1887

Abstract

Azelastine hydrochloride, a second-generation histamine H1 receptor (H1R) antagonist, exhibits anti-chlamydial effects against (CT) in HeLa cells (genital infection model).

Non-antibiotic pharmaceutical interactions with CT are an understudied field and the anti-chlamydial effects of azelastine are a potential interaction requiring further elucidation.

. To explore the underlying anti-chlamydial mechanisms of azelastine.

We assessed the specificity of azelastine for the chlamydial species and host cell type, the timing of azelastine application and whether the anti-chlamydial effects could be reproduced with different H1R-modulating compounds.

We observed similar anti-chlamydial azelastine effects for as well as for an ocular CT strain in human conjunctival epithelial cells (ocular infection model). Pre-incubating host cells with azelastine before infection mildly reduced chlamydial inclusion numbers and infectivity. Incubation of cells with azelastine initiated concomitantly with the chlamydial infection, or initiated several hours post-infection, reduced inclusion size, number and infectivity, and altered chlamydial morphology. These effects were strongest when azelastine was added shortly after or with the infection. Azelastine effects were not alleviated by increased concentrations of culture medium nutrients. Additionally, we did not observe anti-chlamydial effects when incubating cultures either with a different H1R antagonist or agonist, indicating that azelastine effects are probably H1R-independent.

Accordingly, we conclude that azelastine anti-chlamydial effects are not restricted to a specific chlamydial species, strain or culture model, and are probably not mediated by H1R antagonism. Thus, it appears likely that off-target mechanisms of azelastine may explain our observations.

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2023-05-17
2024-05-05
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References

