J Korean Med Sci.  2023 Apr;38(16):e129. 10.3346/jkms.2023.38.e129.

Anti-Alpha-Toxin Antibody Responses and Clinical Outcomes of Staphylococcus aureus Bacteremia

Affiliations
  • 1Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
  • 2Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
  • 3Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

Abstract

Background
Alpha-toxin (AT), a major virulence factor of Staphylococcus aureus, is an important immunotherapeutic target to prevent or treat invasive S. aureus infections. Previous studies have suggested that anti-AT antibodies (Abs) may have a protective role against S. aureus bacteremia (SAB), but their function remains unclear. Therefore, we aimed to investigate the association between serum anti-AT Ab levels and clinical outcomes of SAB.
Methods
Patients from a prospective SAB cohort at a tertiary-care medical center (n = 51) were enrolled in the study from July 2016 to January 2019. Patients without symptoms or signs of infection were enrolled as controls (n = 100). Blood samples were collected before the onset of SAB and at 2- and 4-weeks post-bacteremia. Anti-AT immunoglobin G (IgG) levels were measured using an enzyme-linked immunosorbent assay. All clinical S. aureus isolates were tested for the presence of hla using polymerase chain reaction.
Results
Anti-AT IgG levels in patients with SAB before the onset of bacteremia did not differ significantly from those in non-infectious controls. Pre-bacteremic anti-AT IgG levels tended to be lower in patients with worse clinical outcomes (7-day mortality, persistent bacteremia, metastatic infection, septic shock), although the differences were not statistically significant. Patients who needed intensive care unit care had significantly lower anti-AT IgG levels at 2 weeks post-bacteremia (P = 0.020).
Conclusion
The study findings suggest that lower anti-AT Ab responses before and during SAB, reflective of immune dysfunction, are associated with more severe clinical presentations of infection.

Keyword

Staphylococcus aureus; Bacteremia; Alpha-Toxin; Anti-Alpha-Toxin Antibody; Antibody Response

Figure

  • Fig. 1 Schematic representation of the protocol for patient selection.WBC = white blood cell.

  • Fig. 2 Anti-AT IgG Ab levels in patients with Staphylococcus aureus bacteremia at different time points during bacteremia duration (pre-bacteremia and 2- and 4-weeks post-bacteremia) according to clinical outcomes: (A) persistent bacteremia ≥ 5 days (n = 10), (B) development of metastatic foci (n = 2), (C) progression to septic shock (n = 7), (D) requiring intensive care unit care (n = 18). Lower and upper box boundaries represent 25th and 75th percentiles, respectively; lines inside the box represent median; lower and upper error lines are 10th and 90th percentiles, respectively; filled circles show data falling outside 10th and 90th percentiles.AT = alpha-toxin, Ab = antibody, IgG = immunoglobin G, ICU = intensive care unit.*P  <  0.05.


