We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

Pathogenic mechanism of Vibrio vulnificus infection

    Kun Lu

    Department of Neurosurgery, First Naval Hospital of Southern Theater Command, Zhanjiang, 524000, China

    ,
    Yang Li‡

    Department of Neurosurgery, First Naval Hospital of Southern Theater Command, Zhanjiang, 524000, China

    ‡These authors contributed equally to this work and share second authorship

    Search for more papers by this author

    ,
    Rui Chen‡

    Department of Orthopedics, First Naval Hospital of Southern Theater Command, Zhanjiang, 524000, China

    ‡These authors contributed equally to this work and share second authorship

    Search for more papers by this author

    ,
    Hua Yang‡

    Department of Neurosurgery, First Naval Hospital of Southern Theater Command, Zhanjiang, 524000, China

    ‡These authors contributed equally to this work and share second authorship

    Search for more papers by this author

    ,
    Yong Wang‡

    Hemodialysis Center, First Naval Hospital of Southern Theater Command, Zhanjiang, 524000, China

    ‡These authors contributed equally to this work and share second authorship

    Search for more papers by this author

    ,
    Wei Xiong

    Department of Neurosurgery, First Naval Hospital of Southern Theater Command, Zhanjiang, 524000, China

    ,
    Fang Xu

    Department of Neurosurgery, First Naval Hospital of Southern Theater Command, Zhanjiang, 524000, China

    ,
    Qijun Yuan

    Department of Neurosurgery, First Naval Hospital of Southern Theater Command, Zhanjiang, 524000, China

    ,
    Haihui Liang

    Department of Neurosurgery, First Naval Hospital of Southern Theater Command, Zhanjiang, 524000, China

    ,
    Xian Xiao

    Department of Neurosurgery, First Naval Hospital of Southern Theater Command, Zhanjiang, 524000, China

    ,
    Renqiang Huang

    Department of Neurosurgery, First Naval Hospital of Southern Theater Command, Zhanjiang, 524000, China

    ,
    Zhipeng Chen

    Department of Neurosurgery, First Naval Hospital of Southern Theater Command, Zhanjiang, 524000, China

    ,
    Chunou Tian

    Department of Neurosurgery, First Naval Hospital of Southern Theater Command, Zhanjiang, 524000, China

    &
    Songqing Wang

    *Author for correspondence:

    E-mail Address: wangsongqing2004@126.com

    Department of Neurosurgery, First Naval Hospital of Southern Theater Command, Zhanjiang, 524000, China

