text:
Molecular Pathogenesis
Haemophilus ducreyi Associates with Phagocytes, Collagen, and Fibrin and Remains Extracellular throughout Infection of Human Volunteers
Margaret E. Bauer, Michael P. Goheen, Carisa A. Townsend, Stanley M. Spinola
Margaret E. Bauer
Departments of Medicine, 1
Michael P. Goheen
Pathology and Laboratory Medicine, 2 and
Carisa A. Townsend
Stanley M. Spinola
Departments of Medicine, 1 Pathology and Laboratory Medicine, 2 and Microbiology and Immunology, 3 Indiana University School of Medicine, Indianapolis, Indiana 46202
DOI: 10.1128/IAI.69.4.2549-2557.2001
In a previous study, Haemophilus ducreyi was found in the pustule and dermis of samples obtained at the clinical end point in the human model of infection. To understand the kinetics of localization, we examined infected sites at 0, 24, and 48 h after inoculation and at the clinical end point. Immediately after inoculation, bacteria were found predominantly in the dermis but also in the epidermis. Few bacteria were detectable at 24 h; however, by 48 h, bacteria were readily seen in the pustule and dermis.H. ducreyi was associated with polymorphonuclear leukocytes and macrophages in the pustule and at its base, but was not associated with T cells, Langerhans' cells, or fibroblasts.H. ducreyi colocalized with collagen and fibrin but not laminin or fibronectin. Association with phagocytes, collagen, and fibrin was seen as early as 48 h and persisted at the pustular stage of disease. Optical sectioning by confocal microscopy and transmission electron microscopy both failed to demonstrate intracellular H. ducreyi. These data identify collagen and fibrin as potentially important targets of adherence in vivo and strongly suggest that H. ducreyi remains extracellular throughout infection and survives by resisting phagocytic killing in vivo.
Haemophilus ducreyiis the causative agent of chancroid, a sexually transmitted genital ulcer disease that facilitates the transmission of the human immunodeficiency virus (HIV). H. ducreyienters the host through microabrasions that occur during intercourse and primarily remains localized in the skin. To study the pathogenesis of chancroid, we developed a human model of H. ducreyiinfection in which volunteers are inoculated on the upper arm withH. ducreyi and observed until a painful pustule forms or disease resolves (4, 25, 26). The clinical course and the histopathology of experimental infection resemble naturally occurring disease (4, 20).
We recently reported methods to immunodetect H. ducreyiin pustules from experimentally infected volunteers (6).H. ducreyi was identified in these lesions with polyclonal anti-H. ducreyi antiserum, whose specificity was established by simultaneously staining sections with the polyclonal antiserum and a panel of monoclonal antibodies (MAbs) recognizingH. ducreyi surface antigens. In this study, we found that H. ducreyi is concentrated at the base of the pustule and is more sparsely distributed throughout the pustule and in the subpustular dermis. H. ducreyi did not associate with keratinocytes or fibroblasts. Within the pustule, H. ducreyi appears to associate with polymorphonuclear leukocytes (PMNs). These findings were limited to the pustular stage of disease, and we did not examine whether H. ducreyi interacted with other cells or structures in the skin.
In addition to components found in normal skin, pustules contain T cells, PMNs, and macrophages (20). In vitro,H. ducreyi adheres to and invades keratinocytes and fibroblasts as well as epithelial cell lines (11, 15, 18, 19, 23,30, 31), although invasion of fibroblasts is controversial (1, 19). H. ducreyi adheres to types I and III collagen, fibronectin, and laminin in vitro (5). Little is known about the interactions of H. ducreyiwith these structures or cell types in vivo other than the organism's general location at the pustular stage of disease.
In the present study, we examined the association of H. ducreyi with PMNs, macrophages, T cells, fibroblasts, and Langerhans' cells at both the papular and pustular stages of disease. We also examined the association of the bacteria with dermal tissue components and whether H. ducreyi invades cells in vivo throughout experimental infection.
Human subjects.Volunteers included 21 healthy adults (mean age ± standard deviation, 35 ± 10 years; 13 women, 8 men) who participated in parent-mutant trials (3, 7, 9, 28, 32; R. S. Young, C. K. Ward, K. R. Fortney, B. P. Katz, A. F. Hood, E. J. Hansen, and S. M. Spinola, unpublished data) or who were infected or donated tissue specifically for this study (see Tables 1 and 2). Informed consent was obtained from the subjects for participation and for HIV serology in accordance with the human experimentation guidelines of the U.S. Department of Health and Human Services and the Institutional Review Board of Indiana University-Purdue University at Indianapolis. Enrollment procedures, exclusion criteria, inoculation protocols, and calculations of estimated delivered doses (EDD) have been described in detail elsewhere (25, 26).
Sources of tissue samples analyzed by confocal microscopy
Tissue specimens.Tissue specimens from infected sites were obtained by biopsy from 20 of the volunteers. Thirteen subjects were biopsied at the clinical end point, which is defined as development of a painful pustule, resolution of disease at all sites, or 14 days of infection. Two volunteers were inoculated at two sites each with 35000HP and biopsied immediately after inoculation (Table 1). Four volunteers were inoculated at three sites each with 35000HP and assigned to biopsy at 24 h or on the first day of pustule formation (Table 1). An additional volunteer was inoculated but only developed transient infection and was not biopsied. One volunteer donated uninfected tissue. All inoculated volunteers were treated with oral ciprofloxacin as described elsewhere (4).
Specimens were fixed in 4% paraformaldehyde and processed for microscopy as described previously (6), except that specimens were fixed for 3 h. Samples obtained for this study were initially examined for the presence of bacteria by staining every 10th section of each specimen with polyclonal antiserum raised againstH. ducreyi, as described previously (6) (Table 1). To confirm that the structures recognized by the polyclonal antiserum were H. ducreyi, the specimens were simultaneously stained with the polyclonal serum and MAbs that recognize H. ducreyi antigens, as described (6).
Primary Abs and stains. H. ducreyi was detected with rabbit polyclonal antiserum raised against wholeH. ducreyi cells (6, 13) and with murine MAb 5C9 or BB11, which recognize H. ducreyi lipoprotein (Hlp) (14) and the GroEL homolog heat shock protein (Hsp) (10), respectively.
Murine MAbs raised against human antigens included anti-CD1a MAb O10 (Beckman Coulter, Inc., Fullerton, Calif.) for Langerhans' cells, anti-CD3 MAb UCHT1 (Dako Corporation, Carpinteria, Calif.) for T cells, anti-CD45 MAb H130 for leukocytes (Pharmingen International, San Diego, Calif.), anti-CD68 MAb PG-M1 (Dako Corporation) for macrophages, antifibronectin MAb 568 (Novocastra Laboratories, Ltd., Burlingame, Calif.), and antilaminin MAb 4C7 (Dako Corporation). Rabbit polyclonal anti-human type I collagen antiserum was purchased from Novocastra Labs. Rabbit polyclonal anti-human fibrinogen was purchased from Dako Corp. Anti-multicytokeratin MAbs AE1 and AE3, antineutrophil elastase MAb NP57, antivimentin MAb VIM 3B4, and tetramethyl rhodamine isothiocyanate (TRITC)-labeled Lens culinaris agglutinin (LCA), used to stain eukaryotic cell membranes, were described previously (6).
Secondary Abs.Secondary Abs were purchased from Jackson ImmunoResearch Laboratories (West Grove, Penn.) and have been described previously (6). These included goat anti-rabbit immunoglobulin G (IgG) and goat anti-mouse IgG which were affinity purified and conjugated with fluorescein isothiocyanate (FITC) or indodicarbocyanine (Cy5). Normal goat serum was also obtained from Jackson ImmunoResearch Laboratories.
Preliminary experiments showed that the secondary Abs cross-reacted with human leukocytes in the tissues. Thus, for sections stained with MAbs recognizing leukocyte antigens, the secondary Abs were absorbed with human leukocytes prior to use. To obtain leukocytes, whole blood was donated by a healthy adult volunteer after informed consent was obtained. Two volumes of 0.2% NaCl were added to hypotonically lyse erythrocytes, followed by 2 volumes of 1.6% NaCl. Cells were collected by centrifugation, and the process was repeated three to five times until no erythrocytes remained. Leukocytes were fixed by rocking for 15 min at room temperature in 4% paraformaldehyde in phosphate-buffered saline (PBS) (5) and washed three times in PBS.
