Chancroid pathophysiology: Difference between revisions
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==Overview== | ==Overview== | ||
Chancroid may develop after transmission of ''Haemophilus ducreyi'' through breaks in human [[epithelium]], most commonly through sexual contact. Fimbrialike proteins, Flp1, Flp2, Flp3, are suspected to form [[pili]] that assist in [[adhesion]] and microcolony formation. ''H. ducreyi'' induces secretion of [[interleukin-6]] (IL-6) and [[interleukin-8]] (IL-8), which causes inflammatory cells to form [[abscesses]], leading to the formation of [[papules]] that may progress into [[Boil|pustules]]. ''H. ducreyi'' cytolethal distending toxin (HdCDT) is a major [[virulence factor]] that contributes to [[necrosis]] of [[myeloid]] and [[Epithelium|epithelial]] cells, causing ulceration. Associated conditions include: [[coinfection]] with [[Human Immunodeficiency Virus (HIV)]], since HIV and ''H. ducreyi'' facilitate each others infection, and [[coinfection]] with ''[[Treponema pallidum]]'', since [[syphilis]] is shown to commonly occur with chancroid. On microscopic examination, a three-zone structure is typical. | |||
==Pathophysiology== | ==Pathophysiology== | ||
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===Transmission=== | ===Transmission=== | ||
*Chancroid may develop after transmission of class I or class II of the bacterium ''Haemophilus ducreyi'' through sexual contact.<ref name="ChancroidMedlinePlus">Chancroid. MedlinePlus (Decemner 2, 2015). https://www.nlm.nih.gov/medlineplus/ency/article/000635.htm Accessed January 6, 2015.</ref> | *Chancroid may develop after transmission of class I or class II of the bacterium ''Haemophilus ducreyi'' through sexual contact.<ref name="ChancroidMedlinePlus">Chancroid. MedlinePlus (Decemner 2, 2015). https://www.nlm.nih.gov/medlineplus/ency/article/000635.htm Accessed January 6, 2015.</ref> | ||
*A class I | *A class I genetically distinct subclade strain of ''H. ducreyi'' may serve as the etiologic agent of non-sexually transmitted skin [[ulcers]].<ref name="pmid25271477">{{cite journal| author=Marks M, Chi KH, Vahi V, Pillay A, Sokana O, Pavluck A et al.| title=Haemophilus ducreyi associated with skin ulcers among children, Solomon Islands. | journal=Emerg Infect Dis | year= 2014 | volume= 20 | issue= 10 | pages= 1705-7 | pmid=25271477 | doi=10.3201/eid2010.140573 | pmc=PMC4193279 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25271477}}</ref><ref name="pmid25774793">{{cite journal| author=Gaston JR, Roberts SA, Humphreys TL| title=Molecular phylogenetic analysis of non-sexually transmitted strains of Haemophilus ducreyi. | journal=PLoS One | year= 2015 | volume= 10 | issue= 3 | pages= e0118613 | pmid=25774793 | doi=10.1371/journal.pone.0118613 | pmc=PMC4361675 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25774793 }} </ref> | ||
*''H. ducreyi'' is an [[obligate]] human [[pathogen]]. | |||
===Pathogenesis=== | ===Pathogenesis=== | ||
*''H. ducreyi'' enters the skin through breaks in the epithelium. | *''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.<ref name="SpinolaFortney2003">{{cite journal|last1=Spinola|first1=S. M.|last2=Fortney|first2=K. R.|last3=Katz|first3=B. P.|last4=Latimer|first4=J. L.|last5=Mock|first5=J. R.|last6=Vakevainen|first6=M.|last7=Hansen|first7=E. J.|title=Haemophilus ducreyi Requires an Intact flp Gene Cluster for Virulence in Humans|journal=Infection and Immunity|volume=71|issue=12|year=2003|pages=7178–7182|issn=0019-9567|doi=10.1128/IAI.71.12.7178-7182.2003}}</ref><ref name="pmid1391058">{{cite journal| author=Abeck D, Johnson AP| title=Pathophysiological concept of Haemophilus ducreyi infection (chancroid) | journal=Int J STD AIDS | year= 1992 | volume= 3 | issue= 5 | pages= 319-23 | pmid=1391058 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1391058}}</ref> | *''H. ducreyi'' produces 3 fimbrialike proteins (Flp), Flp1, Flp2, and Flp3 that help the bacteria adhere to subcutaneous [[Epithelium|epithelial]] cells and [[fibroblasts]].<ref name="SpinolaFortney2003">{{cite journal|last1=Spinola|first1=S. M.|last2=Fortney|first2=K. R.|last3=Katz|first3=B. P.|last4=Latimer|first4=J. L.|last5=Mock|first5=J. R.|last6=Vakevainen|first6=M.|last7=Hansen|first7=E. J.|title=Haemophilus ducreyi Requires an Intact flp Gene Cluster for Virulence in Humans|journal=Infection and Immunity|volume=71|issue=12|year=2003|pages=7178–7182|issn=0019-9567|doi=10.1128/IAI.71.12.7178-7182.2003}}</ref><ref name="pmid1391058">{{cite journal| author=Abeck D, Johnson AP| title=Pathophysiological concept of Haemophilus ducreyi infection (chancroid) | journal=Int J STD AIDS | year= 1992 | volume= 3 | issue= 5 | pages= 319-23 | pmid=1391058 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1391058}}</ref> | ||