    Published Online:https://doi.org/10.2217/fmb-2022-0243

    Vibrio vulnificus is a fatal, opportunistic human pathogen transmitted through the consumption of raw/undercooked seafood or direct contact. V. vulnificus infection progresses rapidly and has severe consequences; some cases may require amputation or result in death. Growing evidence suggests that V. vulnificus virulence factors and regulators play a large role in disease progression, involving host resistance, cellular damage, iron acquisition, virulence regulation and host immune responses. Its disease mechanism remains largely undefined. Further evaluation of pathogenic mechanisms is important for selecting appropriate measures to prevent and treat V. vulnificus infection. In this review, the possible pathogenesis of V. vulnificus infection is described to provide a reference for treatment and prevention.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Heng SP, Letchumanan V, Deng CY et al. Vibrio vulnificus: an environmental and clinical burden. Front. Microbiol. 8, 997 (2017).
    • 2. Coerdt KM, Khachemoune A. Vibrio vulnificus: review of mild to life-threatening skin infections. Cutis 107(2), e12–e17 (2021).
    • 3. Wong KC, Brown AM, Luscombe GM et al. Antibiotic use for Vibrio infections: important insights from surveillance data. BMC Infect. Dis. 15, 226 (2015).
    • 4. Jones MK, Oliver JD. Vibrio vulnificus: disease and pathogenesis. Infect. Immun. 77(5), 1723–1733 (2009). •• The biological types and possible pathogenesis of Vibrio vulnificus are summarized in detail.
    • 5. Chang CY, Wu KH, Wu PH et al. In-hospital mortality associated with necrotizing soft tissue infection due to Vibrio vulnificus: a matched-pair cohort study. World J. Emerg. Surg. 17(1), 28 (2022).
    • 6. Hong G, Wu B, Lu C et al. Emergency treatment of 16 patients with necrotizing fasciitis caused by Vibrio vulnificus infection complicated with septic shock. Chin. Med. J. (Engl.) 127(10), 1984–1986 (2014).
    • 7. Chao WN, Tsai CF, Chang HR et al. Impact of timing of surgery on outcome of Vibrio vulnificus-related necrotizing fasciitis. Am. J. Surg. 206(1), 32–39 (2013).
    • 8. Zhao H, Xu L, Dong H et al. Correlations between clinical features and mortality in patients with Vibrio vulnificus infection. PLOS ONE 10(8), e0136019 (2015).
    • 9. Stamm LV. Role of TLR4 in the host response to Vibrio vulnificus, an emerging pathogen. FEMS Immunol. Med. Microbiol. 58(3), 336–343 (2010).
    • 10. Anderson M, Knudson M, Frieberg E et al. Fatal Vibrio vulnificus sepsis in vertically acquired hepatitis C. J. Pediatr. Gastroenterol. Nutr. 56(5), e32–e33 (2013).
    • 11. Bisharat N, Bronstein M, Korner M et al. Transcriptome profiling analysis of Vibrio vulnificus during human infection. Microbiology (Reading) 159(Pt 9), 1878–1887 (2013).
    • 12. Leng F, Lin S, Wu W et al. Epidemiology, pathogenetic mechanism, clinical characteristics, and treatment of Vibrio vulnificus infection: a case report and literature review. Eur. J. Clin. Microbiol. Infect. Dis. 38(11), 1999–2004 (2019).
    • 13. Duong-Nu TM, Jeong K, Hong SH et al. A stealth adhesion factor contributes to Vibrio vulnificus pathogenicity: flp pili play roles in host invasion, survival in the blood stream and resistance to complement activation. PLoS Pathog. 15(8), e1007767 (2019).
    • 14. Murciano C, Lee CT, Fernandez-Bravo A et al. MARTX toxin in the zoonotic serovar of Vibrio vulnificus triggers an early cytokine storm in mice. Front. Cell Infect. Microbiol. 7, 332 (2017).