Secondary Abs were diluted to a working concentration in PBS and subjected to two rounds of incubation with 107paraformaldehyde-fixed leukocytes by rocking for 45 min at room temperature in the dark. Cells were removed by centrifugation before the Abs were used in staining.
Immunofluorescence staining.Tissue sections were stained as previously described (2, 6). Briefly, sections were permeabilized with Triton X-100, blocked with normal goat serum, stained with primary Ab, blocked again with normal goat serum, and incubated with fluorescently labeled secondary Ab. Sections stained with the anti-CD68 MAb were incubated in Retrieve-All antigen unmasking solution (Signet Pathology Systems, Inc., Dedham, Mass.) for 10 min at 92°C, followed by 10 min at room temperature, and washed three times in PBS prior to the permeabilization step. When used, TRITC-LCA was added simultaneously with the secondary Ab. Samples were mounted as described (6).
Negative controls were described previously (6) and included omitting each primary Ab, omitting each secondary Ab, and staining sections of uninfected upper arm skin. There was some background of tissue autofluorescence in the FITC channel; otherwise, no positive signals were observed in the negative controls.
Confocal microscopy.Stained sections were examined on a Bio-Rad MRC 1024 confocal laser scanning microscope. Samples examined for intracellular bacteria were optically sectioned in 0.2-μm steps. Images were collected separately for FITC, TRITC, and Cy5 signals, and the images were colorized and combined using MetaMorph (Universal Imaging Corp., West Chester, Penn.) or Adobe Photoshop (Adobe Systems, Inc., San Jose, Calif.) software.
TEM.Specimens for transmission electron microscopy (TEM) were processed as described elsewhere (12). Briefly, specimens were fixed in 4% paraformaldehyde, embedded in LR White resin, sectioned, and stained with uranyl acetate and lead citrate. For immunogold labeling, sections were stained with rabbit polyclonal antiserum raised against whole H. ducreyi cells, followed by goat anti-rabbit IgG labeled with 15-nm gold particles.
H. ducreyi delivered to epidermis and dermis during inoculation.In the human model, bacteria are delivered into the skin via puncture wounds made by the tines of an allergy testing device (25, 26). To examine where H. ducreyi is placed in the skin, we inoculated two volunteers with 35000HP at two sites that were biopsied immediately after inoculation. One site was inoculated with an EDD of 50 CFU, and three sites were inoculated with an EDD of 500 CFU (Table 1). Specimens from these sites were processed as described above, and sections were doubly stained forH. ducreyi with polyclonal antiserum and the anti-H. ducreyi MAb 5C9 or BB11. A few sections from each specimen contained puncture wounds from the inoculation device.H. ducreyi was occasionally found along these puncture wounds (Fig. 1A). Although most of the bacteria were in the dermis, some H. ducreyi were found with keratinocytes in the epidermis (Fig. 1B). We also sawH. ducreyi along the epidermal surface of some sections (data not shown). These data show that H. ducreyi was delivered principally to the dermis but also to the epidermis in the human model.
Deposition of H. ducreyi in skin. Sections from tissue biopsied immediately postinoculation were stained with polyclonal anti-H. ducreyi antiserum and MAb BB11. (A) Puncture wound made by inoculation device. Arrows indicate bacteria along puncture wound. (B) Bacteria (arrow) at the epidermis with keratinocytes. Ep, epidermis. Bars, 50 μm.
Kinetics of localization of H. ducreyi.At the clinical end point, H. ducreyi bacteria are found in the pustule with PMNs, primarily clustered at the pustule base, and are also seen in the dermis (6). The organism does not colocalize with keratinocytes or fibroblasts at the pustular stage of disease (6). To examine the kinetics of localization, volunteers were infected with 35000HP and assigned to biopsy either at 24 h or on the first day of pustule formation. Specimens harvested included an erythematous macule, small papules from 24 h of infection, larger papules from 48 h, and newly formed pustules (Table 1). These samples, along with uninfected tissue and specimens harvested on day 0, were used to localizeH. ducreyi with respect to PMNs, keratinocytes, and fibroblasts.
Small pockets of PMNs and fibroblasts were scattered in the dermis of uninfected tissue and tissue harvested on day 0 (Fig.2A and data not shown). By 24 h, PMNs had infiltrated the epidermis, forming small micropustules, and had collected in the dermis (Fig. 2B through D). Keratinocytes surrounding these micropustules were swollen, but the epidermis was intact (data not shown). More fibroblasts were evident at 24 h than in uninfected tissue (data not shown). H. ducreyiwas found in only one section of one sample at 24 h (Table 1); therefore, we cannot make statements about bacterial localization at this time point.
Kinetics of lesion formation in the human model. Sections were stained with anti-PMN elastase. Panels represent tissue harvested immediately after inoculation (A), an erythematous macule at 24 h (B), papules at 24 h (C and D), a papule at 48 h (E), and a pustule at 48 h (F). Arrows indicate intraepidermal micropustules in 24-h samples. Bars, 150 μm.
At 48 h, the PMN infiltrate was more extensive, and samples had both intraepidermal micropustules and larger pustules that merged with the dermal infiltrate (Fig. 2E and F). The 48-h specimens also contained greater numbers of fibroblasts, and keratinocyte swelling was still evident. In addition, the basilar epidermis was eroded by some pustules. Overall, little morphologic difference was observed at the microscopic level between samples clinically scored as papules and those scored as pustules (Fig. 2E and F). All specimens at 48 h contained H. ducreyi (Table 1), primarily at the base of pustules and in the subpustular dermis (Fig.3A and B). A few bacteria were seen within the pustules associated with PMNs (data not shown).H. ducreyi was found near keratinocytes at the pustule base but did not colocalize with them (Fig. 3A). Similarly, bacteria in the dermis were near fibroblasts, but no colocalization was observed (data not shown). Thus, H. ducreyi was found in the dermis and pustule within 48 h of inoculation. Because no gross differences were observed between samples obtained at 48 h and at the clinical end point, no other time points were examined.
Localization of H. ducreyi in tissues from papular and pustular stages of disease. P, pustule or micropustule. De, dermis. Scale bars represent 100 μm in panels A through F, 50 μm in panels G and I, and 5 μm in panel H. (A) Papule at 48 h doubly stained with polyclonal anti-H. ducreyi antiserum (green) and anticytokeratin MAbs (red). Arrow indicates bacteria (green) in dermis below micropustule. (B) A 48-h papule doubly stained with polyclonal anti-type I collagen (red) and the anti-H. ducreyi MAb BB11 (green). Arrow indicates bacteria colocalizing with collagen (yellow). (C) Section stained as in panel B showing colocalization (yellow) of H. ducreyi and collagen. (D through F) Low-power view of consecutive sections from one pustule stained with polyclonal anti-H. ducreyi antiserum (green) and MAb recognizing PMN elastase (D), CD68 (E), or CD3 (F) (red). (G) Higher-power view of the base of a pustule. Section was stained with polyclonal anti-H. ducreyi antiserum (green), anti-CD68 (red), and the lectin LCA, which stains plasma membranes (blue). Colocalization of anti-CD68 (red) and LCA (blue) on the macrophage cell surface is represented in pink. Note the bacteria between the macrophages and the PMNs of the pustule. (H) High-power view of section stained with polyclonal anti-H. ducreyi antiserum (green) and anti-CD68 (red). Arrow indicates bacteria colocalizing with a macrophage (yellow). (I) Base of a pustule stained with polyclonal anti-H. ducreyi antiserum (green) and anti-CD3 (red). Note that the bacteria do not colocalize with the T cells.
