#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

CXCL9 Contributes to Antimicrobial Protection of the Gut during Infection Independent of Chemokine-Receptor Signaling


Host defense peptides are an essential part of the innate immune response to pathogens, particularly at mucosal surfaces. Some chemokines, previously known for their ability to recruit immune cells to a site of inflammation, have been identified to have direct antimicrobial activity in vitro against a variety of pathogens. Despite this, it was unknown whether chemokines play a role in protecting the gut mucosa against enteric pathogens, independent of their immunological receptors. Using a mouse model of enteric pathogen infection with both wild type mice and genetic knockouts, we showed that the chemokine CXCL9 has direct antimicrobial activity against pathogen infection. This antimicrobial activity prevented the invasion of bacteria into intestinal crypts, thus protecting the host from immunopathology. Neutralization of this CXCL9-dependent antimicrobial activity increased host susceptibility to infection, leading to bacterial penetration into intestinal crypts and increased tissue pathology. These data support the importance of a receptor-independent role for chemokines in host defense at mucosal surfaces and may offer alternative treatment strategies for infections, particularly in regards to organisms that are resistant to conventional antibiotics.


Vyšlo v časopise: CXCL9 Contributes to Antimicrobial Protection of the Gut during Infection Independent of Chemokine-Receptor Signaling. PLoS Pathog 11(2): e32767. doi:10.1371/journal.ppat.1004648
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004648

Souhrn

Host defense peptides are an essential part of the innate immune response to pathogens, particularly at mucosal surfaces. Some chemokines, previously known for their ability to recruit immune cells to a site of inflammation, have been identified to have direct antimicrobial activity in vitro against a variety of pathogens. Despite this, it was unknown whether chemokines play a role in protecting the gut mucosa against enteric pathogens, independent of their immunological receptors. Using a mouse model of enteric pathogen infection with both wild type mice and genetic knockouts, we showed that the chemokine CXCL9 has direct antimicrobial activity against pathogen infection. This antimicrobial activity prevented the invasion of bacteria into intestinal crypts, thus protecting the host from immunopathology. Neutralization of this CXCL9-dependent antimicrobial activity increased host susceptibility to infection, leading to bacterial penetration into intestinal crypts and increased tissue pathology. These data support the importance of a receptor-independent role for chemokines in host defense at mucosal surfaces and may offer alternative treatment strategies for infections, particularly in regards to organisms that are resistant to conventional antibiotics.


Zdroje

1. Griffith JW, Sokol CL, Luster AD (2014) Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu Rev Immunol 32: 659–702. doi: 10.1146/annurev-immunol-032713-120145 24655300

2. Yang D (2003) Many chemokines including CCL20/MIP-3 display antimicrobial activity. J Leukocyte Biol 74: 448–455. 12949249

3. Cole AM, Ganz T, Liese AM, Burdick MD, Liu L, et al. (2001) Cutting edge: IFN-inducible ELR- CXC chemokines display defensin-like antimicrobial activity. J Immunol 167: 623–627. 11441062

4. Hancock RE, Sahl HG (2006) Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol 24: 1551–1557. 17160061

5. Zasloff M (2002) Antimicrobial peptides of multicellular organisms. Nature 415: 389–395. 11807545

6. Brogden KA (2005) Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol 3: 238–250. 15703760

7. Bevins CL, Salzman NH (2011) Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. Nat Rev Microbiol 9: 356–368. doi: 10.1038/nrmicro2546 21423246

8. Crawford MA, Burdick MD, Glomski IJ, Boyer AE, Barr JR, et al. (2010) Interferon-inducible CXC chemokines directly contribute to host defense against inhalational anthrax in a murine model of infection. PLoS Pathog 6: e1001199. doi: 10.1371/journal.ppat.1001199 21124994

9. Egesten A, Eliasson M, Johansson HM, Olin AI, Morgelin M, et al. (2007) The CXC chemokine MIG/CXCL9 is important in innate immunity against Streptococcus pyogenes. J Infect Dis 195: 684–693. 17262710

10. Karlsson C, Eliasson M, Olin AI, Morgelin M, Karlsson A, et al. (2009) SufA of the opportunistic pathogen finegoldia magna modulates actions of the antibacterial chemokine MIG/CXCL9, promoting bacterial survival during epithelial inflammation. J Biol Chem 284: 29499–29508. doi: 10.1074/jbc.M109.025957 19628464

11. Linge HM, Collin M, Giwercman A, Malm J, Bjartell A, et al. (2008) The Antibacterial Chemokine MIG/CXCL9 Is Constitutively Expressed in Epithelial Cells of the Male Urogenital Tract and Is Present in Seminal Plasma. J Interf Cytokine Res 28: 190–196.

