Toxic shock syndrome pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Overview

The pathophysiology of toxic shock syndrome can be explained based on the etiological agent causing the disease. The general mechanism for all the etiological agents is the same, which involves non-specific activation of T lymphocytes by toxins acting as superantigens leading to release of cytokines.[1] There are small differences in the mechanism of cytokine production which can be explained individually for the organisms involved.

Pathophysiology

Toxic shock syndrome (TSS) is known to be caused by the intoxication by one of the various exotoxins produced by Staphylococcus aureus, namely toxic shock syndrome toxin-1 (TSST-1). It may also be caused by some strains of Streptococcus pyogenes or Group A streptococcal (GAS) infection. There have been reports of TSS caused by Clostridium perfringens and Clostridium sordelli in women undergoing medical abortion.[2][3][4][5][6]

S. aureus associated Toxic Shock Syndrome (TSS)

S. aureus strains are facultative aerobes, which colonize the human mucosal surfaces like vagina and anterior nares.[7]

Pathogenesis

  • Various attachment proteins for example, fibronectin-binding proteins and collagen-binding proteins among many others, facilitate attachment to host cells, or interfere with host immune responses through the antiphagocytic action of proteins such as protein A. After attachment to host cells (particularly epithelial cells), the S. aureus produces cytolysins, which aid entry of the Toxic shock syndrome toxin-1 (TSST-1--the major toxin involved in TSS) into the system.
  • TSST-1 is a protein based exotoxin, which acts as a superantigen (SAg). SAgs bind to certain regions of major histocompatibility complex (MHC) class II molecules of antigen-presenting cells (APCs) outside the traditional antigen-binding site, and at the same time bind in their native form to T cells at specific sites of the variable region of the beta chain (Vbeta) of the T cell receptor (TcR). This interaction triggers the activation (proliferation) of the targeted T lymphocytes and leads to release of high amounts of various cytokines and other effectors by immune cells. [1]
  • The SAg with the help of cytolysins, specially α-toxin, binds by its dodecapeptide region to human epithelial cells, possibly CD40 or another unknown receptor, stimulating the production of pro-inflammatory chemokines including TNF-alpha, IL-6 and MIP-3α.[8] The SAg must cross the mucosal barrier to cause disease, but it seems likely that submucosal SAg activities, rather than systemic activities, are sufficient for TSS production. [9]
  • SAgs cause release of IL-1 beta and IL-6 from antigen presenting cells (APC) and have a direct action on the hypothalamic temperature control center.
  • Staphylococcal toxic shock syndrome toxin 1 (TSST-1) is also the cause of menstrual toxic shock syndrome (mTSS) associated with vaginal colonization by Staphylococcus aureus; IL-8 and MIP-3α may originate from vaginal epithelial cells, which are highly chemotactic.[10]

Genetics

  • The gene encoding toxic shock syndrome toxin is carried by a mobile genetic element of S. aureus in the SaPI family of pathogenicity islands.[11]

GAS associated Toxic Shock Syndrome (Toxic shock-like syndrome-TSLS)

Pathogenesis

  • Streptococcus pyogenes, a beta-hemolytic bacterium that belongs to Lancefield serogroup A, also known as the group A streptococci (GAS) (particularly those harboring the M protein, specifically M1, M3 and M18) which are capable of producing the superantigens speA, speB and speC have been associated with severe cases of streptococcal toxic shock syndrome, also called Toxic shock-like syndrome (TSLS).[12][13]
  • Systemic invasion by the GAS is required for producing TSLS, which is in contrast to TSS caused by S.aureus (which only requires mucosal invasion to produce TSS). GAS associated TSS is not tampon-associated, because streptococci are anaerobic organisms and thus do not require oxygen for growth and toxin production (unlike S. aureus associated TSS).
  • The pyrogenic exotoxin type A gene is associated with group A streptococcal strains isolated from patients with TSLS and may play a causative role in this illness.[14]
  • SpeA and SpeB non-specifically activate T cells causing release of pro-inflammatory cytokines like IL-6, IL-8, and MIP-3α[15], which leads to fever, rash, capillary leak, and subsequent hypotension, the major symptoms of toxic shock syndrome. SpeB degrades immunoglobulins and cytokines, as well as through cleavage of C3b, inhibiting recruitment of phagocytic cells and the complement activation pathway.[16]

Genetics

  • TSLS causing strains of streptococci have genetic sequences that code for exotoxins spe A, B and C. [17]

Clostridium associated Toxic Shock Syndrome (TSS)

