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Cited by 21Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Infections and Studies

Hyphal Als proteins act as CR3 ligands to promote immune responses against Candida albicans

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Zhou, Tingting, Solis, Norma V., Marshall, Michaela, Yao, Qing, Garleb, Rachel, Yang, Mengli, Pearlman, Eric, Filler, Scott G. +1 more·2024·Nature Communications
DOI 10.1038/s41467-024-48093-8PMC PMC11082240
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Abstract

Patients with decreased levels of CD18 (β2 integrins) suffer from life-threatening bacterial and fungal infections. CD11b, the α subunit of integrin CR3 (CD11b/CD18, α M β 2), is essential for mice to fight against systemic Candida albicans infections. Live elongating C. albicans activates CR3 in immune cells. However, the hyphal ligands that activate CR3 are not well defined. Here, we discovered that the C. albicans Als family proteins are recognized by the I domain of CD11b in macrophages. This recognition synergizes with the β-glucan-bound lectin-like domain to activate CR3, thereby promoting Syk signaling and inflammasome activation. Dectin-2 activation serves as the “outside-in signaling” for CR3 activation at the entry site of incompletely sealed phagosomes, where a thick cuff of F-actin forms to strengthen the local interaction. In vitro, CD18 partially contributes to IL-1β release from dendritic cells induced by purified hyphal Als3. In vivo, Als3 is vital for C. albicans clearance in mouse kidneys. These findings uncover a novel family of ligands for the CR3 I domain that promotes fungal clearance.

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  • C. albicans Als3 adhesin binds to epithelial cell receptors E-cadherin, EGFR, Her2, and c-Met, and to macrophage receptor CR3.

    “the Als3 adhesin of C. albicans binds to receptors on epithelial cells, such as E-cadherin, EGFR, Her2, and c-Met, and receptors on macrophages, such as CR325–28.”

    From Adhesin Als4112 promotes Candida auris skin colonization through interactions with keratinocytes and extracellular matrix proteins (2025) · cites this paper as [28]

    The Discussion (page not available in our copy) says Als3 adheres to endothelial or epithelial cells via E-cadherin, EGFR, and HER2. The Results section on hyphal Als proteins and CR3 (page not available) reports direct binding between purified Als3 and CR3 and examines that interaction in macrophages. The cited paper does not identify c-Met as an Als3 receptor; searches for c-Met and the MET receptor found no supporting passage. (LLM, conf=0.88)