*''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.<ref name="pmid1391058" | *''H. ducreyi'' recruits inflammatory cells to the infected area and induces secretion of [[Interleukin 6|interleukin-6]] (IL-6) and [[Interleukin 8|interleukin-8]] (IL-8) from epithelial cells. IL-8 induces [[Neutrophil|neutrophils]] and [[Macrophage|macrophages]] to form [[abscesses]], which may cause the presentation of erythematous [[papules]] which progress into intradermal [[pustules]].<ref name="pmid1391058" /><ref name="ChancroidWikipedia">Chancroid. Wikipedia (July 16, 2015). https://en.wikipedia.org/wiki/Chancroid Accessed on January 6, 2016.</ref><ref name="WisingAzem2005">{{cite journal|last1=Wising|first1=Catharina|last2=Azem|first2=Jozef|last3=Zetterberg|first3=Madeleine|last4=Svensson|first4=Liselott A.|last5=Ahlman|first5=Karin|last6=Lagergård|first6=Teresa|title=Induction of apoptosis/necrosis in various human cell lineages by Haemophilus ducreyi cytolethal distending toxin|journal=Toxicon|volume=45|issue=6|year=2005|pages=767–776|issn=00410101|doi=10.1016/j.toxicon.2005.01.016}}</ref> | ||
*Ulcers develop after secretion of the virulence factor ''H. ducreyi'' cytolethal distending toxin (HdCDT), which causes necrosis of myeloid and epithelial cells.<ref name=" | *[[Ulcers]] develop after secretion of the virulence factor ''H. ducreyi'' cytolethal distending toxin (HdCDT), which causes [[necrosis]] of [[myeloid]] and epithelial cells.<ref name="WisingAzem2005" /> | ||
*It is presumed that iron plays an essential role in chancroid pathogenesis.<ref name="pmid1391058" | *It is presumed that iron plays an essential role in chancroid pathogenesis.<ref name="pmid1391058" /> | ||
*''H. ducreyi'' has the ability to avoid phagocytosis.<ref name=" | *''H. ducreyi'' has the ability to avoid [[phagocytosis]].<ref name="WisingAzem2005" /> | ||
====Virulence Factors==== | ====Virulence Factors==== | ||
*''H. Ducreyi'' produces and secretes 2 major virulence factors: fimbrialike protein (Flp) and ''H. ducreyi'' cytolethal distending toxin (HdCDT). | *''H. Ducreyi'' produces and secretes 2 major virulence factors: fimbrialike protein (Flp) and ''H. ducreyi'' cytolethal distending toxin (HdCDT). | ||
::'''Flp''': | ::'''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.<ref name="SpinolaFortney2003" | ::*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 [[Fibroblast|fibroblasts]] and pathogenesis of chancroid.<ref name="SpinolaFortney2003" /> | ||
::'''HdCDT''':<ref name="FrisanCortes-Bratti2003">{{cite journal|last1=Frisan|first1=Teresa|last2=Cortes-Bratti|first2=Ximena|last3=Chaves-Olarte|first3=Esteban|last4=Stenerlow|first4=Bo|last5=Thelestam|first5=Monica|title=The Haemophilus ducreyi cytolethal distending toxin induces DNA double-strand breaks and promotes ATM-dependent activation of RhoA|journal=Cellular Microbiology|volume=5|issue=10|year=2003|pages=695–707|issn=1462-5814|doi=10.1046/j.1462-5822.2003.00311.x}}</ref> | ::'''HdCDT''':<ref name="FrisanCortes-Bratti2003">{{cite journal|last1=Frisan|first1=Teresa|last2=Cortes-Bratti|first2=Ximena|last3=Chaves-Olarte|first3=Esteban|last4=Stenerlow|first4=Bo|last5=Thelestam|first5=Monica|title=The Haemophilus ducreyi cytolethal distending toxin induces DNA double-strand breaks and promotes ATM-dependent activation of RhoA|journal=Cellular Microbiology|volume=5|issue=10|year=2003|pages=695–707|issn=1462-5814|doi=10.1046/j.1462-5822.2003.00311.x}}</ref><ref name="LiSharipo2002">{{cite journal|last1=Li|first1=LiQi|last2=Sharipo|first2=Anatoly|last3=Chaves-Olarte|first3=Esteban|last4=Masucci|first4=Maria G.|last5=Levitsky|first5=Victor|last6=Thelestam|first6=Monica|last7=Frisan|first7=Teresa|title=The Haemophilus ducreyi cytolethal distending toxin activates sensors of DNA damage and repair complexes in proliferating and non-proliferating cells|journal=Cellular Microbiology|volume=4|issue=2|year=2002|pages=87–99|issn=1462-5814|doi=10.1046/j.1462-5822.2002.00174.x}}</ref> | ||