Pathogenesis

  • Toxic shock syndrome after abortion can be caused by C. perfringens as well as C. sordellii, can be nonfatal, and can occur after spontaneous abortion and abortion induced by medical regimens other than mifepristone and misoprostol,[18] although a fatal case of C. sordellii toxic shock syndrome after medical abortion with mifepristone and misoprostol was reported in 2001, in Canada.[19]
  • Clostridium sordellii strains can produce two large clostridial cytotoxins (LCCs); lethal toxin (TcsL) and hemorrhagic toxin (TcsH), similar to those produced by Clostridium difficile, Clostridium novyi and Clostridium perfringens.[20]
  • TcsL is the most important virulence factor required for producing Toxic shock syndrome (TSS).[21] It is a major pathogenicity factor, which in addition to its in vivo effects, is cytotoxic to cultured cell lines. It causes reorganization of the cytoskeleton accompanied by morphological changes. The TcsL is a single-chain protein toxin, which comprises of three sites: receptor-binding, translocation and catalytic site. These sites reflect the self-mediated cell entry via receptor-mediated endocytosis, translocation into the cytoplasm, and execution of their cytotoxic activity by an inherent enzyme activity, respectively. Enzymatically, the toxins catalyze the transfer of a glucosyl moiety from UDP-glucose to the intracellular target proteins which are the Rho and Ras GTPases.
  • Rho and Rac are the main regulators of the cell barrier integrity; Rho plays a key role in the maintenance of tight junctions, a structure existing between endothelial cells, whereas Rac is a major regulator of the integrity of VE-cadherin junctions, mainly adherens junctions.[22]
  • The covalent attachment of the glucose moiety to a conserved threonine within the effector region of the GTPases causes inactivation of Rho-GTPases.[23]
  • Glucosylation of Rac, another major target for TcsL, leads to alteration in Rac-dependent adherens junctions, vascular leakage, subsequent edema formation and the refractory shock like syndrome seen in C. sordelii infections. In conclusion, death induced by TcsL seems to be the consequence of an increase in vascular permeability, resulting from modifications of endothelial cells. Extravasation of blood fluid into the pleural cavity leads to anoxia and finally to cardiorespiratory failure, in the absence of inflammation. [24]

Gross Pathology

There are no specific gross pathology findings associated with toxic shock syndrome.