H. ducreyi associated with phagocytes in vivo.Macrophages and PMNs are both recruited to sites of infection in the human model (20, 25, 26), andH. ducreyi is found with PMNs in vivo (6). To examine the interaction of H. ducreyi with macrophages, tissue sections were simultaneously stained for the bacteria and CD68. For comparison, consecutive tissue sections were doubly stained for H. ducreyi and PMNs. Macrophages had begun to infiltrate the dermis below micropustules by 24 h, and many macrophages were present throughout the upper dermis at 48 h. Macrophages were also occasionally seen in the pustules and micropustules (data not shown). H. ducreyi colocalized with macrophages in the dermis at 48 h (data not shown). At the clinical end point, most of the macrophages had coalesced into a band at the pustule base where the bacteria were most numerous (Fig. 3D and E). H. ducreyi was frequently associated with PMNs in the pustule. At the pustule base, H. ducreyi colocalized more commonly with PMNs (Fig. 3G), but the bacteria were also associated with macrophages (Fig. 3H). Thus,H. ducreyi associated with both these professional phagocytes in vivo.
H. ducreyi did not associate with Langerhans' cells.Langerhans' cells are resident skin cells observed in specimens at the clinical end point (20, 25). To examine the interaction of H. ducreyi with Langerhans' cells, sections were doubly stained with polyclonal anti-H. ducreyi antiserum and an anti-CD1a MAb. In all specimens examined, including uninfected skin, Langerhans' cells resided in the epidermis and stained heavily in glands and hair follicles (data not shown). Very few CD1a+ cells were found outside these areas, and CD1a+ cells were not found in the pustule. H. ducreyi did not colocalize with the CD1a+ cells (data not shown).
H. ducreyi did not associate with T cells.T cells account for approximately 70% of the perivascular mononuclear cell infiltrate in lesions at the pustular stage of disease (20). To localize H. ducreyi with respect to T cells, tissue sections were doubly stained for H. ducreyi and CD3. Very few T cells were present in uninfected tissue, but small clusters of T cells were found at 24 and 48 h (data not shown). At the clinical end point, T cells were sparsely distributed throughout the upper dermis near the pustule (Fig. 3F). Dense pockets of T cells resided in the deep dermis (data not shown). In the subpustular dermis, H. ducreyi was occasionally found near T cells, but did not colocalize with them (Fig. 3I). The bacteria were rarely found in the deep dermis, and H. ducreyi did not colocalize with T cells in any specimen.
H. ducreyi did not invade cells in vivo. H. ducreyi invades some eukaryotic cell types in vitro; however, it is not known whether the organism invades cells in vivo. In the present study, H. ducreyi associated with PMNs and macrophages but not with keratinocytes, T cells, or Langerhans' cells in vivo. To examine invasion by H. ducreyi in vivo, sections in which H. ducreyiassociated with PMNs or macrophages in the x/y plane were subjected to optical sectioning along the z axis. We examined 2 to 17 independent fields in each of nine specimens. The optical sections were stacked and animated, which allowed the relative positions of the bacterial and eukaryotic cells to be examined in three dimensions. Figure 4 shows images taken at 1-μm intervals through a section stained with polyclonal anti-H. ducreyi antiserum and an anti-PMN elastase MAb. In frozen sections, this MAb stains around the cell rather than in the cytoplasm. The bacteria were associated with the surface of cells but were not intracellular (Fig. 4). Similar results were observed when sections were stained for the panleukocyte marker CD45 or for CD68 (data not shown). Overall, the bacteria were extracellular with respect to phagocytes.
Optical sectioning through a pustule. Panels A through F represent, in order, images taken in 1-μm steps through a section stained with polyclonal anti-H. ducreyi antiserum (green) and anti-PMN elastase MAb (red). The arrow in each panel points to one edge of the PMN. Note the bacteria on the outside but not within the PMN. Bar, 5 μm.
In vivo, H. ducreyi was found in close proximity with fibroblasts but rarely colocalized with them (data not shown) (6). Since some investigators have reported thatH. ducreyi invades this cell type in vitro (19), we examined specimens for invasion of fibroblasts in vivo. Sections were stained with an antivimentin MAb and polyclonal anti-H. ducreyi antiserum, and we optically sectioned areas that contained bacteria near fibroblasts. We found no evidence of bacteria colocalizing with or invading fibroblasts by this method (data not shown).
To search for intracellular H. ducreyi more closely, seven specimens from pustules harvested at the clinical end point were prepared for TEM (Table 2). Bacteria were found in only two specimens, most likely due to the relatively small number of H. ducreyi in the tissue (29). In one specimen, the bacteria were found only at the outer edge of the pustule and were surrounded by necrotic PMNs and eukaryotic cell debris (data not shown), which did not allow us to examine intracellularity. In the second specimen, bacteria were found at the base of the pustule among PMNs (Fig. 5A). Immunogold labeling with anti-H. ducreyi antiserum confirmed that the bacteria were H. ducreyi (Fig. 5B). H. ducreyi were frequently surrounded by fibrin clots and were often seen adjacent to PMNs (Fig. 5A); however, no intracellularH. ducreyi were found.
Sources of tissue samples analyzed by TEMa
Transmission electron micrographs of H. ducreyi in a pustule. (A) H. ducreyi at the base of the pustule surrounded by fibrin (arrow) and adjacent to a PMN. Bar, 1 μm. (B) Immunogold labeling of H. ducreyi with polyclonal anti-H. ducreyi antiserum and gold-conjugated secondary Ab. Bar, 0.1 μm.
H. ducreyi associated with fibrin in vivo.TEM analysis suggested that H. ducreyi associated with fibrin in vivo. To examine this interaction by confocal microscopy, tissue sections were doubly stained with polyclonal antifibrinogen antiserum and the anti-H. ducreyi MAb BB11. Fibrin was present in the dermis at 24 and 48 h and formed a lattice throughout the pustules at 48 h and the clinical end point; little fibrin was seen in the micropustules at 24 h (Fig.6F and data not shown). NumerousH. ducreyi colocalized with fibrin in the pustule, particularly at its base (Fig. 6F). At higher magnification, the fibrin appeared to surround the bacterial cells (Fig. 6G).
H. ducreyi association with ECM proteins at the pustular stage. (A through C) Low-power images at the pustule base of consecutive tissue sections stained for H. ducreyi (green) and for collagen (A), fibronectin (B), or laminin (C) (red). Arrows indicate bacteria at the pustule base. Arrowhead in panel C indicates remains of the basement membrane. Bars, 100 μm. (D) Section stained with polyclonal anti-type I collagen (red) and MAb BB11 (green). Note the colocalizing signals between collagen andH. ducreyi (yellow). Bar, 25 μm. (E) Section stained as in panel D. Bar, 25 μm. (F) Pustule within a section stained with polyclonal antifibrinogen (red) and the anti-H. ducreyiMAb BB11 (green). Note the colocalizing signals between the bacteria and the fibrin strands (yellow). Bar, 25 μm. (G) Higher-power view of a section stained as in panel F, showing fibrin (red) surroundingH. ducreyi (green). Bar, 10 μm.
H. ducreyi associated with collagen in vivo. H. ducreyi binds to type I and III collagen, fibronectin, and laminin in vitro (5). To localize the organism with respect to extracellular matrix (ECM) proteins in vivo, we simultaneously stained sections for H. ducreyi and MAbs recognizing type I collagen, fibronectin, or laminin.
The anticollagen MAb stained the dermis uniformly in uninfected tissue (data not shown). At 24 and 48 h, collagen stained most brightly in the dermis adjacent to the micropustules. At 48 h, the collagen signals were brightest where the bacteria were most numerous (Fig. 3B), and many bacteria colocalized with type I collagen in these areas (Fig.3C). Similarly, at the clinical end point, the brightest collagen staining was at the pustule base where H. ducreyi was clustered (Fig. 6A). H. ducreyi frequently colocalized with collagen in this area (Fig. 6D) and often appeared to follow the contours of the collagen fibers (Fig. 6E).
In contrast to collagen, fibronectin stained most brightly in the subpustular dermis somewhat distal to the pustule base (Fig. 6B). Fibronectin and laminin outlined dermal capillaries (Fig. 6B and C). Laminin was present in the basement membrane, which was disrupted below pustules at 48 h and at the clinical end point (Fig. 6C).H. ducreyi colocalized with fibronectin and laminin in only 1 of 12 specimens; otherwise, no association was observed between H. ducreyi and either fibronectin or laminin in vivo (data not shown). These data showed that H. ducreyi associated with type I collagen in vivo.
