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FIGURE 1.4 Regional estimates of HSV-2 prevalence in 2003. Adapted from Looker KJ, Garnett GP, Schmid GP. An estimate of the global prevalence and incidence of herpes simplex virus type 2 infection. Bulletin of the World Health Organization, October 2008, 86(10): 808–9.
(G)
(E)
(A)
(B)
(H)
(F)
(I)
(C)
(D)
FIGURE 3.1 Schematic of the mucosal immune system throughout the human female reproductive tract (FRT). As seen in the drawing on the left side, the vagina and ectocervix are lined with squamous epithelial cells. Columnar cells are present throughout the upper FRT, including the endocervix, uterine endometrium, and Fallopian tubes. Panels A–D are confocal photomicrographs showing the distribution of immune cells throughout the uterus. Frozen sections were directly stained with three fluorescently tagged monoclonal antibodies: an epithelial cell-specific antibody (Cy3-labeled clone BerEP4, red color panels A–D), anti-CCR5 (FITC-labeled clone 2D7, green color panels A–D), and anti-CXCR4 (Cy5-labeled 12G5, blue color panels A–D). Panel A: epithelial gland extending from the myometrial interface (far left) to the luminal epithelium (right-hand side). Panels B–D show higher magnification fields from the same region. The luminal epithelium, in contrast to the adjacent glands, retains a relatively intense BerEP4 expression (red color panels A and D). CCR5 expression is prominent on the lymphoid aggregates located in the stratum basalis immediately adjacent to the myometrium (D in panel B). Epithelial expression of CCR5 is low in the stratum basalis and increases in the proximal third of the stratum functionalis. Panel E: vaginal squamous cells expressing GalCer (green), which is expressed on parabasal epithelial cells (p) and in the surface regions of the cornified layer. b: basal epithelial cells; P: parabasal epithelial cells; c: cornified layer of epithelial cells; dp: submucosal stromal papillae; pre: precornified layer. Panel F: this photo plate consists of a lymphoid aggregate in the uterine endometrium at the late proliferative stage of the menstrual cycle. The three fluorochromes are T cells (Cy3anti-CD3, red), B cells (FITC-anti-CD19, green), and macrophages (Cy5-anti-CD14, blue). Panel G: CD8+ T cells present in both the submucosa and the squamous epithelium. Panel H: CD14 expression is found on both stroma and squamous epithelium macrophages. Panel I: CD1a-positive dendritic cells (DC) are present in the squamous epithelium (blue). Panel A–D (Yeaman et al., 2003); panel F (Yeaman et al., 2004); panel E, G, H, and I (Yeaman et al., 2004). From Wira et al. (2010).
FIGURE 3.2 The human female reproductive tract (FRT) is the prime site of infection and the potential solution to the control of sexually transmitted pathogens. Shown on the right side of this illustration (triangle) is the directional flow of sperm and sexually transmitted pathogens which, when deposited in the vagina, move rapidly in response to ciliary activity and muscle contractions (circular and longitudinal) that create a functionally united peristaltic pump with the formation of eddy currents. Each of these contributes to upstream movement from the vagina, through the cervix, and into the uterus and Fallopian tubes. As seen on the left, luminal secretions consisting of soluble aspects of the innate and adaptive immune systems, as well as limited numbers of immune cells, move downward from the Fallopian tubes to the vagina, forming a first line of defense against sexually transmitted pathogens. All aspects of immune protection are present in the FRT and are controlled throughout the menstrual cycle by estradiol and progesterone.
(A)
(B)
(C)
FIGURE 3.3 Typical examples of Doppler ultrasonography scans taken 10–20 min after application of 10–12 MBq 99m-technetium-labeled microspheres to the posterior vaginal fornix, demonstrating (from left to right) the rapid uptake into the uterus and unilateral transport to the right Fallopian tube (A), uptake into the uterus only (B), and bilateral transport into the oviducts (C). A marker is placed at half distance between the symphysis and umbilicus (Reprinted from Wildt et al. (1998) and Zervomanolakis et al. (2007) with permission.)