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  1. [1]Pappas PG Lionakis MS Arendrup MC Ostrosky-Zeichner L Kullberg BJ Invasive candidiasis Nat. Rev. Dis. Prim. 2018 4 18026 10.1038/nrdp.2018.26 29749387 · DOI · Paper page
  2. [2]Tso GHW Experimental evolution of a fungal pathogen into a gut symbiont Science 2018 362 589 10.1126/science.aat0537 30385579 · DOI
  3. [3]Moyes DL Candidalysin is a fungal peptide toxin critical for mucosal infection Nature 2016 532 64 68 10.1038/nature17625 27027296 PMC4851236 · DOI
  4. [4]Li XV Immune regulation by fungal strain diversity in inflammatory bowel disease Nature 2022 603 672 678 10.1038/s41586-022-04502-w 35296857 PMC9166917 · DOI
  5. [5]Witchley JN Candida albicans morphogenesis programs control the balance between gut commensalism and invasive infection Cell Host Microbe 2019 25 432 443.e436 10.1016/j.chom.2019.02.008 30870623 PMC6581065 · DOI
  6. [6]Stuart LM Paquette N Boyer L Effector-triggered versus pattern-triggered immunity: how animals sense pathogens Nat. Rev. Immunol. 2013 13 199 206 10.1038/nri3398 23411798 PMC4121468 · DOI
  7. [7]Rogers NC Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins Immunity 2005 22 507 517 10.1016/j.immuni.2005.03.004 15845454 · DOI
  8. [8]Negoro PE Spleen tyrosine kinase is a critical regulator of neutrophil responses to Candida species mBio 2020 11 e02043 19 10.1128/mBio.02043-19 32398316 PMC7218286 · DOI
  9. [9]Robinson MJ Dectin-2 is a Syk-coupled pattern recognition receptor crucial for Th17 responses to fungal infection J. Exp. Med. 2009 206 2037 2051 10.1084/jem.20082818 19703985 PMC2737172 · DOI
  10. [10]Li B Yeast beta-glucan amplifies phagocyte killing of iC3b-opsonized tumor cells via complement receptor 3-Syk-phosphatidylinositol 3-kinase pathway J. Immunol. 2006 177 1661 1669 10.4049/jimmunol.177.3.1661 16849475 · DOI
  11. [11]Ward RA Vyas JM The first line of defense: effector pathways of anti-fungal innate immunity Curr. Opin. Microbiol. 2020 58 160 165 10.1016/j.mib.2020.10.003 33217703 PMC7746574 · DOI
  12. [12]Brown GD Dectin-1 is a major β-Glucan receptor on macrophages J. Exp. Med. 2002 196 407 412 10.1084/jem.20020470 12163569 PMC2193936 · DOI
  13. [13]Sato K Dectin-2 is a pattern recognition receptor for fungi that couples with the Fc receptor gamma chain to induce innate immune responses J. Biol. Chem. 2006 281 38854 38866 10.1074/jbc.M606542200 17050534 · DOI
  14. [14]Taylor PR Dectin-1 is required for β-glucan recognition and control of fungal infection Nat. Immunol. 2007 8 31 38 10.1038/ni1408 17159984 PMC1888731 · DOI
  15. [15]Saijo S Dectin-2 recognition of α-mannans and induction of Th17 cell differentiation is essential for host defense against Candida albicans Immunity 2010 32 681 691 10.1016/j.immuni.2010.05.001 20493731 · DOI
  16. [16]Lu Y Su C Wang A Liu H Hyphal development in Candida albicans requires two temporally linked changes in promoter chromatin for initiation and maintenance PLoS Biol. 2011 9 e1001105 10.1371/journal.pbio.1001105 21811397 PMC3139633 · DOI
  17. [17]Fagerholm SC Guenther C Llort Asens M Savinko T Uotila LM Beta2-integrins and interacting proteins in leukocyte trafficking, immune suppression, and immunodeficiency disease Front Immunol. 2019 10 254 10.3389/fimmu.2019.00254 30837997 PMC6389632 · DOI
  18. [18]Forsyth CB Plow EF Zhang L Interaction of the fungal pathogen Candida albicans with integrin CD11b/CD18: recognition by the I domain is modulated by the lectin-Like domain and the CD18 subunit J. Immunol. 1998 161 6198 6205 10.4049/jimmunol.161.11.6198 9834106 · DOI
  19. [19]Marcil, A. et al. Analysis of PRA1 and its relationship to Candida albicans- macrophage interactions. 76, 4345–4358 (2008). PMC2519410 18625733
  20. [20]Jawhara S Integrin αXβ2 is a leukocyte receptor for Candida albicans and is essential for protection against fungal infections J. Immunol. 2012 189 2468 2477 10.4049/jimmunol.1200524 22844116 PMC3424400 · DOI
  21. [21]Hise AG An essential role for the NLRP3 inflammasome in host defense against the human fungal pathogen Candida albicans Cell Host Microbe 2009 5 487 497 10.1016/j.chom.2009.05.002 19454352 PMC2824856 · DOI
  22. [22]van de Veerdonk FL The inflammasome drives protective Th1 and Th17 cellular responses in disseminated candidiasis Eur. J. Immunol. 2011 41 2260 2268 10.1002/eji.201041226 21681738 PMC3939807 · DOI
  23. [23]Gross O Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence Nature 2009 459 433 436 10.1038/nature07965 19339971 · DOI
  24. [24]Chung Y Critical regulation of early Th17 cell differentiation by interleukin-1 signaling Immunity 2009 30 576 587 10.1016/j.immuni.2009.02.007 19362022 PMC2705871 · DOI