Reference

1. Lowy FD. Staphylococcus aureus infections. N Engl J Med. 1998; 339(8):520–532. PMID: 9709046.
2. Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011; 52(3):e18–e55. PMID: 21208910.
3. Adhikari RP, Ajao AO, Aman MJ, Karauzum H, Sarwar J, Lydecker AD, et al. Lower antibody levels to Staphylococcus aureus exotoxins are associated with sepsis in hospitalized adults with invasive S. aureus infections. J Infect Dis. 2012; 206(6):915–923. PMID: 22807524.
4. van Hal SJ, Jensen SO, Vaska VL, Espedido BA, Paterson DL, Gosbell IB. Predictors of mortality in Staphylococcus aureus bacteremia. Clin Microbiol Rev. 2012; 25(2):362–386. PMID: 22491776.
5. Wang FD, Chen YY, Chen TL, Liu CY. Risk factors and mortality in patients with nosocomial Staphylococcus aureus bacteremia. Am J Infect Control. 2008; 36(2):118–122. PMID: 18313513.
6. Oganesyan V, Peng L, Damschroder MM, Cheng L, Sadowska A, Tkaczyk C, et al. Mechanisms of neutralization of a human anti-α-toxin antibody. J Biol Chem. 2014; 289(43):29874–29880. PMID: 25210036.
7. Wu Y, Liu X, Akhgar A, Li JJ, Mok H, Sellman BR, et al. Prevalence of IgG and neutralizing antibodies against Staphylococcus aureus alpha-toxin in healthy human subjects and diverse patient populations. Infect Immun. 2018; 86(3):e00671-17. PMID: 29263109.
8. Berube BJ, Bubeck Wardenburg J. Staphylococcus aureus α-toxin: nearly a century of intrigue. Toxins (Basel). 2013; 5(6):1140–1166. PMID: 23888516.
9. Otto M. Basis of virulence in community-associated methicillin-resistant Staphylococcus aureus. Annu Rev Microbiol. 2010; 64(1):143–162. PMID: 20825344.
10. Wilke GA, Bubeck Wardenburg J. Role of a disintegrin and metalloprotease 10 in Staphylococcus aureus alpha-hemolysin-mediated cellular injury. Proc Natl Acad Sci U S A. 2010; 107(30):13473–13478. PMID: 20624979.
11. Bonifacius A, Goldmann O, Floess S, Holtfreter S, Robert PA, Nordengrün M, et al. Staphylococcus aureus alpha-toxin limits type 1 while fostering type 3 immune responses. Front Immunol. 2020; 11:1579. PMID: 32849537.
12. Chua KY, Monk IR, Lin YH, Seemann T, Tuck KL, Porter JL, et al. Hyperexpression of α-hemolysin explains enhanced virulence of sequence type 93 community-associated methicillin-resistant Staphylococcus aureus. BMC Microbiol. 2014; 14(1):31. PMID: 24512075.
13. Li M, Cheung GY, Hu J, Wang D, Joo HS, Deleo FR, et al. Comparative analysis of virulence and toxin expression of global community-associated methicillin-resistant Staphylococcus aureus strains. J Infect Dis. 2010; 202(12):1866–1876. PMID: 21050125.
14. Bubeck Wardenburg J, Schneewind O. Vaccine protection against Staphylococcus aureus pneumonia. J Exp Med. 2008; 205(2):287–294. PMID: 18268041.
15. Hua L, Hilliard JJ, Shi Y, Tkaczyk C, Cheng LI, Yu X, et al. Assessment of an anti-alpha-toxin monoclonal antibody for prevention and treatment of Staphylococcus aureus-induced pneumonia. Antimicrob Agents Chemother. 2014; 58(2):1108–1117. PMID: 24295977.
16. Kennedy AD, Bubeck Wardenburg J, Gardner DJ, Long D, Whitney AR, Braughton KR, et al. Targeting of alpha-hemolysin by active or passive immunization decreases severity of USA300 skin infection in a mouse model. J Infect Dis. 2010; 202(7):1050–1058. PMID: 20726702.
17. Sampedro GR, DeDent AC, Becker RE, Berube BJ, Gebhardt MJ, Cao H, et al. Targeting Staphylococcus aureus α-toxin as a novel approach to reduce severity of recurrent skin and soft-tissue infections. J Infect Dis. 2014; 210(7):1012–1018. PMID: 24740631.
18. Spaulding AR, Lin YC, Merriman JA, Brosnahan AJ, Peterson ML, Schlievert PM. Immunity to Staphylococcus aureus secreted proteins protects rabbits from serious illnesses. Vaccine. 2012; 30(34):5099–5109. PMID: 22691432.
19. Colque-Navarro P, Söderquist B, Holmberg H, Blomqvist L, Olcén P, Möllby R. Antibody response in Staphylococcus aureus septicaemia--a prospective study. J Med Microbiol. 1998; 47(3):217–225. PMID: 9511827.
20. Jacobsson G, Colque-Navarro P, Gustafsson E, Andersson R, Möllby R. Antibody responses in patients with invasive Staphylococcus aureus infections. Eur J Clin Microbiol Infect Dis. 2010; 29(6):715–725. PMID: 20383551.
21. Kim NH, Sung JY, Choi YJ, Choi SJ, Ahn S, Ji E, et al. Toll-like receptor 2 downregulation and cytokine dysregulation predict mortality in patients with Staphylococcus aureus bacteremia. BMC Infect Dis. 2020; 20(1):901. PMID: 33256638.
22. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987; 40(5):373–383. PMID: 3558716.