    • 15. Li G, Wang MY. The role of Vibrio vulnificus virulence factors and regulators in its infection-induced sepsis. Folia. Microbiol. (Praha) 65(2), 265–274 (2020). •• Summarizes the role of V. vulnificus virulence factors in sepsis.
    • 16. Kashimoto T, Ueno S, Hayashi H et al. Depletion of lymphocytes, but not neutrophils, via apoptosis in a murine model of Vibrio vulnificus infection. J. Med. Microbiol. 54(Pt 1), 15–22 (2005).
    • 17. Lo HR, Lin JH, Chen YH et al. RTX toxin enhances the survival of Vibrio vulnificus during infection by protecting the organism from phagocytosis. J. Infect. Dis. 203(12), 1866–1874 (2011).
    • 18. Chen CL, Chien SC, Leu TH et al. Vibrio vulnificus MARTX cytotoxin causes inactivation of phagocytosis-related signaling molecules in macrophages. J. Biomed. Sci. 24(1), 58 (2017).
    • 19. Tsuchiya T, Mitsuo E, Hayashi N et al. Vibrio vulnificus damages macrophages during the early phase of infection. Infect. Immun. 75(9), 4592–4596 (2007).
    • 20. Lopez-Perez M, Jayakumar JM, Haro-Moreno JM et al. Evolutionary model of cluster divergence of the emergent marine pathogen Vibrio vulnificus: from genotype to ecotype. mBio 10(1), e02852-18 (2019).
    • 21. Lee TH, Cha SS, Lee CS et al. Monoclonal antibodies against Vibrio vulnificus RtxA1 elicit protective immunity through distinct mechanisms. Infect. Immun. 82(11), 4813–4823 (2014).
    • 22. Lee SJ, Jung YH, Oh SY et al. Vibrio vulnificus VvpE inhibits mucin 2 expression by hypermethylation via lipid raft-mediated ROS signaling in intestinal epithelial cells. Cell Death Dis. 6, e1787 (2015).
    • 23. Kim CM, Park RY, Chun HJ et al. Vibrio vulnificus metalloprotease VvpE is essentially required for swarming. FEMS Microbiol. Lett. 269(1), 170–179 (2007).
    • 24. Paranjpye RN, Strom MS. A Vibrio vulnificus type IV pilin contributes to biofilm formation, adherence to epithelial cells, and virulence. Infect. Immun. 73(3), 1411–1422 (2005).
    • 25. Wright AC, Simpson LM, Oliver JD. Role of iron in the pathogenesis of Vibrio vulnificus infections. Infect. Immun. 34(2), 503–507 (1981).
    • 26. Thiaville PC, Bourdage KL, Wright AC et al. Genotype is correlated with but does not predict virulence of Vibrio vulnificus biotype 1 in subcutaneously inoculated, iron dextran-treated mice. Infect. Immun. 79(3), 1194–1207 (2011).
    • 27. Garrett SB, Garrison-Schilling KL, Cooke JT et al. Capsular polysaccharide production and serum survival of Vibrio vulnificus are dependent on antitermination control by RfaH. FEBS Lett. 590(24), 4564–4572 (2016).
    • 28. Kim HY, Ayrapetyan M, Oliver JD. Survival of Vibrio vulnificus genotypes in male and female serum, and production of siderophores in human serum and seawater. Foodborne Pathog. Dis. 11(2), 119–125 (2014).
    • 29. Yun NR, Kim DM. Vibrio vulnificus infection: a persistent threat to public health. Korean J. Intern. Med. 33(6), 1070–1078 (2018).
    • 30. Hor LI, Chang YK, Chang CC et al. Mechanism of high susceptibility of iron-overloaded mouse to Vibrio vulnificus infection. Microbiol. Immunol. 44(11), 871–878 (2000).
    • 31. Simpson LM, Oliver JD. Siderophore production by Vibrio vulnificus. Infect. Immun. 41(2), 644–649 (1983).
    • 32. Barnes AD, Pfeifer HJ, Zbylicki BR et al. Two novel proteins, TtpB2 and TtpD2, are essential for iron transport in the TonB2 system of Vibrio vulnificus. MicrobiologyOpen 9(1), e00947 (2020).
