involves controlling mucin expression, which is a key method 87 used to prevent bacterial infections associated with these diseases (16,18). A better 88 understanding of the mechanisms by which pathogens utilize mucins will provide novel 89 approaches to control infectious processes and prevent bacterial colonization. 90 The complexity of mammalian epithelial mucosal surfaces and the additional functions of 91 the innate immune system can mask the roles of individual mucins at epithelial barriers. Using 92 the model organism, Caenorhabditis elegans, we can tease apart the roles of individual mucins at 93 the intestinal epithelial barrier. This model provides the advantage of a simple organism’s small 94 genome size and the absences of adaptive immunity. C. elegans eats bacteria found in 95 decomposing organic matter (19). Several pathogens are present in the environment in which C. 96 elegans feeds, which can impair the growth of the nematode and induce stress responses, 97 ultimately leading to nematode death (20). The ability to distinguish between pathogenic and 98 non-pathogenic microbes is critical for the survival of the nematodes and thus, C. elegans has 99 methods to recognize and counteract pathogens. One of these responses is the upregulation of 100 mucins during infection (21,22). 101 Herein we explore the role of mul-1 during pathogen infection and find that pathogens 102 use the immune factor to gain a competitive advantage in the host. We identified mul-1 as a 103 mucin, that when inhibited, enhances resistance to P. aeruginosa and S. enterica infection. This 104 is despite the fact that mul-1 gene expression is induced upon infection by these pathogens as 105 part of the general immune response.
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