FIGURE 3.4 Hormonal changes in blood during a typical menstrual cycle of women. During the first half of the menstrual cycle (proliferative stage) estradiol is produced by the ovary in response to the production of follicle stimulating hormone (FSH) made by the pituitary gland in response to signals from the hypothalamus. At ovulation (midcycle), luteinizing hormone (LH) and FSH levels increase to induce ovulation. During the second half (secretory stage) estradiol and progesterone are the dominant hormones that prepare the FRT for implantation and possible pregnancy. These hormones also regulate the mucosal immune system present throughout the FRT to optimize conditions for successful fertilization while protecting against potential pathogens.
FIGURE 3.5 Sex hormone suppression of immune function in the human female reproductive tract (FRT) (uterus and vagina) results in a ‘window of vulnerability’ that increases the potential for viral, bacterial, and fungal infectivity. During a normal menstrual cycle, estradiol and progesterone suppress aspects of the innate, humoral, and cell-mediated immune systems, thereby creating a ‘window of vulnerability’ lasting for 7–10 days following ovulation, in which the potential for STI in the FRT is enhanced. Suppression by sex hormones optimizes conditions for procreation in the upper (Fallopian tubes, FT; uterus, UT; endocervix, CX) and lower (ectocervix; vagina, VAG) FRT, and coincides with the recruitment of potentially infectable cells and upregulation of coreceptors essential for pathogen uptake. Dynamic endocrine changes during the cycle lead to shifts in immune protection in the FRT with aspects of the innate immune system (antimicrobials) enhanced to theoretically offset the suppression of cytotoxic T lymphocyte (CTL) activity (uterus). Adapted from Wira & Fahey, (2008).
FIGURE 3.6 The mucosal immune system in the human FRT contains an array of protective mechanisms that extend throughout both the upper and the lower tract. Consisting of resident epithelial cells and underlying stromal cells, as well as immune cells that migrate into the uterus, cervix and vagina, immune protection is provided by both the innate and adaptive (cell mediated and humoral) immune systems. In anticipation of pathogenic challenge, soluble protection is delivered through innate immune cells, (left panel) that secrete cytokines, chemokines, and antimicrobials constitutively, as well as in response to pathogenic challenge. In this way, secreted immune factors provide initial protection through their antimicrobial activity while recruiting and activating adaptive immune protection, should such backup be necessary. Specific adaptive responses are driven by antigen presentation to T and B cells directly by dendritic cells, macrophages and epithelial cells in the mucosa or following activation by CD4+ T cell migration from circulation. Once activated through cytokine stimulation, T and B cells proliferate and differentiate. The cell-mediated response (middle panel) is characterized by the production of IFNγ and the apoptosis of infected cells by cytotoxic CD8+ T cells. IFNγ also stimulates the production of intracellular antiviral genes that block viral replication. The humoral response (right panel) is mediated by B cell differentiation into antibody-secreting plasma cells. Both IgG and IgA are produced in the FRT and are secreted into the mucosa. Antibodies bind to pathogens, blocking infection by mediating phagocytosis or complement pathways.
FIGURE 6.1 A relief on the tomb of Ankhmahor from the 6th Dynasty (4300 years ago). This image is in the public domain. http://en.wikipedia.org/wiki/File:Egypt_circ.jpg.
(A)
(B)
(C)
FIGURE 6.2 Foreskin tissues obtained at the time of male circumcision in Rakai, Uganda, have predominantly focal inflammatory lesions containing CD1a+ dendritic cells (A), and CD4+ (B) and CD8+ (C) T lymphocytes. The cells are stained by red precipitate.
FIGURE 9.2A HIV Prevention Cascade for Topical/Oral PrEP with 50% Coverage/ Adherence. Adapted from Barker et al., JAIDS, 2011.
FIGURE 9.2B HIV Prevention Cascade for Topical/Oral PrEP with 95% Coverage/ Adherence. Adapted from Barker et al., JAIDS, 2011.
Biomedical Factors
Behavioral Factors
Associated Factors
Media Coverage
Cultural & Social Influences Politics
Licensure
Time
Policies & Guidelines
STI Vaccine Acceptance: •Providers •Parents •Adolescents
STI Vaccine Available
Reduction in Incidence of Targeted & Other STIs
False Reassurance (Target STI) False Reassurance (Other STI)
Risk Compensation
STI Vaccine Coverage
FIGURE 11.1 Model of Interactions among Biomedical, Behavioral, and Associated Factors.