::*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 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 | ::*HdCDT induces DNA double-stranded breaks that result in cellular responses similar to that of ionizing radiation. | ||
::*The effect of HdCDT is cell type-specific. | ::*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. | ::*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. | ::*RhoA activation is not detected in [[lymphocytes]]. | ||
*Other virulence factors that have been isolated include the following:<ref name="Nika2002">{{cite journal|last1=Nika|first1=J. R.|title=Haemophilus ducreyi Requires the flp Gene Cluster for Microcolony Formation In Vitro|journal=Infection and Immunity|volume=70|issue=6|year=2002|pages=2965–2975|issn=00199567|doi=10.1128/IAI.70.6.2965-2975.2002}}</ref> | |||
:*Lipooligosaccharide | |||
:*Hemolysin | |||
:*Copper-zinc superoxide dismutase | |||
:*Outer membrane proteins (OMP) DsrA, PAL, and hemoglobin-binding OMP | |||
====Adhesion==== | ====Adhesion==== | ||
*The ''tadA'' gene is though to be an important regulator for expression of the ''flp'' gene cluster. | *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''. | *Flp1, Flp2, and Flp3 are suspected to play a role in forming [[Pilus|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.<ref name="SpinolaFortney2003"></ref> | *''In vitro'', animal, and human models demonstrate that Flps are necessary for ''H. ducreyi'' to form microcolonies, which enables pathogenesis.<ref name="SpinolaFortney2003" /> | ||
==Associated Conditions== | |||
*''H. ducreyi'' and [[Human Immunodeficiency Virus (HIV)]] facilitate each other's transmission.<ref name="Spinola2002">{{cite journal|last1=Spinola|first1=S. M.|title=Immunopathogenesis of Haemophilus ducreyi Infection (Chancroid)|journal=Infection and Immunity|volume=70|issue=4|year=2002|pages=1667–1676|issn=00199567|doi=10.1128/IAI.70.4.1667-1676.2002}}</ref> | |||
:*HIV transmission may be enhanced by the following mechanisms: | |||
::*''H. ducreyi'''s ability to cause cell cycle arrest and [[apoptosis]] in [[Lymphocyte|lymphocytes]]. | |||
::*The chancroidal ulcer's promotion of viral shedding into [[blood]] and [[semen]].<ref name="pmid9419194">{{cite journal| author=Dyer JR, Eron JJ, Hoffman IF, Kazembe P, Vernazza PL, Nkata E et al.| title=Association of CD4 cell depletion and elevated blood and seminal plasma human immunodeficiency virus type 1 (HIV-1) RNA concentrations with genital ulcer disease in HIV-1-infected men in Malawi. | journal=J Infect Dis | year= 1998 | volume= 177 | issue= 1 | pages= 224-7 | pmid=9419194 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9419194 }} </ref> | |||
::*Establishment of an entry point for [[Human Immunodeficiency Virus (HIV)|HIV]] via an ulcer. | |||
:*Presence of HIV may result in atypical manifestations of chancroid including: increased number of lesions, extragenital lesions, extended therapy.<ref name="pmid2650859">{{cite journal| author=Morse SA| title=Chancroid and Haemophilus ducreyi. | journal=Clin Microbiol Rev | year= 1989 | volume= 2 | issue= 2 | pages= 137-57 | pmid=2650859 | doi= | pmc=PMC358107 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2650859 }} </ref><ref name="pmid2368772">{{cite journal| author=Quale J, Teplitz E, Augenbraun M| title=Atypical presentation of chancroid in a patient infected with the human immunodeficiency virus. | journal=Am J Med | year= 1990 | volume= 88 | issue= 5N | pages= 43N-44N | pmid=2368772 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2368772 }} </ref> | |||
*[[Coinfection]] with ''[[Treponema pallidum]]'': | |||
:*[[Syphilis]] has been shown to commonly occur with chancroid<ref name="pmid26042815">{{cite journal| author=Workowski KA, Bolan GA, Centers for Disease Control and Prevention| title=Sexually transmitted diseases treatment guidelines, 2015. | journal=MMWR Recomm Rep | year= 2015 | volume= 64 | issue= RR-03 | pages= 1-137 | pmid=26042815 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26042815 }} </ref> | |||
==Microscopic Pathology== | |||
On microscopic pathology, the following characteristic features may be present in chancroid:<ref name="pmid1391058" /> | |||
*Three-zone structure: | |||
:*Narrow superficial zone - contains necrotic tissue, [[erythrocytes]], [[fibrin]], and degenerated [[leucocytes]] | |||