  1. Bastidas RJ, Elwell CA, Engel JN, Valdivia RH. Chlamydial intracellular survival strategies. Cold Spring Harb Perspect Med 2013; 3:a010256 [View Article] [PubMed]
    [Google Scholar]
  2. Elwell C, Mirrashidi K, Engel J. Chlamydia cell biology and pathogenesis. Nat Rev Microbiol 2016; 14:385–400 [View Article] [PubMed]
    [Google Scholar]
  3. Jordan S, Nelson D, Geisler W. Chlamydia trachomatis Infections. In Tan M, Hegemann JH, Sütterlin C. eds Chlamydia Biology: From Genome to Disease, 1st. edn Norfolk, UK: Caister Academic Press; 2020 pp 1–30 [View Article]
    [Google Scholar]
  4. Rowley J, Vander Hoorn S, Korenromp E, Low N, Unemo M et al. Chlamydia, gonorrhoea, trichomoniasis and syphilis: global prevalence and incidence estimates, 2016. Bull World Health Organ 2019; 97:548–562P [View Article] [PubMed]
    [Google Scholar]
  5. West SK. Milestones in the fight to eliminate trachoma. Ophthalmic Physiol Opt 2020; 40:66–74 [View Article] [PubMed]
    [Google Scholar]
  6. Wolle MA, West SK. Ocular Chlamydia trachomatis infection: elimination with mass drug administration. Expert Rev Anti Infect Ther 2019; 17:189–200 [View Article] [PubMed]
    [Google Scholar]
  7. Satpathy G, Behera HS, Ahmed NH. Chlamydial eye infections: current perspectives. Indian J Ophthalmol 2017; 65:97–102 [View Article] [PubMed]
    [Google Scholar]
  8. Poston TB, Gottlieb SL, Darville T. Status of vaccine research and development of vaccines for Chlamydia trachomatis infection. Vaccine 2019; 37:7289–7294 [View Article] [PubMed]
    [Google Scholar]
  9. Murray SM, McKay PF. Chlamydia trachomatis: cell biology, immunology and vaccination. Vaccine 2021; 39:2965–2975 [View Article] [PubMed]
    [Google Scholar]
  10. Borel N, Leonard C, Slade J, Schoborg RV. Chlamydial antibiotic resistance and treatment failure in veterinary and human medicine. Curr Clin Microbiol Rep 2016; 3:10–18 [View Article] [PubMed]
    [Google Scholar]
  11. Horner PJ. Azithromycin antimicrobial resistance and genital Chlamydia trachomatis infection: duration of therapy may be the key to improving efficacy. Sex Transm Infect 2012; 88:154–156 [View Article] [PubMed]
    [Google Scholar]
  12. Bommana S, Polkinghorne A. Mini review: antimicrobial control of Chlamydial infections in animals: current practices and issues. Front Microbiol 2019; 10:113 [View Article] [PubMed]
    [Google Scholar]
  13. Wyrick PB, Knight ST. Pre-exposure of infected human endometrial epithelial cells to penicillin in vitro renders Chlamydia trachomatis refractory to azithromycin. J Antimicrob Chemother 2004; 54:79–85 [View Article] [PubMed]
    [Google Scholar]
  14. Kintner J, Lajoie D, Hall J, Whittimore J, Schoborg RV. Commonly prescribed β-lactam antibiotics induce C. trachomatis persistence/stress in culture at physiologically relevant concentrations. Front Cell Infect Microbiol 2014; 4:44 [View Article] [PubMed]
    [Google Scholar]
  15. Panzetta ME, Valdivia RH, Saka HA. Chlamydia persistence: a survival strategy to evade antimicrobial effects in-vitro and in-vivo. Front Microbiol 2018; 9:1–11 [View Article]
    [Google Scholar]
  16. Bavoil PM. What’s in a word: the use, misuse, and abuse of the word “persistence” in Chlamydia biology. Front Cell Infect Microbiol In press 4:27 [View Article] [PubMed]
    [Google Scholar]
  17. Wyrick PB. Chlamydia trachomatis persistence in vitro: an overview. J Infect Dis 2010; 201:88–95 [View Article]
    [Google Scholar]
  18. Schoborg RV. Chlamydia persistence -- a tool to dissect chlamydia--host interactions. Microbes Infect 2011; 13:649–662 [View Article] [PubMed]
    [Google Scholar]
  19. Gitsels A, Sanders N, Vanrompay D. Chlamydial infection from outside to inside. Front Microbiol 2019; 10:2329 [View Article] [PubMed]
    [Google Scholar]
  20. Rother M, Teixeira da Costa AR, Zietlow R, Meyer TF, Rudel T. Modulation of host cell metabolism by Chlamydia trachomatis. Microbiol Spectr 2019; 7: [View Article] [PubMed]
    [Google Scholar]
  21. Chen H, Wen Y, Li Z. Clear victory for Chlamydia: the subversion of host innate immunity. Front Microbiol 2019; 10:1412 [View Article] [PubMed]
    [Google Scholar]
  22. Kothe H, Dalhoff K, Rupp J, Müller A, Kreuzer J et al. Hydroxymethylglutaryl coenzyme A reductase inhibitors modify the inflammatory response of human macrophages and endothelial cells infected with Chlamydia pneumoniae. Circulation 2000; 101:1760–1763 [View Article] [PubMed]