Health Beliefs
•Providers •Parents •Adolescents
STI Vaccine Acceptability
STI Vaccine Development: •Animal Studies & •Clinical Trials
FIGURE 13.2 Cervical cancer progression model. The functional progression model is displayed at the bottom. Classical cytological and colposcopic correlates of normal cervix, human papillomavirus (HPV)-infected cervix, precancer, and cancer are displayed above. Adapted from Schiffman and Wentzensen (2010). From human papillomavirus to cervical cancer. Obstetrics and Gynecology 116: 177–85.
FIGURE 15.1 The chlamydial developmental cycle. 1) Chlamydial infection of susceptible host cells is initiated by the attachment and subsequent parasite-mediated endocytosis of the infectious, but metabolically inactive, elementary body (EB) into mucosal epithelial cells. 2) EB-containing endosomes that resist acidification are then internalized within host-derived membranes, as an endocytic vesicle that develops close to the host cell nucleus. 3) Once resources such as sphingomyelin are obtained from the host cell and the vesicle expands, the EBs differentiate into the metabolically active, non-infectious and larger (0.8 μm) reticulate bodies (RBs). 4, 5) RBs then use host cell ATP and other metabolites to grow and replicate by binary fission within the chlamydial ‘inclusion.’ 6A) Many inducers of persistence (including interferon gamma, amino acid starvation, and antibiotics) will result in deviation from the ‘normal developmental cycle,’ resulting in a viable but non-cultivable growth stage and the formation of large, abnormal developmental forms termed aberrant bodies (ABs), also known as aberrant RBs, or persistent bodies. 6B) In normal development, RBs will continue to divide, undergoing between 8 and 12 rounds of replication. 7) Later in the infectious process, the RBs asynchronously begin to differentiate back into EBs; there is evidence of intermediate bodies (IBs) at this stage and the EBs accumulate within the inclusion. Depending upon the chlamydial species, at 30–80 h post-infection, the infectious EBs that have matured from the RBs are released either by host cell lysis or by a packaged-release mechanism called extrusion (8), allowing the EBs to infect neighboring cells for successive rounds of infection. Figure reproduced by permission (Mitchell, 2010).
FIGURE 15.2 Fully sequenced chlamydial genomes, by year of publication.
FIGURE 15.3 One of the 10 hot spots (IX) of variation in the koala C. pneumoniae genome. This demonstrates some examples of CDS being full length in the koala strain but which have degraded to pseudogenes in one or more of the human strains.
FIGURE 16.1 Gonococcal urethritis and lymphangitis in a male.
FIGURE 16.2 Gonorrhea incidence 1941–2009. Courtesy of the US Centers for Disease Control and Prevention.
FIGURE 16.3 Geographical distribution of gonorrhea in the US, 2009. Courtesy of the US Centers for Disease Control and Prevention.
FIGURE 18.1 Molecular methods such as broad-range 16S rRNA gene PCR with cloning and sequencing have demonstrated that the microbiology of BV is complex, and different subjects may have very different vaginal bacterial communities, as evidenced by these two subjects. The eight most abundant phylotypes (species level operational taxonomic units) are displayed for each subject.
FIGURE 18.2 Fluorescence micrograph showing a vaginal epithelial cell coated with bacteria from a subject with BV. Labeled bacteria are shown hybridizing with probes for (BV-associated bacteria) BVAB-1 (green) and BVAB-2 (red). DAPI (4’,6-diamidino-2-phenylindole, a fluorescent stain that binds strongly to A-T rich regions in DNA) stains cell nuclei blue in this image.
FIGURE 18.3 Factors involved in the pathogenesis of BV.
FIGURE 18.4 Typical vaginal discharge caused by BV.
FIGURE 18.6 Gram stain of normal vaginal fluid, showing Gram-positive rods with blunt ends consistent with lactobacilli. (×1000 Magnification.) Photograph provided by Lorna K. Rabe.
FIGURE 18.7 Gram stain of vaginal fluid from a woman with bacterial vaginosis showing absence of lactobacilli and large numbers of Gram-negative or Gram-variable coccobacilli. Curved Gram-variable rods are consistent with Mobiluncus. (×1000 Magnification.) Photograph provided by Lorna K. Rabe.