23. Paterson DL, Ko WC, Von Gottberg A, Mohapatra S, Casellas JM, Goossens H, et al. International prospective study of Klebsiella pneumoniae bacteremia: implications of extended-spectrum beta-lactamase production in nosocomial Infections. Ann Intern Med. 2004; 140(1):26–32. PMID: 14706969.
24. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996; 22(7):707–710. PMID: 8844239.
25. Friedman ND, Kaye KS, Stout JE, McGarry SA, Trivette SL, Briggs JP, et al. Health care--associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections. Ann Intern Med. 2002; 137(10):791–797. PMID: 12435215.
26. Jang HC, Kim SH, Kim KH, Kim CJ, Lee S, Song KH, et al. Salvage treatment for persistent methicillin-resistant Staphylococcus aureus bacteremia: efficacy of linezolid with or without carbapenem. Clin Infect Dis. 2009; 49(3):395–401. PMID: 19569970.
27. Rose WE, Shukla SK, Berti AD, Hayney MS, Henriquez KM, Ranzoni A, et al. Increased endovascular Staphylococcus aureus inoculum is the link between elevated serum interleukin 10 concentrations and mortality in patients with bacteremia. Clin Infect Dis. 2017; 64(10):1406–1412. PMID: 28205673.
28. Kullar R, McKinnell JA, Sakoulas G. Avoiding the perfect storm: the biologic and clinical case for reevaluating the 7-day expectation for methicillin-resistant Staphylococcus aureus bacteremia before switching therapy. Clin Infect Dis. 2014; 59(10):1455–1461. PMID: 25048852.
29. Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary. Clin Infect Dis. 2011; 52(3):285–292. PMID: 21217178.
30. Colque-Navarro P, Jacobsson G, Andersson R, Flock JI, Möllby R. Levels of antibody against 11 Staphylococcus aureus antigens in a healthy population. Clin Vaccine Immunol. 2010; 17(7):1117–1123. PMID: 20445005.
31. Sharma-Kuinkel BK, Wu Y, Tabor DE, Mok H, Sellman BR, Jenkins A, et al. Characterization of alpha-toxin hla gene variants, alpha-toxin expression levels, and levels of antibody to alpha-toxin in hemodialysis and postsurgical patients with Staphylococcus aureus bacteremia. J Clin Microbiol. 2015; 53(1):227–236. PMID: 25392350.
32. Tkaczyk C, Hua L, Varkey R, Shi Y, Dettinger L, Woods R, et al. Identification of anti-alpha toxin monoclonal antibodies that reduce the severity of Staphylococcus aureus dermonecrosis and exhibit a correlation between affinity and potency. Clin Vaccine Immunol. 2012; 19(3):377–385. PMID: 22237895.
33. Dryla A, Prustomersky S, Gelbmann D, Hanner M, Bettinger E, Kocsis B, et al. Comparison of antibody repertoires against Staphylococcus aureus in healthy individuals and in acutely infected patients. Clin Diagn Lab Immunol. 2005; 12(3):387–398. PMID: 15753252.
34. Julander IG, Granström M, Hedström SA, Möllby R. The role of antibodies against alpha-toxin and teichoic acid in the diagnosis of staphylococcal infections. Infection. 1983; 11(2):77–83. PMID: 6862637.
35. Meyer TC, Michalik S, Holtfreter S, Weiss S, Friedrich N, Völzke H, et al. A comprehensive view on the human antibody repertoire against Staphylococcus aureus antigens in the general population. Front Immunol. 2021; 12:651619. PMID: 33777051.
36. Fritz SA, Tiemann KM, Hogan PG, Epplin EK, Rodriguez M, Al-Zubeidi DN, et al. A serologic correlate of protective immunity against community-onset Staphylococcus aureus infection. Clin Infect Dis. 2013; 56(11):1554–1561. PMID: 23446627.
37. Tabor DE, Yu L, Mok H, Tkaczyk C, Sellman BR, Wu Y, et al. Staphylococcus aureus alpha-toxin is conserved among diverse hospital respiratory isolates collected from a global surveillance study and is neutralized by monoclonal antibody MEDI4893. Antimicrob Agents Chemother. 2016; 60(9):5312–5321. PMID: 27324766.
38. Monecke S, Müller E, Büchler J, Stieber B, Ehricht R. Staphylococcus aureus in vitro secretion of alpha toxin (hla) correlates with the affiliation to clonal complexes. PLoS One. 2014; 9(6):e100427. PMID: 24940872.
39. François B, Jafri HS, Chastre J, Sánchez-García M, Eggimann P, Dequin PF, et al. Efficacy and safety of suvratoxumab for prevention of Staphylococcus aureus ventilator-associated pneumonia (SAATELLITE): a multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 2 pilot trial. Lancet Infect Dis. 2021; 21(9):1313–1323. PMID: 33894131.
40. Song KH, Kim ES, Sin HY, Park KH, Jung SI, Yoon N, et al. Characteristics of invasive Staphylococcus aureus infections in three regions of Korea, 2009-2011: a multi-center cohort study. BMC Infect Dis. 2013; 13(1):581. PMID: 24321206.
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