In this study, we localized H. ducreyi in tissue samples from papular and pustular stages of disease in the human model of infection. At the clinical end point and as early as 48 h postinoculation, H. ducreyi colocalized with PMNs, macrophages, collagen, and fibrin. The organism remained extracellular through the pustular stage of disease. Little to no colocalization was observed between H. ducreyi and other eukaryotic components, including keratinocytes, fibroblasts, Langerhans' cells, T cells, fibronectin, and laminin.
In this study, we included specimens from papules and pustules harvested at 24 and 48 h after inoculation. Consistent with an earlier study (20), the cellular infiltrate in these samples was similar to that of pustules from the clinical end point. The main difference was that the cellular infiltrate at 48 h had not yet coalesced into the organized pustule seen at the clinical end point. The paucity of bacteria in samples harvested at 24 h precluded our ability to localize H. ducreyi that early. By 48 h, however, the bacteria were already present in the dermis and pustule, where they are found at the clinical end point. Furthermore, the associations of the bacteria with eukaryotic components seen at the clinical end point were under way by 48 h. Thus, the organism's location and its association with phagocytes, collagen, and fibrin began early in the disease process and remained unchanged through the pustular stage of disease.
The persistent association of H. ducreyi with PMNs and macrophages through the pustular stage suggests that the organism is able to resist killing and clearance by these professional phagocytes. Bacteria have evolved several mechanisms for countering the attacks of PMNs and macrophages. One such strategy is to survive or avoid phagocytosis. We detected no bacteria inside the phagocytes, suggesting that resistance to phagocytic killing is not due to intracellular survival after uptake. Rather, H. ducreyi may survive by either evading phagocytosis or escaping the phagocyte. Another strategy is to suppress or counteract the respiratory burst of PMNs, which is most effective on phagocytosed bacteria and those in close apposition to the PMNs. H. ducreyi has been reported to both induce the PMN respiratory burst and resist its bactericidal effects in vitro (17).H. ducreyi produces a periplasmic copper- and zinc-dependent superoxide dismutase, which may protect the organism from the lethal effects of superoxide radicals produced by the respiratory burst (21, 22, 27).
Despite in vitro evidence that H. ducreyi can adhere to and invade keratinocytes (8, 11, 15), we found no evidence that H. ducreyi directly associates with keratinocytes at the papular or pustular stage of disease in vivo. The inoculation device punctures the skin to 1.9 mm, and the thickness of upper arm epidermis varies from 0.03 to 0.15 mm. Thus, we expected that most of the inoculum was delivered to the dermis. To test the possibility that this artificial route of inoculation bypassed the epidermis, we localized H. ducreyi immediately after inoculation. Although principally seen in the dermis, H. ducreyi was found in the epidermal layer, suggesting that the bacteria are available for interactions with keratinocytes in the human model.H. ducreyi may transiently attach to keratinocytes prior to 48 h; however, these data suggest that adherence to keratinocytes is not a major feature of experimental infection. The epidermal swelling around micropustules indicates that the keratinocytes are activated by 24 h and may play an important role in the host response to H. ducreyi by secreting cytokines such as interleukin-6 (IL-6) and IL-8 as has been shown in vitro (15, 33).
Although the ability of H. ducreyi to invade fibroblasts has been disputed (1), a number of other studies have shown that H. ducreyi invades fibroblasts and epithelial cell lines in vitro (18, 19, 23, 30, 31). We found no evidence by confocal microscopy or TEM of H. ducreyi invading these cell types in vivo. In adherence and invasion assays, 106 to 107 bacteria are allowed to interact with 105 eukaryotic cells. In the human model, infection is achieved with 1 to 100 CFU. Thus, invasion may occur at "pharmacologic" doses of the organism relative to the "physiologic" doses in the model. Additionally, in vitro assays cannot take into account all the complexities of the host environment and immune response. We cannot exclude the possibility thatH. ducreyi invades cells at the ulcerative stage of disease or transiently prior to 48 h; however, invasion is not a significant part of the organism's life cycle at the papular and pustular stages.
H. ducreyi colocalized with fibrin in pustules, as evidenced by TEM and confocal microscopy. During cutaneous wound healing, fibrinogen is either released from platelets or produced by fibroblasts and is cleaved to make fibrin, which serves as a scaffolding for PMNs infiltrating the wounded site (16,24). The organism's interaction with fibrin may occur via a receptor-ligand interaction or may be a less specific consequence of fibrin deposition in the area.
Collagen is the major component of the dermis, and H. ducreyi binds to type I and III collagen in vitro (5). In the present study, we showed that H. ducreyi colocalized with type I collagen in vivo. This interaction was seen as early as 2 days postinoculation and persisted at the pustular stage of disease. H. ducreyi did not bind, however, to fibronectin or laminin, which the organism binds to in vitro (5). These data demonstrate that binding to collagen but not fibronectin or laminin is a biologically relevant phenotype. Type I collagen is the dominant collagen form in normal skin. During cutaneous wound healing, collagen bundles are degraded by matrix metalloproteases, and new collagen is produced by fibroblasts (16, 24). The first collagen type laid down is type III, which is gradually replaced by type I collagen. These collagen types may be important targets of adherence for H. ducreyi. The organism's adherence to collagen but not keratinocytes in vivo may explain the need to abrade the skin in order for infection to occur.
From these results, we propose the following model of H. ducreyi pathogenesis. H. ducreyi shed from an infected site enters the skin through microabrasions that expose a collagen-rich dermis, which the organism may use for initial adherence and colonization. Bacterial components such as lipooligosaccharide and lipoproteins stimulate the innate immune system to recruit phagocytes and promote T-cell homing. Simultaneously, the process of normal cutaneous wound healing begins. Both processes involve expression of cytokines and chemoattractants by resident cells, including keratinocytes and fibroblasts. PMNs and macrophages are recruited to clear infection and cell debris from the wound. Existing ECM is degraded to allow migration of infiltrating cells through the dermis, while activated fibroblasts produce new collagen and fibrin that serve as a matrix for the migrating cells. A fibrin clot filled with phagocytes forms at the epidermal level. In the absence of infection, keratinocytes would migrate to close the wound and the fibrin clot would be sloughed. However, H. ducreyipersist at the base of the wound, and this continued bacterial presence stalls the wound-healing process at the inflammatory phase. Thus, the chancroidal lesion could be seen to represent the failure of a wound to heal because infection could not be cleared.
In summary, we have shown that H. ducreyi associates with PMNs, macrophages, collagen, and fibrin in vivo and that the organism remains extracellular through the pustular stage of disease. Experiments to extend these observations to the ulcerative stage with naturally occurring chancroid are in progress. These findings identify collagen and fibrin as potentially important targets of adherence and demonstrate that evasion of phagocytic killing may be critical to the survival of the bacteria and to the pathogenesis of disease.
We thank Cliffton Bong, Kate Fortney, Royden Young, and Beth Zwickl for help with the clinical trials, Exing Wang for assistance with the confocal microscope, Carrie Phillips for use of the cryostat, and Cathy Ison for providing MAb BB11. We thank Byron Batteiger, Antoinette Hood, and Tricia Humphreys for helpful review of the manuscript.
This work was supported by Public Health Service grants AI27863 and AI31494 from the National Institute of Allergy and Infectious Diseases (NIAID). M.E.B. was supported by Public Health Service grant AI09971 from the NIAID. The clinical samples used in this study were obtained from clinical trials supported by the Sexually Transmitted Diseases Clinical Trials Unit, through contract NO1-AI75329 from the NIAID, and by Public Health Service grants MO1RR00750, AI40263, AI38444, and AI32011 from the NIAID.
Editor: J. T. Barbieri
Received 6 November 2000.
Returned for modification 3 January 2001.
Accepted 11 January 2001.