:*Middle zone - contains edematous inflamed tissue | |||
:*Deep zone - contains plasma cells and [[lymphocytes]] | |||
*Granulomatous base | |||
*Purulent exudates | |||
==References== | ==References== | ||
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[[Category:Bacterial diseases]] | [[Category:Bacterial diseases]] | ||
[[Category:Proteobacteria]] | [[Category:Proteobacteria]] | ||
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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
Chancroid may develop after transmission of Haemophilus ducreyi through breaks in human epithelium, most commonly through sexual contact. Fimbrialike proteins, Flp1, Flp2, Flp3, are suspected to form pili that assist in adhesion and microcolony formation. H. ducreyi induces secretion of interleukin-6 (IL-6) and interleukin-8 (IL-8), which causes inflammatory cells to form abscesses, leading to the formation of papules that may progress into pustules. H. ducreyi cytolethal distending toxin (HdCDT) is a major virulence factor that contributes to necrosis of myeloid and epithelial cells, causing ulceration. Associated conditions include: coinfection with Human Immunodeficiency Virus (HIV), since HIV and H. ducreyi facilitate each others infection, and coinfection with Treponema pallidum, since syphilis is shown to commonly occur with chancroid. On microscopic examination, a three-zone structure is typical.
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 genetically distinct subclade strain of H. ducreyi may serve as the etiologic agent of non-sexually transmitted skin ulcers.[2][3]
- H. ducreyi is an obligate human pathogen.
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][9]
- 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 induces 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:[10]
- 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]
Associated Conditions
- H. ducreyi and Human Immunodeficiency Virus (HIV) facilitate each other's transmission.[11]
- HIV transmission may be enhanced by the following mechanisms:
Microscopic Pathology
On microscopic pathology, the following characteristic features may be present in chancroid:[5]
- Three-zone structure:
- Narrow superficial zone - contains necrotic tissue, erythrocytes, fibrin, and degenerated leucocytes
- Middle zone - contains edematous inflamed tissue
- Deep zone - contains plasma cells and lymphocytes
- Granulomatous base
- Purulent exudates
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 5.3 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 Wising, Catharina; Azem, Jozef; Zetterberg, Madeleine; Svensson, Liselott A.; Ahlman, Karin; Lagergård, Teresa (2005). "Induction of apoptosis/necrosis in various human cell lineages by Haemophilus ducreyi cytolethal distending toxin". Toxicon. 45 (6): 767–776. doi:10.1016/j.toxicon.2005.01.016. ISSN 0041-0101.
- ↑ 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.
- ↑ Li, LiQi; Sharipo, Anatoly; Chaves-Olarte, Esteban; Masucci, Maria G.; Levitsky, Victor; Thelestam, Monica; Frisan, Teresa (2002). "The Haemophilus ducreyi cytolethal distending toxin activates sensors of DNA damage and repair complexes in proliferating and non-proliferating cells". Cellular Microbiology. 4 (2): 87–99. doi:10.1046/j.1462-5822.2002.00174.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.
- ↑ Spinola, S. M. (2002). "Immunopathogenesis of Haemophilus ducreyi Infection (Chancroid)". Infection and Immunity. 70 (4): 1667–1676. doi:10.1128/IAI.70.4.1667-1676.2002. ISSN 0019-9567.
- ↑ Dyer JR, Eron JJ, Hoffman IF, Kazembe P, Vernazza PL, Nkata E; et al. (1998). "Association of CD4 cell depletion and elevated blood and seminal plasma human immunodeficiency virus type 1 (HIV-1) RNA concentrations with genital ulcer disease in HIV-1-infected men in Malawi". J Infect Dis. 177 (1): 224–7. PMID 9419194.
- ↑ Morse SA (1989). "Chancroid and Haemophilus ducreyi". Clin Microbiol Rev. 2 (2): 137–57. PMC 358107. PMID 2650859.
- ↑ Quale J, Teplitz E, Augenbraun M (1990). "Atypical presentation of chancroid in a patient infected with the human immunodeficiency virus". Am J Med. 88 (5N): 43N–44N. PMID 2368772.
- ↑ Workowski KA, Bolan GA, Centers for Disease Control and Prevention (2015). "Sexually transmitted diseases treatment guidelines, 2015". MMWR Recomm Rep. 64 (RR-03): 1–137. PMID 26042815.