    [Google Scholar]
  23. Dechend R, Gieffers J, Dietz R, Joerres A, Rupp J et al. Hydroxymethylglutaryl coenzyme A reductase inhibition reduces Chlamydia pneumoniae-induced cell interaction and activation. Circulation 2003; 108:261–265 [View Article] [PubMed]
    [Google Scholar]
  24. Erkkilä L, Jauhiainen M, Laitinen K, Haasio K, Tiirola T et al. Effect of simvastatin, an established lipid-lowering drug, on pulmonary Chlamydia pneumoniae infection in mice. Antimicrob Agents Chemother 2005; 49:3959–3962 [View Article] [PubMed]
    [Google Scholar]
  25. Tiirola T, Jauhiainen M, Erkkilä L, Bloigu A, Leinonen M et al. Effect of pravastatin treatment on Chlamydia pneumoniae infection, inflammation and serum lipids in NIH/S mice. Int J Antimicrob Agents 2007; 29:741–742 [View Article] [PubMed]
    [Google Scholar]
  26. Kókai D, Mosolygó T, Virók DP, Endrész V, Burián K. N-acetyl-cysteine increases the replication of Chlamydia pneumoniae and prolongs the clearance of the pathogen from mice. J Med Microbiol 2018; 67:702–708 [View Article] [PubMed]
    [Google Scholar]
  27. Kókai D, Paróczai D, Virok DP, Endrész V, Gáspár R et al. Ambroxol treatment suppresses the proliferation of Chlamydia pneumoniae in murine lungs. Microorganisms 2021; 9:1–14 [View Article] [PubMed]
    [Google Scholar]
  28. Kuratli J, Leonard CA, Nufer L, Marti H, Schoborg R et al. Maraviroc, celastrol and azelastine alter Chlamydia trachomatis development in HeLa cells. J Med Microbiol 2020; 69:1351–1366 [View Article] [PubMed]
    [Google Scholar]
  29. Bernstein JA. Azelastine hydrochloride: a review of pharmacology, pharmacokinetics, clinical efficacy and tolerability. Curr Med Res Opin 2007; 23:2441–2452 [View Article] [PubMed]
    [Google Scholar]
  30. Williams PB, Crandall E, Sheppard JD. Azelastine hydrochloride, a dual-acting anti-inflammatory ophthalmic solution, for treatment of allergic conjunctivitis. Clin Ophthalmol 2010; 4:993–1001 [View Article] [PubMed]
    [Google Scholar]
  31. Romero MD, Mölleken K, Hegemann JH, Carabeo RA. Chlamydia adhesion and invasion. In Tang M, Hegemann JH, Sütterlin C. eds Chlamydia Biology: From Genome to Disease, 1st. edn Norfolk, UK: Caister Academic Press; 2020 pp 59–84 [View Article]
    [Google Scholar]
  32. Azari AA, Barney NP. Conjunctivitis: a systematic review of diagnosis and treatment. JAMA 2013; 310:1721–1729 [View Article] [PubMed]
    [Google Scholar]
  33. Mohamed-Noriega K, Mohamed-Noriega J, Valdés-Navarro MA, Cuervo-Lozano EE, Fernández-Espinosa MC et al. Conjunctival infection with Chlamydia trachomatis in sexual partners of patients with adult inclusion conjunctivitis. Int Ophthalmol 2015; 35:179–185 [View Article] [PubMed]
    [Google Scholar]
  34. Pourabbas B, Rezaei Z, Mardaneh J, Shahian M, Alborzi A. Prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae infections among pregnant women and eye colonization of their neonates at birth time, Shiraz, Southern Iran. BMC Infect Dis 2018; 18:477 [View Article] [PubMed]
    [Google Scholar]
  35. Leonard CA, Schoborg RV, Borel N. Damage/Danger Associated Molecular Patterns (DAMPs) modulate Chlamydia pecorum and C. trachomatis serovar E inclusion development in vitro. PLoS One 2015; 10:e0134943 [View Article] [PubMed]
    [Google Scholar]
  36. Russell T, Stoltz M, Weir S. Pharmacokinetics, pharmacodynamics, and tolerance of single- and multiple-dose fexofenadine hydrochloride in healthy male volunteers. Clin Pharmacol Ther 1998; 64:612–621 [View Article] [PubMed]
    [Google Scholar]
  37. Robbins DK, Castles MA, Pack DJ, Bhargava VO, Weir SJ. Dose proportionality and comparison of single and multiple dose pharmacokinetics of fexofenadine (MDL 16455) and its enantiomers in healthy male volunteers. Biopharm Drug Dispos 1998; 19:455–463 [View Article] [PubMed]
    [Google Scholar]
  38. Ashina K, Tsubosaka Y, Nakamura T, Omori K, Kobayashi K et al. Histamine induces vascular hyperpermeability by increasing blood flow and endothelial barrier disruption in vivo. PLoS One 2015; 10:e0132367 [View Article] [PubMed]
    [Google Scholar]
  39. Kuratli J, Leonard CA, Frohns A, Schoborg R, Piazena H et al. Refinement of water-filtered infrared A (wIRA) irradiations of in vitro acute and persistent chlamydial infections. J Photochem Photobiol B 2022; 234:112533 [View Article] [PubMed]