Copyright © 2001 American Society for Microbiology
Alfa M. J.,
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Infection and Immunity Apr 2001, 69 (4) 2549-2557; DOI: 10.1128/IAI.69.4.2549-2557.2001
You are going to email the following Haemophilus ducreyi Associates with Phagocytes, Collagen, and Fibrin and Remains Extracellular throughout Infection of Human Volunteers


text:
FROM node:14.11.0-alpine3.12

RUN npm install -g openapi-examples-validator@4.4.0

ENV NODE_OPTIONS="--unhandled-rejections=strict"
ENTRYPOINT ["openapi-examples-validator"]
CMD ["--help"]

redpajama_set_name: RedPajamaGithub


This weekend, the YouTube FanFest returned to Singapore, bringing excitement, hilarity and some wonderful YouTubers along with it. The event was made up of three live shows and a chaotic red carpet event, giving fans the unique opportunity to connect with their online heroes. It brought together both international and regional YouTube creators, who have a shared audience of over 60 million subscribers. There was stand up comedy, questions and answers and even a surprise visit from the Black Eyed Peas' Apl.De.Ap, who came to spread the word about his new record label- BMBX Entertainment. The two hosts, Dom Lau and Dee Kosh, were amusing and highly engaging-getting the crowd excited with some comedy dance moves and a few videos they had put together.
The evening performance on Saturday sold out quickly and exceeded expectations! Local stars 'Tree Potatoes', who answered some questions before performing a hilarious improvised scene, opened the show. Next came Alodia, a cosplayer from the Philippines, whose outfit changed no less than three times during her brief appearance. Bethany Mota, a beauty guru from the states, came out next, to answer a series of tweeted questions. Fans threw all sorts of gifts onto the stage for her- the most bizarre being a pineapple!
One of the highlights of the weekend was the red carpet event, which allowed people who hadn't been able to get their hands on tickets to see the stars in person. Credit must go to the YouTubers, who all took the time to sign, and take pictures with as many fans as possible. The fans went wild for Bethany Mota, Troye Sivan, Tyler Oakley and Ryan Higa- who seemed to be crowd favorites. The enthusiasm in the atmosphere was infectious, and the feeling of anticipation was shared amongst anassemblage of an estimated 1,000 fans.
In response to roaring chants of 'Troyler' from the crowd, Troye Sivan and Tyler Oakley then walked onto the stage. The duo answered fan questions, which resulted in them doing impressions of each other and wearing lipstick! The show was closed by the brilliant musical act- Trick. Trick were a perfect end to a great night, with their seamless rapping and evident charisma.
All in all, the weekend was a conclusive success, and we hope the FanFest will be back for more fun in 2015!


Below is a list of a few pet friendly hotels near Heathrow Airport, so you can start your trip relaxed and in comfort before travelling your pet abroad.
Call 020 7660 0681 for more information on the hotel's pet policy and possible charges.
Call 020 8759 4888 for more information on the hotel's pet policy and possible charges.
Call 020 8759 2424 for more information on the hotel's pet policy and possible charges.


Our Special Care Nursery provides ongoing care for sick / premature babies not yet ready for discharge to home. Parents are encouraged to visit their baby in the Special Care Nursery at any time. However, occasionally they may be asked to leave the nursery while a procedure is in progress.
The latest equipment should your baby happen to be unwell.
Expert nursing and medical care and equipment should your baby require CPAP ventilation.
Assistance for babies needing full ventilation while waiting transfer to a Neonatal Intensive Care Unit.
Babies from the age of 34 weeks gestation can be admitted to our Special Care Nursery.
Due to babies' increased risk of infection, a strict visiting policy is implemented for all other visitors. If you have a baby admitted to the Special Care Nursery you will receive a Parent's Information Booklet which details the visiting policy and other information pertaining to the nursery.
NB. Visitors are limited to two visitors per baby, and all visitors must wash hands thoroughly on entry to the nursery.


text:
The Dunn List
Csonka Reviews
wrestling / Columns
Evolution Schematic 10.27.07: Chris Jericho (Version .222) [Section 1]
October 27, 2007 | Posted by Mathew Sforcina
Writer's Notes
Well, this is a case of my laziness and logical subject matter being one and the same. Who else would one do right now, than the man that the net is hoping, PRAYING, is coming back soon, what with those darn videos? The fact that I did him a couple of years back and thus it's probably new to most of you AND doesn't need that much updating it just a cool little bonus.
Also, if you are at all interested, there is a video up on Youtube right now of me, a.k.a Massive Q, wrestling Fat Momma from Season 1 of 'Who Wants To Be A Superhero?' and Chewbacca, as well as a promo from me and Fat Momma, all from the Supanova… Whatever they called it, it was a Nerd Convention. As a nerd I can call it that. I have not linked you to it directly since A) it's easily found and B) you can't then complain that I've wasted your time since you'll have to seek it out to find it and thus brought it on yourself. Regardless, as handicap celebrity 'matches' go it's funny. And for the record, I deliberately slipped, really, shoot, I just pretended to slip.
Note, the following ES is rated "HWMNBN". It contains the use of He Who Must Not Be Named.
Ego.
Ego ego ego.
I mean, it's so obvious; it seems redundant to talk about. Chris Jericho is, without question, one of the most egotistical men to ever step into the squared circle. Not that that's a bad thing. After all, to get anywhere in the business, you have to have some ego. And Chris Jericho has lots and lots. And it's worked, obviously. First ever Undisputed World Champion, a member of the Golden Five Club (True Grand Slam Division), and hero to millions.
Not that's always been the case. Jericho's ego has, at times, been grating and tiresome. We haven't always liked it. And at times we've adored it. But Jericho has remained constant. He hasn't changed, just our perception of him has. His ego has stood by him, and taken him to the highest highs this sport has.
As well as some really low lows.
Origins- Born in New York, raised in Canada. "Go Screw Yourself, Eh?"
Chris Jericho was born in New York, the town in which his father played Ice Hockey for the New York Rangers as JR likes to inform us. But while he was born in America (and thus, technically, could run for President if he really wanted to) he was raised in Canada, Manitoba, Winnipeg. There he played sports, doing well in field hockey (which makes sense, since his dad was so good at ice hockey) and water polo (which kinda makes sense I guess, water's just warm ice after all). And then he set his sights on the world of Professional Wrestling.
After getting a degree in journalism, a rare case of Jericho's ego taking second place to common sense (or perhaps his over-powering ego had not yet formed), he began his training in the Hart Brothers Training Camp, a.k.a The Hart Family Dungeon. After a few months, in late 1990, Jericho debuted professionally.
Debut- Sudden Impact. Sounds like a bad Disaster Movie.
Jericho quickly formed a team with Lance Storm, the man Jericho fought in his first professional match. They were called Sudden Impact, and they were, well, young and full of energy and pure athletic talent. They did have some success, being recognized as the first ever Canadian Rocky Mountain Wrestling North American tag team champions, which must be impressive, it's so long.
The first couple of years for Chris Jericho were slow and for the most part uninteresting, at least looking back, I'm sure for him it was just as important as right now. He split up from Lance Storm, and basically learned the ropes and paid his dues. It was during this point that, ironically considering he was trained in the Hart family Dungeon, he molded himself after Shawn Michaels, he looked and wrestled in a style similar to him. Obviously his ego was not really formed at this point, he felt he needed to copy someone successful rather than just be himself.
But after a couple of years, Jericho's career began to build steam. He began to wrestle outside of Canada, touring the San Francisco area with Bay Area Wrestling. He didn't do much that was memorable, but he impressed the right guy to start getting work in Mexico, where he went by the handle of Corazon de Leon, lit. Heart of the Lion. And at this point, Jericho's ego began to assert itself. After all, he was now touring Mexico as well as Canada, he had to be doing something right. And almost immediately, he began to gain ground. He began to team again with Storm, and regained the CRMWNA Tag Titles. He then, one week later, won the CRMW International/North American Title. He would hold the titles for a while, but they did not propel him into the next level, at least at first. A few months after these wins, Jericho took the next step in his career, and began to wrestle in the EMLL company in Mexico.
Phase 1b- Jericho is not one to doubt El Dandy.
It took a few months, but Jericho would win gold in this prestigious company, winning the company's tag titles with his partner El Dandy, beating El Texano and Silver King. He would defend this title for a while, and after a short tour of CWA in Europe, Jericho would return to Mexico and would win the NWA Middle Weight belt in Mexico City, a title he would go on to hold for just under a year. Boosted by his win, within the month Jericho won the CRMW Commonwealth Mid-Heavyweight title. Alas this would not last long, for a couple of weeks later Jericho lost this title to his by now former partner Lance Storm.
This hurt Jericho's ego, so he looked for a way to get away from Canada for a while, and found it in Japan.
Phase 2- Lion Do…what exactly?