12. Collins JW, Keeney KM, Crepin VF, Rathinam VA, Fitzgerald KA, et al. (2014) Citrobacter rodentium: infection, inflammation and the microbiota. Nat Rev Microbiol 12: 612–623. doi: 10.1038/nrmicro3315 25088150

13. Higgins LM, Frankel G, Douce G, Dougan G, MacDonald TT (1999) Citrobacter rodentium infection in mice elicits a mucosal Th1 cytokine response and lesions similar to those in murine inflammatory bowel disease. Infect Immun 67: 3031–3039. 10338516

14. Wiles S, Clare S, Harker J, Huett A, Young D, et al. (2004) Organ specificity, colonization and clearance dynamics in vivo following oral challenges with the murine pathogen Citrobacter rodentium. Cell Microbiol 6: 963–972. 15339271

15. Spehlmann ME, Dann SM, Hruz P, Hanson E, McCole DF, et al. (2009) CXCR2-dependent mucosal neutrophil influx protects against colitis-associated diarrhea caused by an attaching/effacing lesion-forming bacterial pathogen. J Immunol 183: 3332–3343. doi: 10.4049/jimmunol.0900600 19675161

16. Kim YG, Kamada N, Shaw MH, Warner N, Chen GY, et al. (2011) The Nod2 sensor promotes intestinal pathogen eradication via the chemokine CCL2-dependent recruitment of inflammatory monocytes. Immunity 34: 769–780. doi: 10.1016/j.immuni.2011.04.013 21565531

17. Kang YJ, Otsuka M, van den Berg A, Hong L, Huang Z, et al. (2010) Epithelial p38alpha controls immune cell recruitment in the colonic mucosa. PLoS Pathog 6: e1000934. doi: 10.1371/journal.ppat.1000934 20532209

18. Shiomi H, Masuda A, Nishiumi S, Nishida M, Takagawa T, et al. (2010) Gamma interferon produced by antigen-specific CD4+ T cells regulates the mucosal immune responses to Citrobacter rodentium infection. Infect Immun 78: 2653–2666. doi: 10.1128/IAI.01343-09 20351140

19. Reid-Yu SA, Small CL, Coombes BK (2013) CD3(-)NK1.1(+) cells aid in the early induction of a Th1 response to an attaching and effacing enteric pathogen. Eur J Immunol 43: 2638–2649. doi: 10.1002/eji.201343435 23775576

20. Loetscher P, Pellegrino A, Gong JH, Mattioli I, Loetscher M, et al. (2001) The ligands of CXC chemokine receptor 3, I-TAC, Mig, and IP10, are natural antagonists for CCR3. J Biol Chem 276: 2986–2991. 11110785

21. Egesten A, Eliasson M, Olin AI, Erjefalt JS, Bjartell A, et al. (2007) The proinflammatory CXC-chemokines GRO-alpha/CXCL1 and MIG/CXCL9 are concomitantly expressed in ulcerative colitis and decrease during treatment with topical corticosteroids. Int J Colorectal Dis 22: 1421–1427. 17703315

22. Barrow K, Kwon DH (2009) Alterations in two-component regulatory systems of phoPQ and pmrAB are associated with polymyxin B resistance in clinical isolates of Pseudomonas aeruginosa. Antimicrob Agents Chemother 53: 5150–5154. doi: 10.1128/AAC.00893-09 19752280

23. Miller AK, Brannon MK, Stevens L, Johansen HK, Selgrade SE, et al. (2011) PhoQ mutations promote lipid A modification and polymyxin resistance of Pseudomonas aeruginosa found in colistin-treated cystic fibrosis patients. Antimicrob Agents Chemother 55: 5761–5769. doi: 10.1128/AAC.05391-11 21968359

24. Nakka S, Qi M, Zhao Y (2010) The Erwinia amylovora PhoPQ system is involved in resistance to antimicrobial peptide and suppresses gene expression of two novel type III secretion systems. Microbiol Res 165: 665–673. doi: 10.1016/j.micres.2009.11.013 20116983

25. Hancock RE (1984) Alterations in outer membrane permeability. Annu Rev Microbiol 38: 237–264. 6093683

26. Loh B, Grant C, Hancock RE (1984) Use of the fluorescent probe 1-N-phenylnaphthylamine to study the interactions of aminoglycoside antibiotics with the outer membrane of Pseudomonas aeruginosa. Antimicrob Agents Chemoth 26: 546–551.