FIGURE 1.4 Regional estimates of HSV-2 prevalence in 2003. Adapted from Looker KJ, Garnett GP, Schmid GP. An estimate of the global prevalence and incidence of herpes simplex virus type 2 infection. Bulletin of the World Health Organization, October 2008, 86(10): 808–9.
(G)
(E)
(A)
(B)
(H)
(F)
(I)
(C)
(D)
FIGURE 3.1 Schematic of the mucosal immune system throughout the human female reproductive tract (FRT). As seen in the drawing on the left side, the vagina and ectocervix are lined with squamous epithelial cells. Columnar cells are present throughout the upper FRT, including the endocervix, uterine endometrium, and Fallopian tubes. Panels A–D are confocal photomicrographs showing the distribution of immune cells throughout the uterus. Frozen sections were directly stained with three fluorescently tagged monoclonal antibodies: an epithelial cell-specific antibody (Cy3-labeled clone BerEP4, red color panels A–D), anti-CCR5 (FITC-labeled clone 2D7, green color panels A–D), and anti-CXCR4 (Cy5-labeled 12G5, blue color panels A–D). Panel A: epithelial gland extending from the myometrial interface (far left) to the luminal epithelium (right-hand side). Panels B–D show higher magnification fields from the same region. The luminal epithelium, in contrast to the adjacent glands, retains a relatively intense BerEP4 expression (red color panels A and D). CCR5 expression is prominent on the lymphoid aggregates located in the stratum basalis immediately adjacent to the myometrium (D in panel B). Epithelial expression of CCR5 is low in the stratum basalis and increases in the proximal third of the stratum functionalis. Panel E: vaginal squamous cells expressing GalCer (green), which is expressed on parabasal epithelial cells (p) and in the surface regions of the cornified layer. b: basal epithelial cells; P: parabasal epithelial cells; c: cornified layer of epithelial cells; dp: submucosal stromal papillae; pre: precornified layer. Panel F: this photo plate consists of a lymphoid aggregate in the uterine endometrium at the late proliferative stage of the menstrual cycle. The three fluorochromes are T cells (Cy3anti-CD3, red), B cells (FITC-anti-CD19, green), and macrophages (Cy5-anti-CD14, blue). Panel G: CD8+ T cells present in both the submucosa and the squamous epithelium. Panel H: CD14 expression is found on both stroma and squamous epithelium macrophages. Panel I: CD1a-positive dendritic cells (DC) are present in the squamous epithelium (blue). Panel A–D (Yeaman et al., 2003); panel F (Yeaman et al., 2004); panel E, G, H, and I (Yeaman et al., 2004). From Wira et al. (2010).
FIGURE 3.2 The human female reproductive tract (FRT) is the prime site of infection and the potential solution to the control of sexually transmitted pathogens. Shown on the right side of this illustration (triangle) is the directional flow of sperm and sexually transmitted pathogens which, when deposited in the vagina, move rapidly in response to ciliary activity and muscle contractions (circular and longitudinal) that create a functionally united peristaltic pump with the formation of eddy currents. Each of these contributes to upstream movement from the vagina, through the cervix, and into the uterus and Fallopian tubes. As seen on the left, luminal secretions consisting of soluble aspects of the innate and adaptive immune systems, as well as limited numbers of immune cells, move downward from the Fallopian tubes to the vagina, forming a first line of defense against sexually transmitted pathogens. All aspects of immune protection are present in the FRT and are controlled throughout the menstrual cycle by estradiol and progesterone.
(A)
(B)
(C)
FIGURE 3.3 Typical examples of Doppler ultrasonography scans taken 10–20 min after application of 10–12 MBq 99m-technetium-labeled microspheres to the posterior vaginal fornix, demonstrating (from left to right) the rapid uptake into the uterus and unilateral transport to the right Fallopian tube (A), uptake into the uterus only (B), and bilateral transport into the oviducts (C). A marker is placed at half distance between the symphysis and umbilicus (Reprinted from Wildt et al. (1998) and Zervomanolakis et al. (2007) with permission.)