  25. [26]Kankkunen P (1,3)-β-glucans activate both Dectin-1 and NLRP3 inflammasome in human macrophages J. Immunol. 2010 184 6335 6342 10.4049/jimmunol.0903019 20421639 · DOI
  26. [27]Kumar H Involvement of the NLRP3 inflammasome in innate and humoral adaptive immune responses to fungal β-glucan J. Immunol. 2009 183 8061 8067 10.4049/jimmunol.0902477 20007575 · DOI
  27. [28]Ganesan S Caspase-8 modulates dectin-1 and complement receptor 3-driven IL-1β production in response to β-glucans and the fungal pathogen, Candida albicans J. Immunol. 2014 193 2519 2530 10.4049/jimmunol.1400276 25063877 PMC4134963 · DOI
  28. [30]Joly S Sutterwala FS Fungal pathogen recognition by the NLRP3 inflammasome Virulence 2010 1 276 280 10.4161/viru.1.4.11482 21178453 · DOI
  29. [31]Kasper L The fungal peptide toxin Candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes Nat. Commun. 2018 9 4260 10.1038/s41467-018-06607-1 30323213 PMC6189146 · DOI · Paper page
  30. [32]Pietrella D Secreted aspartic proteases of Candida albicans activate the NLRP3 inflammasome Eur. J. Immunol. 2013 43 679 692 10.1002/eji.201242691 23280543 · DOI
  31. [33]Na YR GM-CSF induces inflammatory macrophages by regulating glycolysis and lipid metabolism J. Immunol. 2016 197 4101 4109 10.4049/jimmunol.1600745 27742831 · DOI
  32. [34]Castro-Dopico T GM-CSF calibrates macrophage defense and wound healing programs during intestinal infection and inflammation Cell Rep. 2020 32 107857 10.1016/j.celrep.2020.107857 32640223 PMC7351110 · DOI
  33. [35]Sheppard DC Functional and structural diversity in the Als protein family of Candida albicans J. Biol. Chem. 2004 279 30480 30489 10.1074/jbc.M401929200 15128742 · DOI · Paper page
  34. [36]Lin J The peptide-binding cavity is essential for Als3-mediated adhesion of Candida albicans to human cells J. Biol. Chem. 2014 289 18401 18412 10.1074/jbc.M114.547877 24802757 PMC4140257 · DOI
  35. [37]Hebecker B Dual-species transcriptional profiling during systemic candidiasis reveals organ-specific host-pathogen interactions Sci. Rep. UK 2016 6 36055 10.1038/srep36055 PMC5093689 27808111 · DOI
  36. [38]Simonetti, N., Strippoli, V. & Cassone, A. J. N. Yeast-mycelial conversion induced by N-acetyl-D-glucosamine in Candida albicans. Nature250, 344–346 (1974). 4605454
  37. [39]Gunasekera A Identification of GIG1, a GlcNAc-induced gene in Candida albicans needed for normal sensitivity to the chitin synthase inhibitor nikkomycin Z Eukaryot. Cell 2010 9 1476 1483 10.1128/EC.00178-10 20675577 PMC2950415 · DOI
  38. [40]Su C Lu Y Liu H N-acetylglucosamine sensing by a GCN5-related N-acetyltransferase induces transcription via chromatin histone acetylation in fungi Nat. Commun. 2016 7 12916 10.1038/ncomms12916 27694804 PMC5063960 · DOI
  39. [41]Ichikawa Y Environmentally contingent control of Candida albicans cell wall integrity by transcriptional regulator Cup9 Genetics 2021 218 iyab075 10.1093/genetics/iyab075 33989396 PMC8864738 · DOI · Paper page
  40. [42]Ben-Ami R Fitness and virulence costs of Candida albicans FKS1 hot spot mutations associated with echinocandin resistance J. Infect. Dis. 2011 204 626 635 10.1093/infdis/jir351 21791665 PMC3144175 · DOI · Paper page
  41. [43]Douglas CM Identification of the FKS1 gene of Candida albicans as the essential target of 1,3-beta-D-glucan synthase inhibitors Antimicrob. Agents Chemother. 1997 41 2471 2479 10.1128/AAC.41.11.2471 9371352 PMC164147 · DOI
  42. [44]Maxson ME Integrin-based diffusion barrier separates membrane domains enabling the formation of microbiostatic frustrated phagosomes Elife 2018 7 e34798 10.7554/eLife.34798 29553370 PMC5897098 · DOI
  43. [45]Vetvicka V Thornton BP Ross GD Soluble beta-glucan polysaccharide binding to the lectin site of neutrophil or natural killer cell complement receptor type 3 (CD11b/CD18) generates a primed state of the receptor capable of mediating cytotoxicity of iC3b-opsonized target cells J. Clin. Investig. 1996 98 50 61 10.1172/JCI118777 8690804 PMC507400 · DOI
  44. [46]Hernanz-Falcón P Joffre O Williams DL Reis e Sousa C Internalization of Dectin-1 terminates induction of inflammatory responses Eur. J. Immunol. 2009 39 507 513 10.1002/eji.200838687 19130473 PMC2699426 · DOI
  45. [47]Cross CE Collins HL Bancroft GJ CR3-dependent phagocytosis by murine macrophages: different cytokines regulate ingestion of a defined CR3 ligand and complement-opsonized Cryptococcus neoformans Immunology 1997 91 289 296 10.1046/j.1365-2567.1997.00238.x 9227330 PMC1363860 · DOI
  46. [48]Lishko VK Yakubenko VP Ugarova TP The interplay between integrins αmβ2 and α5β1 during cell migration to fibronectin Exp. Cell Res. 2003 283 116 126 10.1016/S0014-4827(02)00024-1 12565824 · DOI