27. Luperchio SA, Newman JV, Dangler CA, Schrenzel MD, Brenner DJ, et al. (2000) Citrobacter rodentium, the causative agent of transmissible murine colonic hyperplasia, exhibits clonality: synonymy of C. rodentium and mouse-pathogenic Escherichia coli. J Clin Microbiol 38: 4343–4350. 11101562

28. Vallance BA, Deng W, Knodler LA, Finlay BB (2002) Mice lacking T and B lymphocytes develop transient colitis and crypt hyperplasia yet suffer impaired bacterial clearance during Citrobacter rodentium infection. Infect Immun 70: 2070–2081. 11895973

29. Gibson DL, Ma C, Bergstrom KS, Huang JT, Man C, et al. (2008) MyD88 signalling plays a critical role in host defence by controlling pathogen burden and promoting epithelial cell homeostasis during Citrobacter rodentium-induced colitis. Cell Microbiol 10: 618–631. 17979981

30. Cole KE, Strick CA, Paradis TJ, Ogborne KT, Loetscher M, et al. (1998) Interferon-inducible T cell alpha chemoattractant (I-TAC): a novel non-ELR CXC chemokine with potent activity on activated T cells through selective high affinity binding to CXCR3. J Exp Med 187: 2009–2021. 9625760

31. Simmons CP, Goncalves NS, Ghaem-Maghami M, Bajaj-Elliott M, Clare S, et al. (2002) Impaired resistance and enhanced pathology during infection with a noninvasive, attaching-effacing enteric bacterial pathogen, Citrobacter rodentium, in mice lacking IL-12 or IFN-gamma. J Immunol 168: 1804–1812. 11823513

32. Schreiber HA, Loschko J, Karssemeijer RA, Escolano A, Meredith MM, et al. (2013) Intestinal monocytes and macrophages are required for T cell polarization in response to Citrobacter rodentium. J Exp Med 210: 2025–2039. doi: 10.1084/jem.20130903 24043764

33. Cerovic V, Bain CC, Mowat AM, Milling SW (2014) Intestinal macrophages and dendritic cells: what's the difference? Trends Immunol 35: 270–277. doi: 10.1016/j.it.2014.04.003 24794393

34. Cerovic V, Houston SA, Scott CL, Aumeunier A, Yrlid U, et al. (2013) Intestinal CD103(-) dendritic cells migrate in lymph and prime effector T cells. Mucosal Immunol 6: 104–113. doi: 10.1038/mi.2012.53 22718260

35. Mazzini E, Massimiliano L, Penna G, Rescigno M (2014) Oral tolerance can be established via gap junction transfer of fed antigens from CX3CR1(+) macrophages to CD103(+) dendritic cells. Immunity 40: 248–261. doi: 10.1016/j.immuni.2013.12.012 24462723

36. Veckman V, Miettinen M, Matikainen S, Lande R, Giacomini E, et al. (2003) Lactobacilli and streptococci induce inflammatory chemokine production in human macrophages that stimulates Th1 cell chemotaxis. J Leukoc Biol 74: 395–402. 12949243

37. Romagnani P, Rotondi M, Lazzeri E, Lasagni L, Francalanci M, et al. (2002) Expression of IP-10/CXCL10 and MIG/CXCL9 in the thyroid and increased levels of IP-10/CXCL10 in the serum of patients with recent-onset Graves' disease. Am J Pathol 161: 195–206. 12107104

38. Gasperini S, Marchi M, Calzetti F, Laudanna C, Vicentini L, et al. (1999) Gene expression and production of the monokine induced by IFN-gamma (MIG), IFN-inducible T cell alpha chemoattractant (I-TAC), and IFN-gamma-inducible protein-10 (IP-10) chemokines by human neutrophils. J Immunol 162: 4928–4937. 10202039

39. Liao F, Rabin RL, Yannelli JR, Koniaris LG, Vanguri P, et al. (1995) Human Mig chemokine: biochemical and functional characterization. J Exp Med 182: 1301–1314. 7595201