He debuted for the WAR promotion in Japan, going by the name Lion Do. But WAR did not use him enough, and he needed to find another company to work for as well, and he found one in America, Smokey Mountain Wrestling. But his ego had taken a blow with his loss to Storm, and thus he needed a partner. And he got one, in…Lance Storm?
Well, it makes sense. They did know each other, and in Jericho's eyes, if he had just beaten him, why not team with him, and remove one obstacle? The duo were dubbed The Thrillseekers, since by then they must have realized that Sudden Impact as a name sucked and besides, Lance Storm is nothing but a thrillseeker. The rest of 1994 was uneventful in terms of long term effect, in that while Jericho probably learnt a great deal and got his ego back to it's normal level (which would be severely inflated), nothing much happened that is worth noting.
It was 1995 that saw Jericho begin to gain ground again. He had won the Junior Heavyweight Tournament in New Mexico, a prestigious tournament, in March. He had lost to Gedo in the finals of the WAR International Junior Heavy Weight Belt Tournament, but he had beaten him for the belt later on, and had a huge successful title defense against Ultimo Dragon at WAR's 3rd Anniversary show.
By this time, he had split up from Storm again, and feuded with him over the CRMW Commonwealth Mid-Heavyweight Title, winning it in May of 1995. But the year was capped off with a loss in the second round of the 1995 Super J Cup 2nd Stage, losing to Wild Pegasus (a.k.a Chris Benoit). So at this point, Jericho needed another ego boost, or at least another playing field. And he found the one that everyone was talking about.
Phase 3- What else is there to say, except EC-F'n-W?
February 1996, Chris Jericho debuted in ECW. But the next major belts he would win would come in WAR, where he and Gedo (Jericho obviously, at this time, was working under the "If you can't beat them (easily), join them" philosophy) won the WAR International Junior Tag Team titles by beating the team of Yuji Yasuraoka and Lance Storm. He would also defend the belts successfully against the duo of Jushin "Thunder" Liger and Takaiwa, a formidable team.
Back in ECW, Jericho's first major problems were with Tazz, who was on his "Path Of Rage", trying to get Sabu to fight him. Chris Jericho put up a good fight, but fell to the Tazzmission, thanks to Tazz working on Jericho's neck, although the official verdict was a Jericho win via DQ, thanks to Tazz keeping the Tazzmission held on after the bell. Tazz continued to assault Jericho after the match was over, causing fellow Hart trained wrestler Brian Pillman to come out…and watch on in glee.
Jericho continued to alternate his ECW, WAR, Canada and Mexican dates in this time, which would explain why he didn't really do that well for the first half of 1996, too much rushing about. But eventually, Jericho's natural ability and ego would lead to his next major title, at Hardcore Heaven 1996, where Jericho pinned Pitbull #2 to win the ECW TV Title. His reign would only last 3 weeks however, for when he defended the title at the Heat Wave 96 show in a 4 Way elimination match against Pitbull #2, Too Cold Scorpio and Shane Douglas, Jericho would be the first man eliminated, being pinned by Scorpio. Jericho then demanded, and got, a one on one match with Scorpio at the next major ECW event, 'The Doctor Is In'. Jericho would be pinned by Scorpio.
This, like most major losses at this point in Jericho's career, affected him. So he looked for a new company to wrestle in. And this time, he stepped up and became a member of WCW.
Phase 4- "You Wanna Be Famous?"
Chris Jericho's first WCW match was a good start, beating Mr. JL (a.k.a Jerry Lynn). His first major WCW match, his PPV debut was less successful, with a loss to Chris Benoit at Fall Brawl 1996. Chris Jericho was, at this point, for lack of a better way to put it, a happy-go-lucky kinda guy. He was always smiling, and shaking hands with the fans and all that. And why not? He was in WCW, where the big boys play, his career was improving and all that, why not be happy?
But he was unhappy when he got his first major shot at the WCW Cruiserweight Title, against Syxx, a.k.a X-Pac at Halloween Havoc. For Syxx was a member of the nWo, and the referee for the match was Nick Patrick. Who was in the nWo's back pocket. And, surprise surprise, Patrick was biased and in the end quick-counted Jericho's shoulders down. Jericho responded by standing up for all the mistreated WCW Wrestlers who Patrick had cheated out of wins and challenged Patrick to a match at the next WCW PPV, World War III. But, just to be fair, Jericho wrestled the match with one hand tied behind his back, what with him being a real wrestler and Patrick not being a real wrestler. But thanks to Jericho's HBK worship, a Superkick gave the fans a small amount of revenge on Patrick, as well as Long, who was in Jericho's corner for moral support/to stop the nWo getting any funny ideas.
Jericho then survived for a while in the World War III match itself, but fell when the wrestlers all entered the one ring. The rest of 96 was uneventful for Jericho, he would be a part of WCW's Cruiserweight division, but would not do anything notable. Although he would win the "Newcomer of the Year" award as voted on by WCW fans. It was not until the start of 1997 when Jericho, as part of WCW's talent exchanges, began to work for New Japan Pro Wrestling as well as WCW. This seemed to give Jericho an (what else) ego boost. He won the tag match he was involved in at the XXXIVth Clash of the Champions. Jericho tried, but lost to Masahiro Chono at nWo Souled Out 97, which is understandable, what with it being an nWo run and controlled show.
But he didn't let that loss slow him down, he continued to work hard and stand up for the fans, and got a US Title shot at Superbrawl the next month, although he lost in a good match to Eddy Guerrero. That put Jericho back down the pecking order, and he had to re-earn his position, getting relegated to lower down, while also working NJPW every so often. But Jericho kept his head down, and continued to quietly build wins, respect and his ego. And so, after tying for 3rd place with Jushin "Thunder" Liger and Shinjiro Otani in New Japan's Top of the Super Jr. Tournament, on a special Saturday episode of Nitro on June 28th, 1997, Chris Jericho beat Syxx to become the new WCW Cruiserweight Champion.
Phase 4b- Chris Jericho with a belt… and he's a good guy?
Jericho was proud of his new title, and after beating Ultimo Dragon at Bash At The Beach, was looking forward to a long and successful title reign.
He almost immediately lost the belt to Alex Wright.
Phase 4c- Chris Jericho without a belt… and he's still a good guy?
Jericho got his rematch at Road Wild, but came up short against the German wrestler. But he then got another rematch, and regained the belt.
Phase 4d- Ok, Jericho, belt…STILL a good guy?
Jericho quickly regained his composure and went back to becoming a fighting champion. He defended his belt against Eddy Guerrero, who had recently snapped and wanted the title badly, at last ever Clash of the Champions. He then defended it against Eddy again at Fall Brawl.
And lost the belt.
Phase 4e- Here we go!
Jericho would not let the loss faze him, at least at first. He still kept up his bouncing happy go lucky act, and got some wins under his belt, beating his old partner Gedo at Halloween Havoc, and getting a surprising win over Scott Hall on an episode of Nitro. He then lost his shot in the World War III match, but then almost everyone lost that. But then something funny happened. Jericho began to lose on Nitro. Often, and continuously. He then would beat up chairs, and then he eventually attacked WCW Ring Announcer Dave Penzer. After apologizing to Dave, on the first Nitro of 1998, Jericho lost to US Champ DDP in less than 2 minutes, to which Jericho re-snapped. And then, Jericho got a WCW Cruiserweight title match at Souled Out 1998, against Rey Mysterio Jr. And Jericho destroyed Rey's knee, and won the match, won the title, and 'stole' Mysterio's knee, or at least his career for the better part of several months.
Phase 5- Jericho, our Paragon Of Virtue.
Jericho's ego had finally manifested itself. Jericho was sick and tired of being mistreated, and started to claim that there was a conspiracy against him. He also began collecting trophies, Rey's knee, Juventud Guerrera's mask (at Superbrawl). At then Jericho fought Dean Malenko at Uncensored 1998, where Jericho (who had begun claming that he was the 'Master of 1004 Holds' as opposed to Malenko's 1001, despite the fact that most of Jericho's holds were just an armbar, and an ARM-bar, and an arm-BAR, and an ARM-BAR, and…) made Malenko tap out. Malenko then went 'home', disgusted with his loss.