FIGURE 3.4 Hormonal changes in blood during a typical menstrual cycle of women. During the first half of the menstrual cycle (proliferative stage) estradiol is produced by the ovary in response to the production of follicle stimulating hormone (FSH) made by the pituitary gland in response to signals from the hypothalamus. At ovulation (midcycle), luteinizing hormone (LH) and FSH levels increase to induce ovulation. During the second half (secretory stage) estradiol and progesterone are the dominant hormones that prepare the FRT for implantation and possible pregnancy. These hormones also regulate the mucosal immune system present throughout the FRT to optimize conditions for successful fertilization while protecting against potential pathogens.
FIGURE 3.5 Sex hormone suppression of immune function in the human female reproductive tract (FRT) (uterus and vagina) results in a ‘window of vulnerability’ that increases the potential for viral, bacterial, and fungal infectivity. During a normal menstrual cycle, estradiol and progesterone suppress aspects of the innate, humoral, and cell-mediated immune systems, thereby creating a ‘window of vulnerability’ lasting for 7–10 days following ovulation, in which the potential for STI in the FRT is enhanced. Suppression by sex hormones optimizes conditions for procreation in the upper (Fallopian tubes, FT; uterus, UT; endocervix, CX) and lower (ectocervix; vagina, VAG) FRT, and coincides with the recruitment of potentially infectable cells and upregulation of coreceptors essential for pathogen uptake. Dynamic endocrine changes during the cycle lead to shifts in immune protection in the FRT with aspects of the innate immune system (antimicrobials) enhanced to theoretically offset the suppression of cytotoxic T lymphocyte (CTL) activity (uterus). Adapted from Wira & Fahey, (2008).
FIGURE 3.6 The mucosal immune system in the human FRT contains an array of protective mechanisms that extend throughout both the upper and the lower tract. Consisting of resident epithelial cells and underlying stromal cells, as well as immune cells that migrate into the uterus, cervix and vagina, immune protection is provided by both the innate and adaptive (cell mediated and humoral) immune systems. In anticipation of pathogenic challenge, soluble protection is delivered through innate immune cells, (left panel) that secrete cytokines, chemokines, and antimicrobials constitutively, as well as in response to pathogenic challenge. In this way, secreted immune factors provide initial protection through their antimicrobial activity while recruiting and activating adaptive immune protection, should such backup be necessary. Specific adaptive responses are driven by antigen presentation to T and B cells directly by dendritic cells, macrophages and epithelial cells in the mucosa or following activation by CD4+ T cell migration from circulation. Once activated through cytokine stimulation, T and B cells proliferate and differentiate. The cell-mediated response (middle panel) is characterized by the production of IFNγ and the apoptosis of infected cells by cytotoxic CD8+ T cells. IFNγ also stimulates the production of intracellular antiviral genes that block viral replication. The humoral response (right panel) is mediated by B cell differentiation into antibody-secreting plasma cells. Both IgG and IgA are produced in the FRT and are secreted into the mucosa. Antibodies bind to pathogens, blocking infection by mediating phagocytosis or complement pathways.
FIGURE 6.1 A relief on the tomb of Ankhmahor from the 6th Dynasty (4300 years ago). This image is in the public domain. http://en.wikipedia.org/wiki/File:Egypt_circ.jpg.
(A)
(B)
(C)
FIGURE 6.2 Foreskin tissues obtained at the time of male circumcision in Rakai, Uganda, have predominantly focal inflammatory lesions containing CD1a+ dendritic cells (A), and CD4+ (B) and CD8+ (C) T lymphocytes. The cells are stained by red precipitate.
FIGURE 9.2A HIV Prevention Cascade for Topical/Oral PrEP with 50% Coverage/ Adherence. Adapted from Barker et al., JAIDS, 2011.
FIGURE 9.2B HIV Prevention Cascade for Topical/Oral PrEP with 95% Coverage/ Adherence. Adapted from Barker et al., JAIDS, 2011.
Biomedical Factors
Behavioral Factors
Associated Factors
Media Coverage
Cultural & Social Influences Politics
Licensure
Time
Policies & Guidelines
STI Vaccine Acceptance: •Providers •Parents •Adolescents
STI Vaccine Available
Reduction in Incidence of Targeted & Other STIs
False Reassurance (Target STI) False Reassurance (Other STI)
Risk Compensation
STI Vaccine Coverage
FIGURE 11.1 Model of Interactions among Biomedical, Behavioral, and Associated Factors.