    [Google Scholar]
  40. Staub E, Marti H, Biondi R, Levi A, Donati M et al. Novel Chlamydia species isolated from snakes are temperature-sensitive and exhibit decreased susceptibility to azithromycin. Sci Rep 2018; 8:5660 [View Article] [PubMed]
    [Google Scholar]
  41. Onorini D, Donati M, Marti H, Biondi R, Levi A et al. The influence of centrifugation and incubation temperatures on various veterinary and human chlamydial species. Vet Microbiol 2019; 233:11–20 [View Article] [PubMed]
    [Google Scholar]
  42. Bates D, Mächler M, Bolker BM, Walker SC. Fitting linear mixed-effects models using lme4. J Stat Softw 2015; 67: [View Article]
    [Google Scholar]
  43. Hartig F. Package ‘DHARMa; 2022 http://florianhartig.github.io/DHARMa/
  44. Simons FER. Advances in H1-antihistamines. N Engl J Med 2004; 351:2203–2217 [View Article] [PubMed]
    [Google Scholar]
  45. Liu H, Farley JM. Effects of first and second generation antihistamines on muscarinic induced mucus gland cell ion transport. BMC Pharmacol 2005; 5:1–10 [View Article] [PubMed]
    [Google Scholar]
  46. Jain S, Panyutin A, Liu N, Xiao C, Piñol RA et al. Melanotan II causes hypothermia in mice by activation of mast cells and stimulation of histamine 1 receptors. Am J Physiol Endocrinol Metab 2018; 315:E357–E366 [View Article] [PubMed]
    [Google Scholar]
  47. Bosma R, van den Bor J, Vischer HF, Labeaga L, Leurs R. The long duration of action of the second generation antihistamine bilastine coincides with its long residence time at the histamine H1 receptor. Eur J Pharmacol 2018; 838:107–111 [View Article] [PubMed]
    [Google Scholar]
  48. Hackstadt T, Scidmore-Carlson MA, Shaw EI, Fischer ER. The Chlamydia trachomatis IncA protein is required for homotypic vesicle fusion. Cell Microbiol 1999; 1:119–130 [View Article] [PubMed]
    [Google Scholar]
  49. Brockett MR, Liechti GW. Persistence alters the interaction between Chlamydia trachomatis and its host cell. Infect Immun 2021; 89:e0068520 [View Article] [PubMed]
    [Google Scholar]
  50. Hybiske K, Heuer D. The chlamydial inclusion. In Tan M, Hegemann JH, Sütterlin C. eds Chlamydia Biology: From Genome to Disease, 1st. edn Norfolk, UK: Caister Academic Press; 2020 pp 85–110 [View Article]
    [Google Scholar]
  51. Arias-Montaño JA, Young JM. Characteristics of histamine H1 receptors on HeLa cells. Eur J Pharmacol 1993; 245:291–295 [View Article] [PubMed]
    [Google Scholar]
  52. Smit MJ, Bloemers SM, Leurs R, Tertoolen LG, Bast A et al. Short-term desensitization of the histamine H1 receptor in human HeLa cells: involvement of protein kinase C dependent and independent pathways. Br J Pharmacol 1992; 107:448–455 [View Article] [PubMed]
    [Google Scholar]
  53. Sharif NA, Xu SX, Magnino PE, Pang IH. Human conjunctival epithelial cells express histamine-1 receptors coupled to phosphoinositide turnover and intracellular calcium mobilization: role in ocular allergic and inflammatory diseases. Exp Eye Res 1996; 63:169–178 [View Article] [PubMed]
    [Google Scholar]
  54. Seo KY, Jeon S, Choi SH, Chung SH. Niflumic acid reduces histamine-induced MUC5AC expression in human conjunctival epithelial cells. Ophthalmic Res 2011; 46:181–186 [View Article] [PubMed]
    [Google Scholar]
  55. Lambiase A, Micera A, Bonini S. Multiple action agents and the eye: do they really stabilize mast cells?. Curr Opin Allergy Clin Immunol 2009; 9:454–465 [View Article] [PubMed]
    [Google Scholar]
  56. Singh U, Bernstein JA, Haar L, Luther K, Jones WK. Azelastine desensitization of transient receptor potential vanilloid 1: a potential mechanism explaining its therapeutic effect in nonallergic rhinitis. Am J Rhinol Allergy 2014; 28:215–224 [View Article] [PubMed]
    [Google Scholar]
  57. Amichai B, Grunwald MH, Brenner L. Fexofenadine hydrochloride--a new anti-histaminic drug. Isr Med Assoc J 2001; 3:207–209 [PubMed]
    [Google Scholar]
  58. Belland RJ, Zhong G, Crane DD, Hogan D, Sturdevant D et al. Genomic transcriptional profiling of the developmental cycle of Chlamydia trachomatis. Proc Natl Acad Sci 2003; 100:8478–8483 [View Article] [PubMed]
    [Google Scholar]