This lead to Jericho taunting Malenko mercilessly on "Monday Night Jericho". He now had the Cruiserweight Belt, Rey's knee, Juvi's mask, and Dean's Dignity. He would continue to rip Malenko week after week, not letting up. He also added a trophy or two, beating Prince Iaukea at Spring Stampede and then taking his Hawaiian Towel. And then Jericho's ego got the better of him.
At Slamboree, there was a Cruiserweight Battle Royal to determine who would get the shot at Jericho's title immediately following it. Lots of cruisers were in the match, including a masked newcomer, Ciclope, who somehow managed to get to the end, along with Juvi, who then eliminated himself? Ciclope then unmasked, perhaps to avoid Jericho claiming it as a trophy to reveal…Dean Malenko!
Phase 5b- I love the Killer Kowaliski Kl…Clause.
Jericho lost the title in quick fashion, but he had not yet begun to fight. Did he demand a rematch? Did he prove his worth by beating all the other Cruisers? No no no, he began to campaign and, basically, whine about his loss. He claimed that Malenko's name was not on the list of participants in the Cruiser Battle Royal (Ciclope was), and that thus Malenko should not have been allowed into the match. J.J. Dillon said that he needed precedent. And Jericho found it, in the Chapter 11, Section 5, Codicil 8 of the 1934 NWA rulebook, also known as the 'Killer Kowalski Clause', which was an old clause Killer had always demanded upon, in that as champion, he had to know in advance exactly who he would face. but then Dillon, proving how untrustworthy he was, would not allow it. Jericho tried going to Ted Turner, but despite Jane Fonda being a fan, Jericho was out of luck. But eventually, Dean Malenko, tired of Jericho's whining, agreed to vacate the title, and they would fight at the Great American Bash for the belt.
And then Jericho taunted Dean so much that Dean grabbed a chair, hit Jericho with it…and got DQed, thus giving Jericho his fourth Cruiserweight Title reign.
Phase 5c- Monday Night Jericho Baby!
Jericho continued his seemingly unstoppable ride, getting Dean DQed again in their last ever match for the belt. Admittedly, Jericho lost the belt to Rey Mysterio at Bash at the Beach, thanks to Malenko, but Jericho regained it the next night to become a 5 time champion, thanks to the fact that Malenko was suspended at the time, and thus any match in which he interfered would be declared null and void.
But then, at the next PPV, Road Wild, Jericho ran out of excuses, back alleys and just plain luck when Dean Malenko, as special guest referee, counted Jericho's shoulders down and got the belt off Jericho.
Phase 6- No Belt For You!
A couple of days later, Jericho won Booker T's TV Title by beating Booker's brother Stevie Ray.
Phase 7- I mean, Belt For You!
Chris Jericho was now WCW TV Champion, and he was proud of that fact. But it wasn't enough for Jericho. No no no, he wanted more. So, at Fall Brawl, the next WCW PPV, Jericho laid down a challenge to then WCW World Champion Bill Goldberg, title vs. title. And after attempting to mock Goldberg's guided entrance (and getting lost along the way), Jericho came down to the ring (with some rather pathetic pyro) and awaited Goldberg.
But it was, alas, an almost midget, whom Jericho easily beat. So now Jericho began to claim that he held a win over "Greenberg", and began to step up his claims for a title vs. title match, and generally, well, act like an egotistical bastard, since, after all, that's what he is. He gained his own security guards, just like Goldberg's, although they were perhaps a little less…professional. One man, the "Jericholic Ninja" was some loser with a mullet and sunglasses. And the other man, part of "Jericho Personal Security", would become very well known later on. But for now, they were Jericho's guards. And then, on an episode of Nitro, Jericho once again claimed that he would get his Unification match. After Jericho entered the ring with his 'troops', he turned to jaw with some fans while his Goldberg came out.
But then out walked the Real Goldberg with the fake one over his shoulder. Jericho was, surprisingly, shocked, and ran away after tossing a couple of his guards in the way. Jericho then disappeared for a week or so, and then (now with only his JPS guard with him), challenged Goldberg to another fight on an episode of Thunder, but technically won by count-out when Goldberg no-showed (perhaps Jericho, in an attempt to boost his ego/fool the fans challenged Goldberg when he knew Goldberg was not at the arena and thus could claim that Goldberg was afraid of him). But now, he claimed, he was 3-0 over Goldberg! And then the next week, after beating Raven, he laid down another challenge. But this time, Diamond Dallas Page, who was set to fight Goldberg at the next PPV, Halloween Havoc, answered, and the two had a match, that Jericho won by DQ when Goldberg ran out and speared Jericho, almost clear out of his boots.
This marked a lull in Jericho's desire to fight Goldberg, having felt the spear he did not want to feel it again any time soon. So he went back to the other man he was having problems with, Raven. And Jericho beat Raven at Halloween Havoc in a fast paced and very good opening match. He then decided to keep the security team, or at least just the JPS, who was officially named as Ralphus at this time, on the same night that Jericho was speared for a second time, while standing in the aisle way. Then Jericho got distracted by the debuting Bobby Duncum Jr, who got a count out win over Jericho in his debut WCW match on Nitro, Jericho walking out. So at World War III 98, Jericho had a rematch with Duncum for the TV title, a match that Jericho would win thanks to Ralphus' distraction of the ref, allowing Jericho to use the TV Title belt to bash Duncum in the head. Jericho also got to enter the WWIII match itself, but alas did not do well, having just fought a tough TV title match. And then, one week later, Jericho lost the TV title to Konnan of the nWo Wolfpac.
Phase 7b- Jericho, with Ralphus.
Jericho was now fighting 2 fights, while he was still having troubles with Duncum, he now had to try to get 'his' TV title back. But soon enough Konnan vs. Jericho came to the forefront, probably because Jericho stole Konnan's belt, and the two fought at Starrcade 98. But alas, Jericho tapped out to the Tequila Sunrise.
At this point, Jericho gave up on getting gold any time soon, and set his sights on a man who was bothering him, Perry Saturn. And in order to make sure he could beat Saturn, he got into Scott Dickenson's head. Scott, a WCW referee, was upset over Saturn's actions as of late, in terms of their interaction. So after Jericho got into his head, he then began to favor Jericho and be biased against Saturn. Saturn, naturally, was pissed off at this, and asked for a fair rematch. Jericho refused…unless Saturn agreed to wear a dress if he loses, in which case Saturn could have his rematch. Saturn wasn't thrilled, but accepted it.
This turned out to be a mistake, as at Souled Out 99, after the match was changed by the higher ups in WCW to "Loser Wears a Dress for 90 Days", Saturn lost after Ralphus modeled the dress then Dickenson rolled the two men over so that Saturn's small package became Jericho's, and then quick counted Saturn down. Saturn then, as a man of his word, began to wear dresses to the ring.
But after this win, Jericho lost a bit of steam. He wasn't on TV as much. And then at Superbrawl IX, Jericho had to fight Saturn again, and this time Jericho would have to put on the dress if he lost. But when Scott Dickenson was the ref, Saturn didn't trust him and walked out on the match after DVD'ing both Jericho and Dickenson.
At this point, Jericho and Saturn began to have problems with Hugh Morris. But this was only a distraction, as Jericho and Saturn agreed to have one final battle at the next PPV, Uncensored, in a Dog Collar Match. Jericho tried to stop Saturn wearing the dress, which Saturn was now using as a driving force, but it was to no avail, as at Uncensored, after Jericho failed to force Ralphus to wear the collar, and a hard fought match, Jericho was pinned.
Phase 7c- Fading, fading…
This marked the beginning of a death spiral for Jericho. His ego was shot to hell. Jericho lost in the opening round of the US Title Tournament to Scott Steiner (despite Chris Jericho's ornamental sash, which said in Japanese…"Chris Jericho"), then got to reenter the tournament after an injury to Hennig, and thus due to WCW's Rulebook, Page 46, consult 8, the Silent Brian Macnee clause, which states that if a wrestler cannot continue in a tournament, the person who wrestled last that lost will take his place, Jericho got a second chance, since he was last in. Jericho was thus able to replace Hennig (after much whin…discussion with J.J. Dillon and Ric Flair), beat Chris Adams to advance, then in the semi finals, fought Booker T, and lost.