  47. [49]Zhang K Chen J The regulation of integrin function by divalent cations Cell Adh Migr. 2012 6 20 29 10.4161/cam.18702 22647937 PMC3364134 · DOI
  48. [50]Thornton BP Vĕtvicka V Pitman M Goldman RC Ross GD Analysis of the sugar specificity and molecular location of the beta-glucan-binding lectin site of complement receptor type 3 (CD11b/CD18) J. Immunol. 1996 156 1235 1246 10.4049/jimmunol.156.3.1235 8558003 · DOI
  49. [51]McGreal EP The carbohydrate-recognition domain of Dectin-2 is a C-type lectin with specificity for high mannose Glycobiology 2006 16 422 430 10.1093/glycob/cwj077 16423983 · DOI
  50. [52]May RC Bruton’s Tyrosine Kinase (BTK) and Vav1 contribute to Dectin1-Dependent phagocytosis of Candida albicans in macrophages PLoS Pathog. 2013 9 e1003446 10.1371/journal.ppat.1003446 23825946 PMC3694848 · DOI
  51. [53]Harburger DS Calderwood DA Integrin signalling at a glance J. Cell Sci. 2009 122 159 163 10.1242/jcs.018093 19118207 PMC2714413 · DOI
  52. [55]Oliva C Turnbough CL Kearney JF CD14-Mac-1 interactions in Bacillus anthracis spore internalization by macrophages Proc. Natl Acad. Sci. USA 2009 106 13957 13962 10.1073/pnas.0902392106 19666536 PMC2729002 · DOI
  53. [56]Freeman SA Integrins form an expanding diffusional barrier that coordinates phagocytosis Cell 2016 164 128 140 10.1016/j.cell.2015.11.048 26771488 PMC4715264 · DOI
  54. [57]Hohl TM Metabolic competition between host and pathogen dictates inflammasome responses to fungal infection PLoS Pathog. 2020 16 e1008695 10.1371/journal.ppat.1008695 32750090 PMC7433900 · DOI
  55. [58]Tucey TM Glucose homeostasis is important for immune cell viability during Candida challenge and host survival of systemic fungal infection Cell Metab. 2018 27 988 1006.e1007 10.1016/j.cmet.2018.03.019 29719235 PMC6709535 · DOI
  56. [59]Phan QT Als3 is a Candida albicans invasin that binds to cadherins and induces endocytosis by host cells PLoS Biol. 2007 5 543 557 10.1371/journal.pbio.0050064 PMC1802757 17311474 · DOI · Paper page
  57. [60]Edwards JL Brown EJ Ault KA Apicella MA The role of complement receptor 3 (CR3) in Neisseria gonorrhoeae infection of human cervical epithelia Cell. Microbiol. 2001 3 611 622 10.1046/j.1462-5822.2001.00140.x 11553013 · DOI
  58. [61]Han X Complement receptor 3 mediates Aspergillus fumigatus internalization into alveolar epithelial cells with the increase of intracellular phosphatidic acid by activating FAK Virulence 2021 12 1980 1996 10.1080/21505594.2021.1958042 34338598 PMC8331038 · DOI
  59. [62]Hynes RO Integrins: bidirectional, allosteric signaling machines Cell 2002 110 673 687 10.1016/S0092-8674(02)00971-6 12297042 · DOI
  60. [63]Reis ES Mastellos DC Hajishengallis G Lambris JD New insights into the immune functions of complement Nat. Rev. Immunol. 2019 19 503 516 10.1038/s41577-019-0168-x 31048789 PMC6667284 · DOI
  61. [64]Zhu LL C-type lectin receptors Dectin-3 and Dectin-2 form a heterodimeric pattern-recognition receptor for host defense against fungal infection Immunity 2013 39 324 334 10.1016/j.immuni.2013.05.017 23911656 · DOI
  62. [65]Salazar F Brown GD Antifungal innate immunity: a perspective from the last 10 years J. Innate Immun. 2018 10 373 397 10.1159/000488539 29768268 PMC6784043 · DOI
  63. [66]Huang JH CR3 and Dectin-1 collaborate in macrophage cytokine response through association on lipid rafts and activation of Syk-JNK-AP-1 pathway PLoS Pathog. 2015 11 e1004985 10.1371/journal.ppat.1004985 26132276 PMC4488469 · DOI
  64. [68]Cao F The Flo8 transcription factor is essential for hyphal development and virulence in Candida albicans Mol. Biol. Cell 2006 17 295 307 10.1091/mbc.e05-06-0502 16267276 PMC1345667 · DOI
  65. [69]Lu Y Su C Solis NV Filler SG Liu H Synergistic regulation of hyphal elongation by hypoxia, CO(2), and nutrient conditions controls the virulence of Candida albicans Cell Host Microbe 2013 14 499 509 10.1016/j.chom.2013.10.008 24237696 PMC4049569 · DOI
  66. [70]Wang A Raniga PP Lane S Lu Y Liu H Hyphal chain formation in Candida albicans: Cdc28-Hgc1 phosphorylation of Efg1 represses cell separation genes Mol. Cell Biol. 2009 29 4406 4416 10.1128/MCB.01502-08 19528234 PMC2725740 · DOI
  67. [71]Nguyen N Quail MMF Hernday AD An efficient, rapid, and recyclable system for CRISPR-mediated genome editing in Candida albicans mSphere 2017 2 e00149 00117 10.1128/mSphereDirect.00149-17 28497115 PMC5422035 · DOI
  68. [72]Pfaffl MW A new mathematical model for relative quantification in real-time RT-PCR Nucleic Acids Res. 2001 29 e45 10.1093/nar/29.9.e45 11328886 PMC55695 · DOI · Paper page
  69. [74]Ratitong, B., Marshall, M. & Pearlman, E. β-Glucan-stimulated neutrophil secretion of IL-1α is independent of GSDMD and mediated through extracellular vesicles. Cell Rep.35, 109139 (2021). PMC8186457 34010648

