Chancroid pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Nate Michalak, B.A.; Serge Korjian M.D.
Overview
Pathophysiology
Transmission
- Chancroid may develop after transmission of class I or class II of the bacterium Haemophilus ducreyi through sexual contact.[1]
- A class I gentically distinct subclade strain of H. ducreyi may serve as the etiologic agent of non-sexually transmitted skin ulcers.[2][3]
Pathogenesis
- H. ducreyi enters the skin through breaks in the epithelium.
- H. ducreyi produces 3 fimbrialike proteins (Flp), Flp1, Flp2, and Flp3 that help the bacteria adhere to subcutaneous epithelial cells and fibroblasts.[4][5]
- H. ducreyi recruits inflammatory cells to the infected area and induces secretion of interleukin 6 (IL-6) and interleukin 8 (IL-8) from epithelial cells. IL-8 induces neutrophils and macrophages to form abscesses, which may cause the presentation of erythematous papules which progress into intradermal pustules.[5][6][7]
- Ulcers develop after secretion of the virulence factor H. ducreyi cytolethal distending toxin (HdCDT), which causes necrosis of myeloid and epithelial cells.[7]
- It is presumed that iron plays an essential role in chancroid pathogenesis.[5]
- H. ducreyi has the ability to avoid phagocytosis.[7]
Virulence Factors
- H. Ducreyi produces and secretes 2 major virulence factors: fimbrialike protein (Flp) and H. ducreyi cytolethal distending toxin (HdCDT).
- Flp:
- A 12.8 kb Flp operon regulates the expression of 3 fimbrialike proteins, Flp1, Flp2, and Flp3 in a type IV secretion system. These proteins have been demonstrated to play an important role in adherence to fibroblasts and pathogenesis of chancroid.[4]
- HdCDT:[8]
- HdCDT is a tripartite protein complex consisting of CdtA, CdtB, and CdtC subunits, all of which are required to produce the active form of the toxin.
- HdCDT activates DNase, inducing DNA double-stranded breaks that result in cellular responses similar to that of ionizing radiation.
- The effect of HdCDT is cell type-specific.
- In epithelial cells and fibroblasts, DNA damage activates ATM kinases, which activate RhoA GTPase leading to induction of actin stress fibers and cell distention.
- RhoA activation is not detected in lymphocytes.
- Flp:
- Other virulence factors that have been isolated include the following:[9]
- Lipooligosaccharide
- Hemolysin
- Copper-zinc superoxide dismutase
- Outer membrane proteins (OMP) DsrA, PAL, and hemoglobin-binding OMP
Adhesion
- The tadA gene is though to be an important regulator for expression of the flp gene cluster.
- Flp1, Flp2, and Flp3 are suspected to play a role in forming pili on the cellular surface of H. ducreyi.
- In vitro, animal, and human models demonstrate that Flps are necessary for H. ducreyi to form microcolonies, which enables pathogenesis.[4]
Gross Pathology
On gross pathology, the following characteristic features may be present in chancroid:
References
- ↑ Chancroid. MedlinePlus (Decemner 2, 2015). https://www.nlm.nih.gov/medlineplus/ency/article/000635.htm Accessed January 6, 2015.
- ↑ Marks M, Chi KH, Vahi V, Pillay A, Sokana O, Pavluck A; et al. (2014). "Haemophilus ducreyi associated with skin ulcers among children, Solomon Islands". Emerg Infect Dis. 20 (10): 1705–7. doi:10.3201/eid2010.140573. PMC 4193279. PMID 25271477.
- ↑ Gaston JR, Roberts SA, Humphreys TL (2015). "Molecular phylogenetic analysis of non-sexually transmitted strains of Haemophilus ducreyi". PLoS One. 10 (3): e0118613. doi:10.1371/journal.pone.0118613. PMC 4361675. PMID 25774793.
- ↑ 4.0 4.1 4.2 Spinola, S. M.; Fortney, K. R.; Katz, B. P.; Latimer, J. L.; Mock, J. R.; Vakevainen, M.; Hansen, E. J. (2003). "Haemophilus ducreyi Requires an Intact flp Gene Cluster for Virulence in Humans". Infection and Immunity. 71 (12): 7178–7182. doi:10.1128/IAI.71.12.7178-7182.2003. ISSN 0019-9567.
- ↑ 5.0 5.1 5.2 Abeck D, Johnson AP (1992). "Pathophysiological concept of Haemophilus ducreyi infection (chancroid)". Int J STD AIDS. 3 (5): 319–23. PMID 1391058.
- ↑ Chancroid. Wikipedia (July 16, 2015). https://en.wikipedia.org/wiki/Chancroid Accessed on January 6, 2016.
- ↑ 7.0 7.1 7.2 Chancroid in Emergency Medicine. Medscape (February 12, 2014). http://emedicine.medscape.com/article/781520-overview#a5 Accessed January 8, 2016.
- ↑ Frisan, Teresa; Cortes-Bratti, Ximena; Chaves-Olarte, Esteban; Stenerlow, Bo; Thelestam, Monica (2003). "The Haemophilus ducreyi cytolethal distending toxin induces DNA double-strand breaks and promotes ATM-dependent activation of RhoA". Cellular Microbiology. 5 (10): 695–707. doi:10.1046/j.1462-5822.2003.00311.x. ISSN 1462-5814.
- ↑ Nika, J. R. (2002). "Haemophilus ducreyi Requires the flp Gene Cluster for Microcolony Formation In Vitro". Infection and Immunity. 70 (6): 2965–2975. doi:10.1128/IAI.70.6.2965-2975.2002. ISSN 0019-9567.