    • 33. Kustusch RJ, Kuehl CJ, Crosa JH. The ttpC gene is contained in two of three TonB systems in the human pathogen Vibrio vulnificus, but only one is active in iron transport and virulence. J. Bacteriol. 194(12), 3250–3259 (2012).
    • 34. Duong-Nu TM, Jeong K, Hong SH et al. All three TonB systems are required for Vibrio vulnificus CMCP6 tissue invasiveness by controlling flagellum expression. Infect. Immun. 84(1), 254–265 (2016).
    • 35. Datta S, Kenton RJ. Characterization of temperature-dependent hemin uptake receptors HupA and HvtA in Vibrio vulnificus. MicrobiologyOpen 8(10), e905 (2019).
    • 36. Kim CM, Park RY, Choi MH et al. Ferrophilic characteristics of Vibrio vulnificus and potential usefulness of iron chelation therapy. J. Infect. Dis. 195(1), 90–98 (2007).
    • 37. Kim YR, Lee SE, Kook H et al. Vibrio vulnificus RTX toxin kills host cells only after contact of the bacteria with host cells. Cell Microbiol. 10(4), 848–862 (2008).
    • 38. Lee JH, Rho JB, Park KJ et al. Role of flagellum and motility in pathogenesis of Vibrio vulnificus. Infect. Immun. 72(8), 4905–4910 (2004).
    • 39. Goo SY, Han YS, Kim WH et al. Vibrio vulnificus IlpA-induced cytokine production is mediated by Toll-like receptor 2. J. Biol. Chem. 282(38), 27647–27658 (2007).
    • 40. Goo SY, Lee HJ, Kim WH et al. Identification of OmpU of Vibrio vulnificus as a fibronectin-binding protein and its role in bacterial pathogenesis. Infect. Immun. 74(10), 5586–5594 (2006).
    • 41. Lee SJ, Jung YH, Oh SY et al. Vibrio vulnificus VvhA induces NF-κB-dependent mitochondrial cell death via lipid raft-mediated ROS production in intestinal epithelial cells. Cell Death Dis. 6, 1655 (2015).
    • 42. Song EJ, Lee SJ, Lim HS et al. Vibrio vulnificus VvhA induces autophagy-related cell death through the lipid raft-dependent c-Src/NOX signaling pathway. Sci. Rep. 6, 27080 (2016).
    • 43. Yuan Y, Feng Z, Wang J. Vibrio vulnificus hemolysin: biological activity, regulation of vvhA expression, and role in pathogenesis. Front. Immunol. 11, 599439 (2020). • This article summarizes the latest progress in understanding the regulation of VVHA gene expression, the biological activity of V. vulnificus hemolysin and its role in pathogenesis.
    • 44. Chung KJ, Cho EJ, Kim MK et al. RtxA1-induced expression of the small GTPase Rac2 plays a key role in the pathogenicity of Vibrio vulnificus. J. Infect. Dis. 201(1), 97–105 (2010).
    • 45. Lee BC, Choi SH, Kim TS. Vibrio vulnificus RTX toxin plays an important role in the apoptotic death of human intestinal epithelial cells exposed to Vibrio vulnificus. Microbes Infect. 10(14-15), 1504–1513 (2008).
    • 46. Kim YR, Lee SE, Kang IC et al. A bacterial RTX toxin causes programmed necrotic cell death through calcium-mediated mitochondrial dysfunction. J. Infect. Dis. 207(9), 1406–1415 (2013).
    • 47. Guo RH, Lim JY, Tra My DN et al. Vibrio vulnificus RtxA1 toxin expression upon contact with host cells is RpoS-dependent. Front. Cell. Infect. Microbiol. 8, 70 (2018).
    • 48. Gong Y, Guo RH, Rhee JH et al. TolCV1 has multifaceted roles during Vibrio vulnificus infection. Front. Cell. Infect. Microbiol. 11, 673222 (2021). • TolCV1 plays a key role in the RtxA1 secretion, drug resistance and lethality of V. vulnificus and may be an attractive target for designing new drugs to treat V. vulnificus infection.