Health Beliefs
•Providers •Parents •Adolescents
STI Vaccine Acceptability
STI Vaccine Development: •Animal Studies & •Clinical Trials
FIGURE 13.2 Cervical cancer progression model. The functional progression model is displayed at the bottom. Classical cytological and colposcopic correlates of normal cervix, human papillomavirus (HPV)-infected cervix, precancer, and cancer are displayed above. Adapted from Schiffman and Wentzensen (2010). From human papillomavirus to cervical cancer. Obstetrics and Gynecology 116: 177–85.
FIGURE 15.1 The chlamydial developmental cycle. 1) Chlamydial infection of susceptible host cells is initiated by the attachment and subsequent parasite-mediated endocytosis of the infectious, but metabolically inactive, elementary body (EB) into mucosal epithelial cells. 2) EB-containing endosomes that resist acidification are then internalized within host-derived membranes, as an endocytic vesicle that develops close to the host cell nucleus. 3) Once resources such as sphingomyelin are obtained from the host cell and the vesicle expands, the EBs differentiate into the metabolically active, non-infectious and larger (0.8 μm) reticulate bodies (RBs). 4, 5) RBs then use host cell ATP and other metabolites to grow and replicate by binary fission within the chlamydial ‘inclusion.’ 6A) Many inducers of persistence (including interferon gamma, amino acid starvation, and antibiotics) will result in deviation from the ‘normal developmental cycle,’ resulting in a viable but non-cultivable growth stage and the formation of large, abnormal developmental forms termed aberrant bodies (ABs), also known as aberrant RBs, or persistent bodies. 6B) In normal development, RBs will continue to divide, undergoing between 8 and 12 rounds of replication. 7) Later in the infectious process, the RBs asynchronously begin to differentiate back into EBs; there is evidence of intermediate bodies (IBs) at this stage and the EBs accumulate within the inclusion. Depending upon the chlamydial species, at 30–80 h post-infection, the infectious EBs that have matured from the RBs are released either by host cell lysis or by a packaged-release mechanism called extrusion (8), allowing the EBs to infect neighboring cells for successive rounds of infection. Figure reproduced by permission (Mitchell, 2010).
FIGURE 15.2 Fully sequenced chlamydial genomes, by year of publication.
FIGURE 15.3 One of the 10 hot spots (IX) of variation in the koala C. pneumoniae genome. This demonstrates some examples of CDS being full length in the koala strain but which have degraded to pseudogenes in one or more of the human strains.
FIGURE 16.1 Gonococcal urethritis and lymphangitis in a male.
FIGURE 16.2 Gonorrhea incidence 1941–2009. Courtesy of the US Centers for Disease Control and Prevention.
FIGURE 16.3 Geographical distribution of gonorrhea in the US, 2009. Courtesy of the US Centers for Disease Control and Prevention.
FIGURE 18.1 Molecular methods such as broad-range 16S rRNA gene PCR with cloning and sequencing have demonstrated that the microbiology of BV is complex, and different subjects may have very different vaginal bacterial communities, as evidenced by these two subjects. The eight most abundant phylotypes (species level operational taxonomic units) are displayed for each subject.
FIGURE 18.2 Fluorescence micrograph showing a vaginal epithelial cell coated with bacteria from a subject with BV. Labeled bacteria are shown hybridizing with probes for (BV-associated bacteria) BVAB-1 (green) and BVAB-2 (red). DAPI (4’,6-diamidino-2-phenylindole, a fluorescent stain that binds strongly to A-T rich regions in DNA) stains cell nuclei blue in this image.
FIGURE 18.3 Factors involved in the pathogenesis of BV.
FIGURE 18.4 Typical vaginal discharge caused by BV.
FIGURE 18.6 Gram stain of normal vaginal fluid, showing Gram-positive rods with blunt ends consistent with lactobacilli. (×1000 Magnification.) Photograph provided by Lorna K. Rabe.
FIGURE 18.7 Gram stain of vaginal fluid from a woman with bacterial vaginosis showing absence of lactobacilli and large numbers of Gram-negative or Gram-variable coccobacilli. Curved Gram-variable rods are consistent with Mobiluncus. (×1000 Magnification.) Photograph provided by Lorna K. Rabe.