40. Di Marzio P, Puddu P, Conti L, Belardelli F, Gessani S (1994) Interferon gamma upregulates its own gene expression in mouse peritoneal macrophages. J Exp Med 179: 1731–1736. 8163951

41. Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8: 958–969. doi: 10.1038/nri2448 19029990

42. Shim EJ, Bang BR, Kang SG, Ma J, Otsuka M, et al. (2013) Activation of p38alpha in T cells regulates the intestinal host defense against attaching and effacing bacterial infections. J Immunol 191: 2764–2770. doi: 10.4049/jimmunol.1300908 23918973

43. Assi K, Bergstrom K, Vallance B, Owen D, Salh B (2013) Requirement of epithelial integrin-linked kinase for facilitation of Citrobacter rodentium-induced colitis. BMC Gastroenterol 13: 137. doi: 10.1186/1471-230X-13-137 24024606

44. Yoshida M, Kobayashi K, Kuo TT, Bry L, Glickman JN, et al. (2006) Neonatal Fc receptor for IgG regulates mucosal immune responses to luminal bacteria. J Clin Invest 116: 2142–2151. 16841095

45. Mahalingam S, Chaudhri G, Tan CL, John A, Foster PS, et al. (2001) Transcription of the interferon gamma (IFN-gamma)-inducible chemokine Mig in IFN-gamma-deficient mice. J Biol Chem 276: 7568–7574. 11024052

46. Tassiulas I, Hu X, Ho H, Kashyap Y, Paik P, et al. (2004) Amplification of IFN-alpha-induced STAT1 activation and inflammatory function by Syk and ITAM-containing adaptors. Nat Immunol 5: 1181–1189. 15467722

47. Kawaguchi S, Ishiguro Y, Imaizumi T, Mori F, Matsumiya T, et al. (2009) Retinoic acid-inducible gene-I is constitutively expressed and involved in IFN-gamma-stimulated CXCL9–11 production in intestinal epithelial cells. Immunol Lett 123: 9–13. doi: 10.1016/j.imlet.2009.01.008 19201382

48. Groom JR, Richmond J, Murooka TT, Sorensen EW, Sung JH, et al. (2012) CXCR3 chemokine receptor-ligand interactions in the lymph node optimize CD4+ T helper 1 cell differentiation. Immunity 37: 1091–1103. doi: 10.1016/j.immuni.2012.08.016 23123063

49. McPhee JB, Small CL, Reid-Yu SA, Brannon JR, Le Moual H, et al. (2014) Host defense peptide resistance contributes to colonization and maximal intestinal pathology by Crohn's disease-associated adherent-invasive Escherichia coli. Infect Immun 82: 3383–3393. doi: 10.1128/IAI.01888-14 24866805

50. Gruenheid S, Le Moual H (2012) Resistance to antimicrobial peptides in Gram-negative bacteria. FEMS Microbiol Lett 330: 81–89. doi: 10.1111/j.1574-6968.2012.02528.x 22339775

51. Egesten A, Frick IM, Morgelin M, Olin AI, Bjorck L (2011) Binding of albumin promotes bacterial survival at the epithelial surface. J Biol Chem 286: 2469–2476. doi: 10.1074/jbc.M110.148171 21098039

52. Datsenko KA, Wanner BL (2000) One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products. Proc Natl Acad Sci U S A 97: 6640–6645. 10829079

53. Lamers RP, Cavallari JF, Burrows LL (2013) The efflux inhibitor phenylalanine-arginine beta-naphthylamide (PAbetaN) permeabilizes the outer membrane of gram-negative bacteria. PLoS One 8: e60666. doi: 10.1371/journal.pone.0060666 23544160

54. Coombes BK, Coburn BA, Potter AA, Gomis S, Mirakhur K, et al. (2005) Analysis of the contribution of Salmonella pathogenicity islands 1 and 2 to enteric disease progression using a novel bovine ileal loop model and a murine model of infectious enterocolitis. Infect Immun 73: 7161–7169. 16239510

55. Kotarsky K, Sitnik KM, Stenstad H, Kotarsky H, Schmidtchen A, et al. (2010) A novel role for constitutively expressed epithelial-derived chemokines as antibacterial peptides in the intestinal mucosa. Mucosal Immunol 3: 40–48. doi: 10.1038/mi.2009.115 19812544

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2015 Číslo 2
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Aktuální možnosti diagnostiky a léčby litiáz
nový kurz
Autori: MUDr. Tomáš Ürge, PhD.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#