    • 49. Guo RH, Gong Y, Kim SY et al. DIDS inhibits Vibrio vulnificus cytotoxicity by interfering with TolC-mediated RtxA1 toxin secretion. Eur. J. Pharmacol. 884, 173407 (2020). • Disodium 4,4′-diisothiocyanate stilbene-2,2′-disulfonate hydrate is a promising treatment model that inhibits the cytotoxicity of V. vulnificus by interfering with TolC-mediated RtxA1 toxin secretion.
    • 50. Fan JJ, Shao CP, Ho YC et al. Isolation and characterization of a Vibrio vulnificus mutant deficient in both extracellular metalloprotease and cytolysin. Infect. Immun. 69(9), 5943–5948 (2001).
    • 51. Kwak JS, Jeong HG, Satchell KJ. Vibrio vulnificus rtxA1 gene recombination generates toxin variants with altered potency during intestinal infection. Proc. Natl Acad. Sci. USA 108(4), 1645–1650 (2011).
    • 52. Jeong HG, Satchell KJ. Additive function of Vibrio vulnificus MARTX(Vv) and VvhA cytolysins promotes rapid growth and epithelial tissue necrosis during intestinal infection. PLoS Pathog. 8(3), e1002581 (2012).
    • 53. Cho C, Choi S, Kim MH et al. Vibrio vulnificus PlpA facilitates necrotic host cell death induced by the pore forming MARTX toxin. J. Microbiol. 60(2), 224–233 (2022).
    • 54. Elgaml A, Higaki K, Miyoshi S. Effects of temperature, growth phase and luxO-disruption on regulation systems of toxin production in Vibrio vulnificus strain L-180, a human clinical isolate. World J. Microbiol. Biotechnol. 30(2), 681–691 (2014).
    • 55. Kim SY, Lee SE, Kim YR et al. Regulation of Vibrio vulnificus virulence by the LuxS quorum-sensing system. Mol. Microbiol. 48(6), 1647–1664 (2003).
    • 56. Lee JH, Rhee JE, Park U et al. Identification and functional analysis of Vibrio vulnificus SmcR, a novel global regulator. J. Microbiol. Biotechnol. 17(2), 325–334 (2007).
    • 57. Jeong HS, Lee MH, Lee KH et al. SmcR and cyclic AMP receptor protein coactivate Vibrio vulnificus vvpE encoding elastase through the RpoS-dependent promoter in a synergistic manner. J. Biol. Chem. 278(46), 45072–45081 (2003).
    • 58. Shao CP, Lo HR, Lin JH et al. Regulation of cytotoxicity by quorum-sensing signaling in Vibrio vulnificus is mediated by SmcR, a repressor of hlyU. J. Bacteriol. 193(10), 2557–2565 (2011).
    • 59. Wen Y, Kim IH, Son JS et al. Iron and quorum sensing coordinately regulate the expression of vulnibactin biosynthesis in Vibrio vulnificus. J. Biol. Chem. 287(32), 26727–26739 (2012).
    • 60. Kim IH, Kim SY, Park NY et al. Cyclo-(l-Phe-l-Pro), a quorum-sensing signal of Vibrio vulnificus, induces expression of hydroperoxidase through a ToxR-LeuO-HU-RpoS signaling pathway to confer resistance against oxidative stress. Infect. Immun. 86(9), e00932-17 (2018).
    • 61. Pei J, Wang H, Wu L et al. Biochemical characterization of a catalase from Vibrio vulnificus, a pathogen that causes gastroenteritis. Acta Biochim. Pol. 64(3), 543–549 (2017).
    • 62. Kim SP, Kim CM, Shin SH. Cyclic AMP and cyclic AMP-receptor protein modulate the autoinducer-2-mediated quorum sensing system in Vibrio vulnificus. Curr. Microbiol. 65(6), 701–710 (2012).
    • 63. Green J, Stapleton MR, Smith LJ et al. Cyclic-AMP and bacterial cyclic-AMP receptor proteins revisited: adaptation for different ecological niches. Curr. Opin. Microbiol. 18, 1–7 (2014).
    • 64. Fang FC, Frawley ER, Tapscott T et al. Bacterial stress responses during host infection. Cell Host Microbe 20(2), 133–143 (2016).
