ABSTRACTThe present study described the susceptibility of C4D guinea pigs to cutaneous infection withTreponema pallidumsubsp.pertenueHaiti B strain. The general manifestations of the disease in adults and neonates differ, to a certain degree, from those induced byT. pallidumsubsp.pallidumNichols strain. Noticeable differences between the infections were reflected in the character of the skin lesions, their onset and persistence, and the kinetics of the humoral response. The incidence and dissemination of cutaneous yaws lesions in very young guinea pigs were remarkably different from the low frequency observed in a similar age group of syphilis infection, 100 versus 17%, respectively. Moreover, as opposed toT. pallidumsubsp.pallidum,T. pallidumsubsp.pertenuedoes not cross the placenta. Offspring born to yaws-infected mothers did not produce immunoglobulin M antibodies and their organs, examined by PCR and rabbit infectivity test (RIT), were all negative. Examination of a large number of tissues and organs in adult, neonate, and maternal yaws by PCR and RIT clearly demonstrated that, unlike syphilis, there was a low incidence and short persistence of the yaws pathogen in internal organs. These findings stress the dermotropic rather than the organotropic character of yaws and provide further evidence of distinctive biological and pathological differences between yaws and venereal syphilis.

The target organs of infection in guinea pigs with asymptomatic acquired or congenital syphilis were identified by PCR and in some cases by rabbit infectivity test (RIT). The prevalence of Treponema pallidum DNA was examined in the following seven organs: the inguinal and mesenteric lymph nodes, spleen, liver, kidney, heart, and brain. Test samples consisted of 95 organs from two genetically different strains of female guinea pigs (C4-deficient and Albany) with different susceptibilities to cutaneous infection by T. pallidum and 195 organs from their asymptomatic offspring. Twenty organs from dams of both strains injected with heat-killed T. pallidum and 19 organs from their progeny served as negative controls. The infections of mothers and neonates were documented by PCR, RIT, and serology. Though any of the organs tested could be infected, there was a spirochetal predilection for some anatomical locations, such as the lymph nodes, heart, and brain, regardless of the strain, route of maternal infection, and age. None of the 49 organs collected from control animals were positive by PCR. In infected C4-deficient dams, one to four organs were positive by PCR, whereas the organs of 7 of their 27 (25%) asymptomatic offspring were treponemal DNA negative, despite evidence of immunoglobulin M treponemal antibodies. Comparative analysis done by both PCR and RIT on a limited number of samples showed 90% agreement between results. An examination of multiple samples obtained from single organs demonstrated that even within 24 h of spirochetemia, when most organs appeared to be infected, not all samples from an individual organ were positive by PCR. A specific immunological response in guinea pigs with congenital syphilis was a more consistent parameter of vertical transmission than was an analysis of T. pallidum DNA.

Early stimulation of the humoral and cellular immune response is clearly one of the hallmarks of natural and experimental syphilis.1 The depth and breadth of the humoral immune response in the early stages of disease is represented by antiphospholipid/anticardiolipin antibodies, antitreponemal antibodies (the majority exhibiting extensive cross-reactions with other pathogenic and nonpathogenic treponemes), and a vast array of autoantibodies to blood cells, serum components, and tissue constituents (Table I). Although certain autoimmune diseases may have a microbial etiology, syphilis is unquestionably an infectious disease. It is not, nor does it represent, an autoimmune state. The varied autoimmune antibody responses associated with or accompanying infection do, however, appear to be triggered as secondary reactions. Were it not for the fact that Treponema pallidum ubsp. pallidum is capable of inciting immuno pathologic mechanisms, it would be easy to discount the presence of autoantibodies as little more than the end result of an infection-related immune injury. In fact, tissue destruction alone can favor the induction of autoimmune antibodies if host proteins are sufficiently altered through the enzymatic actions of an offending organism.