References

  1. ↑ 1.0 1.1 Alouf JE, Müller-Alouf H (2003). "Staphylococcal and streptococcal superantigens: molecular, biological and clinical aspects". Int. J. Med. Microbiol. 292 (7–8): 429–40. doi:10.1078/1438-4221-00232. PMID 12635926.
  2. ↑ McGregor JA, Soper DE, Lovell G, Todd JK (1989). "Maternal deaths associated with Clostridium sordellii infection". Am. J. Obstet. Gynecol. 161 (4): 987–95. PMID 2801850.
  3. ↑ "Clostridium sordellii toxic shock syndrome after medical abortion with mifepristone and intravaginal misoprostol--United States and Canada, 2001-2005". MMWR Morb. Mortal. Wkly. Rep. 54 (29): 724. 2005. PMID 16049422.
  4. ↑ Fischer M, Bhatnagar J, Guarner J, Reagan S, Hacker JK, Van Meter SH, Poukens V, Whiteman DB, Iton A, Cheung M, Dassey DE, Shieh WJ, Zaki SR (2005). "Fatal toxic shock syndrome associated with Clostridium sordellii after medical abortion". N. Engl. J. Med. 353 (22): 2352–60. doi:10.1056/NEJMoa051620. PMID 16319384.
  5. ↑ Sinave C, Le Templier G, Blouin D, Léveillé F, Deland E (2002). "Toxic shock syndrome due to Clostridium sordellii: a dramatic postpartum and postabortion disease". Clin. Infect. Dis. 35 (11): 1441–3. doi:10.1086/344464. PMID 12439811.
  6. ↑ Ho CS, Bhatnagar J, Cohen AL, Hacker JK, Zane SB, Reagan S, Fischer M, Shieh WJ, Guarner J, Ahmad S, Zaki SR, McDonald LC (2009). "Undiagnosed cases of fatal Clostridium-associated toxic shock in Californian women of childbearing age". Am. J. Obstet. Gynecol. 201 (5): 459.e1–7. doi:10.1016/j.ajog.2009.05.023. PMID 19628200.
  7. ↑ Lowy FD (1998). "Staphylococcus aureus infections". N. Engl. J. Med. 339 (8): 520–32. doi:10.1056/NEJM199808203390806. PMID 9709046.
  8. ↑ Brosnahan AJ, Schlievert PM (2011). "Gram-positive bacterial superantigen outside-in signaling causes toxic shock syndrome". FEBS J. 278 (23): 4649–67. doi:10.1111/j.1742-4658.2011.08151.x. PMC 3165073. PMID 21535475.
  9. ↑ Stach CS, Herrera A, Schlievert PM (2014). "Staphylococcal superantigens interact with multiple host receptors to cause serious diseases". Immunol. Res. 59 (1–3): 177–81. doi:10.1007/s12026-014-8539-7. PMC 4125451. PMID 24838262.
  10. ↑ Schlievert PM, Nemeth KA, Davis CC, Peterson ML, Jones BE (2010). "Staphylococcus aureus exotoxins are present in vivo in tampons". Clin. Vaccine Immunol. 17 (5): 722–7. doi:10.1128/CVI.00483-09. PMC 2863369. PMID 20335433.
  11. ↑ Lindsay JA, Ruzin A, Ross HF, Kurepina N, Novick RP (1998). "The gene for toxic shock toxin is carried by a family of mobile pathogenicity islands in Staphylococcus aureus". Mol. Microbiol. 29 (2): 527–43. PMID 9720870.
  12. ↑ Goshorn SC, Schlievert PM (1989). "Bacteriophage association of streptococcal pyrogenic exotoxin type C". J. Bacteriol. 171 (6): 3068–73. PMC 210016. PMID 2566595.
  13. ↑ Stevens DL, Tanner MH, Winship J, Swarts R, Ries KM, Schlievert PM, Kaplan E (1989). "Severe group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A". N. Engl. J. Med. 321 (1): 1–7. doi:10.1056/NEJM198907063210101. PMID 2659990.
  14. ↑ Hauser AR, Stevens DL, Kaplan EL, Schlievert PM (1991). "Molecular analysis of pyrogenic exotoxins from Streptococcus pyogenes isolates associated with toxic shock-like syndrome". J. Clin. Microbiol. 29 (8): 1562–7. PMC 270163. PMID 1684795.
  15. ↑ Llewelyn M, Cohen J (2002). "Superantigens: microbial agents that corrupt immunity". Lancet Infect Dis. 2 (3): 156–62. PMID 11944185.
  16. ↑ Nelson DC, Garbe J, Collin M (2011). "Cysteine proteinase SpeB from Streptococcus pyogenes - a potent modifier of immunologically important host and bacterial proteins". Biol. Chem. 392 (12): 1077–88. doi:10.1515/BC.2011.208. PMID 22050223.
  17. ↑ Sztajnbok J, Lovgren M, Brandileone MC, Marotto PC, Talbot JA, Seguro AC (1999). "Fatal group A Streptococcal toxic shock-like syndrome in a child with varicella: report of the first well documented case with detection of the genetic sequences that code for exotoxins spe A and B, in São Paulo, Brazil". Rev. Inst. Med. Trop. Sao Paulo. 41 (1): 63–5. PMID 10436672.
  18. ↑ Cohen AL, Bhatnagar J, Reagan S, Zane SB, D'Angeli MA, Fischer M, Killgore G, Kwan-Gett TS, Blossom DB, Shieh WJ, Guarner J, Jernigan J, Duchin JS, Zaki SR, McDonald LC (2007). "Toxic shock associated with Clostridium sordellii and Clostridium perfringens after medical and spontaneous abortion". Obstet Gynecol. 110 (5): 1027–33. doi:10.1097/01.AOG.0000287291.19230.ba. PMID 17978116.
  19. ↑ "Clostridium sordellii toxic shock syndrome after medical abortion with mifepristone and intravaginal misoprostol--United States and Canada, 2001-2005". MMWR Morb. Mortal. Wkly. Rep. 54 (29): 724. 2005. PMID 16049422.
  20. ↑ Couchman EC, Browne HP, Dunn M, Lawley TD, Songer JG, Hall V, Petrovska L, Vidor C, Awad M, Lyras D, Fairweather NF (2015). "Clostridium sordellii genome analysis reveals plasmid localized toxin genes encoded within pathogenicity loci". BMC Genomics. 16: 392. doi:10.1186/s12864-015-1613-2. PMC 4434542. PMID 25981746.
  21. ↑ Hao Y, Senn T, Opp JS, Young VB, Thiele T, Srinivas G, Huang SK, Aronoff DM (2010). "Lethal toxin is a critical determinant of rapid mortality in rodent models of Clostridium sordellii endometritis". Anaerobe. 16 (2): 155–60. doi:10.1016/j.anaerobe.2009.06.002. PMC 2856776. PMID 19527792.
  22. ↑ Jou TS, Schneeberger EE, Nelson WJ (1998). "Structural and functional regulation of tight junctions by RhoA and Rac1 small GTPases". J. Cell Biol. 142 (1): 101–15. PMC 2133025. PMID 9660866.
  23. ↑ Just I, Gerhard R (2004). "Large clostridial cytotoxins". Rev. Physiol. Biochem. Pharmacol. 152: 23–47. doi:10.1007/s10254-004-0033-5. PMID 15449191.
  24. ↑ Geny B, Khun H, Fitting C, Zarantonelli L, Mazuet C, Cayet N, Szatanik M, Prevost MC, Cavaillon JM, Huerre M, Popoff MR (2007). "Clostridium sordellii lethal toxin kills mice by inducing a major increase in lung vascular permeability". Am. J. Pathol. 170 (3): 1003–17. doi:10.2353/ajpath.2007.060583. PMC 1864880. PMID 17322384.


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