Cited by

Sorted by citations

Authors
Zhou, T., Solis, N. V., Marshall, M., Yao, Q., Garleb, R., Yang, M., Pearlman, E., Filler, S. G., & Liu, H.
Affiliations
  • University of California, Irvine (US)
  • The Lundquist Institute (US)
  • California Institute of Technology (US)
  • University of California, Los Angeles (US)
Corresponding author
Liu, Haoping
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-05-09
Volume
15
Issue
1
Pages
3926-3926
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-48093-8
PMC
PMC11082240
OpenAlex
W4396765596
Cited by
21
References
5
Citations by year
2026: 9 · 2025: 12
FWCI
7.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (GM117111)
  • U.S. Department of Health & Human Services | NIH | National Eye Institute (R01EY18612)
  • U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research (R01DE022600)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Keywords
Candida albicans, ALS3, CR3, CD18, macrophages, dendritic cells, β-glucan, Syk signaling, inflammasome, IL-1β, Dectin-2, phagosome, F-actin, fungal clearance, innate immunity
MeSH terms
Syk Kinase, Animals, Candida albicans, Candidiasis, Dendritic Cells, Fungal Proteins, Humans, Ligands, Macrophages, Mice, Inbred C57BL, Signal Transduction, Macrophage-1 Antigen, Mice, Knockout, CD18 Antigens, Hyphae, Lectins, C-Type, CD11b Antigen, beta-Glucans, Mice, Interleukin-1beta, Inflammasomes

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