OBJECTIVE: To evaluate the effect of ceftriaxone in treating latent syphilis or asymptomatic neurosyphilis in patients infected with the human immunodeficiency virus (HIV).DESIGN: Follow-up study of patients treated at two HIV-based clinics during 16 months from 1989 to 1991.PATIENTS: Patients were those in whom a clinical diagnosis of latent syphilis or asymptomatic neurosyphilis was made, who received all recommended doses of antimicrobial therapy, and who returned for follow-up visits for 6 or more months.RESULTS: Forty-three patients were treated with ceftriaxone, 1 to 2 g daily for 10 to 14 days. Thirteen underwent lumbar puncture before treatment; 7 (58%) had documented neurosyphilis (pleocytosis in 5, elevated protein levels in 6, VDRL reactive in cerebrospinal fluid [CSF] in 7), and 6 had documented latent syphilis (entirely normal CSF). The remaining 30 were said to have presumed latent syphilis. There was no relation between the diagnosis and the selected dosage of ceftriaxone. Response rates were similar in those who had documented neurosyphilis and documented or presumed latent syphilis. Overall, 28 patients (65%) responded to therapy, 5 (12%) were serofast, 9 (21%) had a serologic relapse, and 1 (2%) who experienced progression to symptomatic neurosyphilis was a therapeutic failure. Thirteen patients received benzathine penicillin for presumed latent syphilis; results were similar to those observed after ceftriaxone therapy, with 8 (62%) responders, 1 (8%) serofast, 2 (15%) relapses, and 2 (15%) failures. CD4 cell counts in responders were not different from those who failed to respond.CONCLUSIONS, Even in the absence of neurologic symptoms, half of the HIV-infected persons who have serologic evidence of syphilis may have neurosyphilis. Although ceftriaxone achieves high serum and CSF levels, 10 to 14 days of treatment with this drug were associated with a 23% failure rate in HIV-infected patients who had latent syphilis or asymptomatic neurosyphilis. Three doses of benzathine penicillin did not have a significantly higher relapse rate and may provide appropriate therapy, at least for documented latent syphilis in persons co-infected with HIV. Studies comparing ceftriaxone with 10 to 14 doses of procaine penicillin are needed to determine the most cost-effective treatment for asymptomatic neurosyphilis or presumed latent syphilis in this group of patients.

The Ig class and IgG subclasses of anti-Treponema pallidum antibodies in human serum were quantified using solid-phase enzyme-linked immunosorbent assays. Development of these assays with monoclonal antibodies, each specific for a human immunoglobulin class or IgG subclass, provided quantitative data concerning the major antibody specificities. In patients with primary syphilis, anti-T. pallidum activity was limited almost exclusively to IgG1 and IgM. Coordinate, restricted expression of IgG1 and IgG3 responses inT. pallidum-specific assays was observed with sera from patients with active secondary syphilis. IgG1 and IgG3 accounted for roughly 53 and 43% of the total anti-treponemal IgG antibody activity, respectively. While IgM antibody levels were elevated in the patients with secondary syphilis, IgG2 and IgG4 levels, if present at all, represented less than 10 and 2% of the total IgG activity, respectively. Ig in sera from patients who had been treated adequately for secondary syphilis were restricted almost entirely to IgG3 and IgG1. Considering the low level of IgG3 in serum, disproportionately high percentages of antitreponemal antibodies were found in this subclass during and after treatment for secondary syphilis. The restricted, coexpression of the IgG1 and IgG3 isotypes may reflect the close genetic linkage of the γ1 and γ3 genes and possibly the impact of immunoregulatory mechanisms in response to the induction and expression of autoantibodies which arise during the course of secondary syphilis.

Normal mice and mice displaying delayed hypersensitivity to Staphylococcus aureus were challenged with a lethal dose of Listeria monocytogenes. Nonspecific antimicrobial activity was assessed by inhibition of bacterial growth in the spleen and by increased survival rates. Administration of specific staphylococcal antigen prior to challenge was a prerequisite for the induction of nonspecific resistance. Both the time of administering eliciting antigen and the route were important consideration for evoking the response. Similar responses were seen in 3 strains of inbred mice following immunization with both encapsulated and nonencapsulated staphylococci. Although enhanced resistance as measured by viable counts in the spleens was achieved after 2 injections, protection as measured by survival required 4 injections of S. aureus followed by elicitation with staphylococcal antigens. Nonspecific resistance could be detected as late as 9 weeks after the disappearance of delayed hypersensitivity.