    • 65. Jang KK, Lee ZW, Kim B et al. Identification and characterization of Vibrio vulnificus plpA encoding a phospholipase A2 essential for pathogenesis. J. Biol. Chem. 292(41), 17129–17143 (2017).
    • 66. Jeong HS, Kim SM, Lim MS et al. Direct interaction between quorum-sensing regulator SmcR and RNA polymerase is mediated by integration host factor to activate vvpE encoding elastase in Vibrio vulnificus. J. Biol. Chem. 285(13), 9357–9366 (2010).
    • 67. Jeong HG, Choi SH. Evidence that AphB, essential for the virulence of Vibrio vulnificus, is a global regulator. J. Bacteriol. 190(10), 3768–3773 (2008). • It was demonstrated that AphB is a global regulatory factor that contributes to the pathogenesis of V. vulnificus.
    • 68. Kim WB, Lee BC, Choi SH. Vibrio vulnificus AphB is involved in interleukin-8 production via an NF-κB-dependent pathway in human intestinal epithelial cells. Biochem. Biophys. Res. Commun. 417(4), 1265–1270 (2012).
    • 69. Liu M, Crosa JH. The regulator HlyU, the repeat-in-toxin gene rtxA1, and their roles in the pathogenesis of Vibrio vulnificus infections. MicrobiologyOpen 1(4), 502–513 (2012).
    • 70. Liu M, Naka H, Crosa JH. HlyU acts as an H-NS antirepressor in the regulation of the RTX toxin gene essential for the virulence of the human pathogen Vibrio vulnificus CMCP6. Mol. Microbiol. 72(2), 491–505 (2009).
    • 71. Gauthier JD, Jones MK, Thiaville P et al. Role of GacA in virulence of Vibrio vulnificus. Microbiology (Reading) 156(Pt 12), 3722–3733 (2010).
    • 72. Brown RN, Gulig PA. Regulation of fatty acid metabolism by FadR is essential for Vibrio vulnificus to cause infection of mice. J. Bacteriol. 190(23), 7633–7644 (2008).
    • 73. Ho YC, Hung FR, Weng CH et al. Lrp, a global regulator, regulates the virulence of Vibrio vulnificus. J. Biomed. Sci. 24(1), 54 (2017).
    • 74. Sun KN, Huang F, Wang MY et al. IL-21 enhances the immune protection induced by the Vibrio vulnificus hemolysin A protein. Inflammation 45(4), 1496–1506 (2022).
    • 75. Wang MY, Liu XF, Xia J et al. Vibrio vulnificus VvhA induces Th1 and Tfh cells to proliferate against Vibrio vulnificus in a mouse model of infection. Future Microbiol. 12, 953–965 (2017).
    • 76. Shin SH, Shin DH, Ryu PY et al. Proinflammatory cytokine profile in Vibrio vulnificus septicemic patients’ sera. FEMS Immunol. Med. Microbiol. 33(2), 133–138 (2002).
    • 77. Lee NY, Lee HY, Lee KH et al. Vibrio vulnificus IlpA induces MAPK-mediated cytokine production via TLR1/2 activation in THP-1 cells, a human monocytic cell line. Mol. Immunol. 49(1–2), 143–154 (2011).
    • 78. Lee BC, Kim MS, Choi SH et al. Involvement of capsular polysaccharide via a TLR2/NF-κB pathway in Vibrio vulnificus-induced IL-8 secretion of human intestinal epithelial cells. Int. J. Mol. Med. 25(4), 581–591 (2010).
    • 79. Lee BC, Kim MS, Cho D et al. Co-culture supernatants from Vibrio vulnificus-infected INT-407 cells induce IL-8 production in intestinal epithelial cells: crucial role of V. vulnificus rtxE. Int. J. Mol. Med. 26(5), 651–659 (2010).
    • 80. Toma C, Higa N, Koizumi Y et al. Pathogenic Vibrio activate NLRP3 inflammasome via cytotoxins and TLR/nucleotide-binding oligomerization domain-mediated NF-κB signaling. J. Immunol. 184(9), 5287–5297 (2010).
    • 81. Qin K, Fu K, Liu J et al. Vibrio vulnificus cytolysin induces inflammatory responses in RAW264.7 macrophages through calcium signaling and causes inflammation in vivo. Microb. Pathog. 137, 103789 (2019).