  59. Guseva NV, Dessus-Babus S, Moore CG, Whittimore JD, Wyrick PB. Differences in Chlamydia trachomatis serovar E growth rate in polarized endometrial and endocervical epithelial cells grown in three-dimensional culture. Infect Immun 2007; 75:553–564 [View Article] [PubMed]
    [Google Scholar]
  60. Lee JK, Enciso GA, Boassa D, Chander CN, Lou TH et al. Replication-dependent size reduction precedes differentiation in Chlamydia trachomatis. Nat Commun 2018; 9:45 [View Article] [PubMed]
    [Google Scholar]
  61. Rosario CJ, Soules K, Hefty SJ, Tan M. Chlamydia biology: from genome to disease. In Tan M, Hegemann JH, Sütterlin C. eds Chlamydia Biology: From Genome to Disease, 1st. edn UK: Caister Academic Press; 2020 pp 219–240 [View Article]
    [Google Scholar]
  62. Fischer A, Rudel T. Safe haven under constant attack-the Chlamydia-containing vacuole. Cell Microbiol 2018; 20:1–7 [View Article] [PubMed]
    [Google Scholar]
  63. Sütterlin C, Derré I. Interaction of the Chlamydial inclusion with the host cell. In Tan M, Hegemann JH, Sütterlin C. eds Chlamydia Biology: From Genome to Disease, 1st. edn Norfolk, UK: Caister Academic Press; 2020 pp 111–134 [View Article]
    [Google Scholar]
  64. El-Nakeeb MA, Abou-Shleib HM, Khalil AM, Omar HG, El-Halfawy OM. Reversal of antibiotic resistance in Gram-positive bacteria by the antihistaminic azelastine. APMIS 2012; 120:215–220 [View Article] [PubMed]
    [Google Scholar]
  65. El-Nakeeb MA, Abou-Shleib HM, Khalil AM, Omar HG, El-Halfawy OM. Membrane permeability alteration of some bacterial clinical isolates by selected antihistaminics. Braz J Microbiol 2011; 42:992–1000 [View Article] [PubMed]
    [Google Scholar]
  66. El-Nakeeb MA, Abou-Shleib HM, Khalil AM, Omar HG, El-Halfawy OM. In vitro antibacterial activity of some antihistaminics belonging to different groups against multi-drug resistant clinical isolates. Braz J Microbiol 2011; 42:980–991 [View Article] [PubMed]
    [Google Scholar]
  67. Peniche AG, Osorio EY, Melby PC, Travi BL. Efficacy of histamine H1 receptor antagonists azelastine and fexofenadine against cutaneous Leishmania major infection. PLoS Negl Trop Dis 2020; 14:e0008482 [View Article] [PubMed]
    [Google Scholar]
  68. Boyd NK, Lee GC, Teng C, Frei CR. In vitro activity of non-antibiotic drugs against Staphylococcus aureus clinical strains. J Glob Antimicrob Resist 2021; 27:167–171 [View Article] [PubMed]
    [Google Scholar]
  69. Tran Van Nhieu G, Dupont G, Combettes L. Ca2+ signals triggered by bacterial pathogens and microdomains. Biochim Biophys Acta - Mol Cell Res 2018; 1865:1838–1845 [View Article]
    [Google Scholar]
  70. Derré I. Chlamydiae interaction with the endoplasmic reticulum: contact, function and consequences. Cell Microbiol 2015; 17:959–966 [View Article] [PubMed]
    [Google Scholar]
  71. Kempuraj D, Huang M, Kandere-Grzybowska K, Basu S, Boucher W et al. Azelastine inhibits secretion of IL-6, TNF-alpha and IL-8 as well as NF-kappaB activation and intracellular calcium ion levels in normal human mast cells. Int Arch Allergy Immunol 2003; 132:231–239 [View Article] [PubMed]
    [Google Scholar]
  72. Hazama H, Nakajima T, Hisada T, Hamada E, Omata M et al. Effects of azelastine on membrane currents in tracheal smooth muscle cells isolated from the guinea-pig. Eur J Pharmacol 1994; 259:143–150 [View Article] [PubMed]
    [Google Scholar]
  73. Park MH, Lee SH, Chu DH, Won KH, Choi BH et al. Effect of azelastine on cardiac repolarization of guinea-pig cardiomyocytes, hERGK+ channel, and human L-type and T-type Ca2+ channel. J Pharmacol Sci 2013; 123:67–77 [View Article] [PubMed]
    [Google Scholar]
  74. Leonard CA, Schoborg RV, Borel N. Productive and penicillin-stressed Chlamydia pecorum infection induces nuclear factor Kappa B activation and interleukin-6 secretion in vitro. Front Cell Infect Microbiol 2017; 7:180 [View Article] [PubMed]
    [Google Scholar]
  75. Nagarajan UM, Turman BJ, Knittler MR, Klos AC. Chlamydia and innate immunity. In Tan M, Hegemann JH, Sütterlin C. eds Chlamydia Biology: From Genome to Disease, 1st. edn UK: Caister Academic Press; 2020 pp 287–312 [View Article]
    [Google Scholar]
  76. Akamatsu H, Miyachi Y, Asada Y, Niwa Y. Effects of azelastine on neutrophil chemotaxis, phagocytosis and oxygen radical generation. Jpn J Pharmacol 1991; 57:583–589 [View Article] [PubMed]
    [Google Scholar]
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