Jericho then almost won the TV title off Booker, but was foiled. This probably would not have happened if he still had Ralphus, but by this time Jericho had decided Ralphus was not worth his upkeep, and had stopped having him as his lackey. But this seemed to be the last straw, and Chris Jericho was gone from WCW screens. Where was he? We would soon get our answer.
Phase 8- Chris Jericho, free agent?
For on June 30, 1999, the WWF web site reported that Jericho had signed with the World Wrestling Federation. But Jericho did not debut immediately, and a lot of people kinda forgot about him. But then on the WWF website, a "Countdown To The Millennium" began. Problem was, it was way to short, it was set to end on a Raw, August 9th. People were a little confused.
Phase 9- Break The Walls Down!
But on that fateful night, Rock was in the ring, talking trash to Big Show as only The Rock can when the countdown ended. And after a quick light show, new music hit, the Titantron showed New York, then a Stripper…
Then 'Jericho'.
And the place went nuts. But not for long. For Jericho, sorry, Y2J, came out with his ego showing and with no holding back. He verbally attacked all the WWF Superstars, insulted the fans, and made a point to insult Rock who was in the ring. Rock responded in kind, and, in the fans eyes, won the battle of the microphones. And Jericho was a little upset over his big entrance getting ruined. His ego was bruised. So much so that instead of doing the logical thing, and go after Rocky, Jericho decided to let Rock's insults slide and try again.
So Jericho, at the first WWF PPV he attended, SummerSlam 1999, he interrupted another popular man, Road Dogg, and insulted the WWF Wrestlers, the fans, Road Dogg, Degeneration X, and Road Dogg's spelling ability. Road Dogg responded in a similar, albeit different way than Rocky, telling Jericho to 'Suck It'.
Jericho finally settled down and focused on one man, that being Ken Shamrock. With his new ally, Howard Finkel (who probably just wanted attention, but that's a matter for another Schematic), Jericho set up Ken and attacked him a few times. This lead to Jericho's first PPV match, set to be against Shamrock (who was a popular and respected guy who was not known to talk much, thus allowing Jericho's ego to soar with his verbal attacks) but then Jericho in a beat down went a little too far and Shamrock got injured, so X-Pac stepped up to the plate to fight Jericho and his newer associate, Mr. Hughes. And it was not the best start, with Mr. Hughes having to deck the ref for a DQ to avoid Jericho losing (once you've been hit with a Broncobuster, while upside down in the Tree Of Woe, is there really any point in trying?). Road Dogg then saved X-Pac from any further beat down.
But that was just Jericho getting his footing. After getting rid of Hughes, who just couldn't cut it (he had dumped Finkel to take on Hughes), a now flunkyless Jericho went after the Intercontinental Championship. It was just that an unusual person was holding it.
Phase 9b- Chris..tina?
For the current WWF Intercontinental Champion was…Chyna. So Jericho got in touch with his Male Chauvinist Pig side, and went after Chyna and her slut-slave The Kat. Jericho generally acted like a prick, his ego convincing him that he could take a woman in the ring, no problem.
Uh…take down a woman in the ring, no problem.
Uh…win the match, no problem. Jericho even went so far as to claim that if he lost, he would go to Sweden and get surgery to become Christina Jericho. But that won't happen, since he was going to win the title at Survivor Series.
But then after kicking out of a Pedigree, laying a wet one on Kat (and possibly making her switch sides, or at least confirming her dual status) and getting some of the loudest cheers from the crowd (most guys, for some reason, like to see a dominate, strong woman get beat on, occasionally), Jericho lost after getting Pedigreed from the top rope.
In the following weeks, Chyna and Kat would taunt Jericho with various surgical instruments and general insults. Jericho responded by breaking Chyna's thumb. So a rematch was signed for Armageddon, Chyna vs. Jericho for the IC belt. And this time round, Jericho got the Walls Of Jericho (the new name for his now adjusted Liontamer. Some people have wondered why he changed when the Liontamer, his old move, was more painful. It's obvious that the Walls is easier to put on, and is also able to be put on anyone, from Trish Stratus to Big Show, whereas the Walls, while more effective, is harder to put on and almost impossible on anyone over a certain height, and was an adjustment that has logic) on Chyna, and there was nowhere for her to go except Tap City. Chris Jericho was OUR New Intercontinental Champion.
After the match, Chyna approached Jericho and…shook his hand. Hmm.
Phase 9c- Ok, so they respect each other. So what?
Jericho and Chyna gained some small degree of respect for each other at this point. But the two didn't like each other by any stretch of the imagination. They just respected each other.
So much so that on an episode of Smackdown, the final of 1999 in fact, the two had another IC title match. One that saw a referee get knocked down, another come out, a steel chair get involved, a back suplex onto said chair, and a double pinfall. The belt was held up for a few days, and then on the first Raw of the new year, Stephanie McMahon-Helmsley, in one of her first acts as the new McMahon in charge, declared that due to the double pinfall, for the first time in WWF history, 2 people were IC champ. Both Chyna and Jericho were champ. Only one could defend the belt at any one time, but if one of them lost the belt, then both would lose it.
This made Jericho and Chyna reluctant partners, who didn't really get on. But they had a common enemy in Hardcore Holly, who managed to get pinfalls over both Chyna and Jericho.
But Steph then realized that her idea was not working, and thus a triple threat match was made for the Royal Rumble, Chyna vs. Jericho vs. Holly, for the Undisputed IC Champion. And in retrospect, putting 'Undisputed' in the title seemed to spur Jericho on. For Jericho got the win and the title by Lionsaulting Chyna (Hey Nute, you missed a name!). He then went on to fight in the Royal Rumble, but alas was eliminated by Chyna in short order, although she was then eliminated straight after. And then…
Phase 10- Jericho's Ego finally gets accepted.
Jericho, now teaming with Chyna on a regular basis, became popular. Being targeted by Kurt Angle, a man the fans were firmly against didn't hurt either. So, suddenly, Jericho was a popular guy, liked by the fans. The first upshot of this was losing the IC belt to European Champion Kurt Angle at No Way Out 2000.
But then Jericho got another chance at Wrestlemania. Kurt Angle, now Euro-Continental (Euro meaning European, Continental meaning Intercontinental) champion, was getting advised by Bob Backlund. And Bob, in an effort to make Kurt tough and make him all that he can be, set up a match at Wrestlemania 2000. Angle vs. Jericho vs. Chris Benoit, who both men were having problems with, for both the IC and Euro belts, one after each other. And Angle did not have to be involved in the falls. Angle, when he learnt it was Bob he did this, locked the Crossface Chickenwing on Bob, but he couldn't get out of the match.
And Jericho had some negatives, and some positives. Sure, Benoit pinned him with the diving headbutt to win the IC belt. But he pinned Benoit with the Lionsault (Back when that was a possible, likely occurrence. The Lionsault's decrease in effectiveness over the following years is more a matter of guys getting used to getting hit by it and thus preparing themselves better, something DAVE is notorious at not getting a grip on) to win the European Title.
Phase 10b- Chris Jericho, Champion of Europe!
The very next night, Chyna turned on Jericho, and cost him the European title to Eddie Guerrero when she became his Mamacita.
Phase 11- Chris Jericho, pissed off good looking Canuck.
But Jericho, to his credit, did not let that faze him. He began to go after Eddie and Chyna, but soon enough got distracted by another man and his woman.
World Champion HHH, with his wife Stephanie. And now with McMahon behind him.
Jericho challenged HHH to a match on the April 17th episode of Raw, and made various disparaging remarks about Steph. Something along the lines of her being a filthy, disgusting, dirty, skanky, brutal, bottom-feeding, trashbag ho, or words to that general effect. HHH then agreed to the match.
And then everything changed. Jericho brought out the APA, Faarooq and Bradshaw, as back up, and HHH knocked out Mike Chioda. And then, Jericho hit the Lionsault, and Earl Hebner, who HHH had been having problems with, came out and counted HHH's shoulders down for the three count. Just like that.
Phase 11b- Chris Jericho, YOUR WWF Champion.
But then 15 minutes later, HHH bullied Hebner into reversing the decision (he had counted fast, a fact everyone agreed upon) in exchange for promising to never touch Hebner again while Earl was a ref. HHH agreed, Hebner reverse the decision, HHH fired him, Pedigreed him, then got his belt back.
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