Objective: To assess whether the culture technique recently developed to isolate Borrelia burgdorferi from patients with chronic lyme disease would improve the sensitivity of the diagnosis of syphilis, especially in HIV infected individuals at high risk for re-exposure to Treponema pallidum.
Methods: A review of the historical literature on cell-wall deficient forms of various spirochetes, especially T. pallidum, was undertaken in an attempt to trace parallels between the apparent insensitivity of serologic and gene amplification techniques used in lyme and what may be a similar insensitivity in syphilis diagnosis.
Results: The sensitivity of non-treponemal tests in the diagnosis of syphilis has historically been questioned. Many pre-1970 authors repeatedly stated that latent syphilis was most likely maintained in part by a spirochetal life cycle distinct from the easily demonstrated binary fission of T. pallidum. This research was abandoned in light of the efficacy of penicillin. The culture of B. burgdorferi from treated lyme patients, however, suggests the existence of sero-negative chronic lyme disease, and re-opens the old question of a life cycle for T. pallidum.
Conclusion: Syphilis and HIV may interact at levels that cannot be presently measured with standard syphilis serology, especially non-treponemal tests. If serology and direct detection by gene amplification are as insensitive for latent syphilis as they seem to be for late lyme, then it may be useful for syphilis researchers to attempt to parallel the B. burgdorferi culture technique with the venereal treponematoses (keeping in mind that T. pallidum loses virulence quickly in culture), in order to establish a new gold standard in this field as well.
S. E. Phillips and colleagues recently cultured virulent Borrelia burgdorferi from the blood of late Lyme disease patients, even from those previously aggressively treated (1). After 6 years of research, and following upon less successful attempts by others (2), Phillips identified precise conditions to foster the reversion of cell-wall deficient forms of B. burgdorferi back into pathogenic spirochetes. This culture technique undermines the presumed sensitivity of antibody techniques and gene amplification for the diagnosis of Lyme, and re-opens the Pandora's box about the persistence and survival mechanisms of all spirochetes, including Treponema pallidum, the cause of the sexually-transmitted disease syphilis. Both animal and human research has suggested that a similar persistence or survival mechanism is responsible for the latency of syphilis, and indeed for much of the reproduction of T. pallidum in humans, the obligate host.
Both chronic Lyme and chronic syphilis may cause suppression of cellular and activation of humoural immune responses (3, 4). This immuno-regulation explains why these infections are rarely cleared, with little evidence for immunologic resolution of either disease in the human host, despite therapy. The discovery of cell-wall deficient B. burgdorferi surviving in a latent form, with an ability to revert back into presumably pathogenic spirochetes, has important implications for understanding how T. pallidum may survive in a host, treatment notwithstanding. Eastern European venereologists believe treponemes maintain latency by surviving in this different stage of the life cycle, citing precedents in other pathogenic spirochetal diseases like leptospiroses and relapsing fever.
Identifying the latency mechanism in syphilis is important, given the skyrocketing rates of untreated syphilis among homosexual males which preceded the current AIDS epidemic (5). While current thinking holds that AIDS occurs solely as a result of infection with HIV, many basic and pressing questions over AIDS pathogenesis remain unanswered. The lack of an effective vaccine, absence of an applicable animal model, and few consistent clinical benefits from the latest combination therapies (HAART) continue to beg the question as to whether other co-factors are necessary for HIV susceptibility and progression toward AIDS.
Developing better syphilis diagnostics in HIV-infected populations is warranted in light of the epidemiological association of past syphilis and both HIV seroconversion and the development of AIDS; the immuno-regulatory effects of re-infection with T. pallidum; the insensitivity of syphilis serology among HIV-infected persons; and the millions of syphilis cases known to have gone untreated or inadequately treated among these populations worldwide.
Efforts to culture virulent treponemes in the binary fission stage have so far been unsuccessful. It may therefore be that a concerted effort, such as applied to Lyme, could reveal T. pallidum as an etiologic agent in sexually-acquired AIDS.
Historical review of spirochetal latency mechanisms and/or life cycle
For decades, theories have been advanced postulating a life-cycle survival mechanism for T. pallidum. Observers in several American centers in the 1940s and 1950s, as in Russia and Hungary, found evidence suggesting atypical forms of treponemes (6 - see figs. 3-9). These findings are summarized in a 1966 bibliographic review by R. R. Willcox (7).
Such a mechanism was sought in order to explain the latency and many of the anomalies observed between clinical syphilis and the classically accepted life cycle of T. pallidum. An example is the rapid re-appearance of infectious syphilis relapse, eg. condyloma lata, which cannot be explained by the traditionally accepted 33-hour life cycle, the binary fission time. Suddenly, in a day or two, patients demonstrate a billion treponemes where they didn't have any before.
An altered form of T. pallidum would also help serve to explain why aspirate virulent for rabbits, when drawn from some human syphilitics, was spirochete free (8), while conversely, a slowly developing rabbit orchitis or failure to infect often occurred with an aspirate teeming with treponemes. At other times, establishing an infection required twice passaging in rabbits, suggesting latency in the intermediate host (9). Inoculations from the viscera of mice were often virulent for rabbits, but the mouse rarely showed treponemes.
T. pallidum has dozens of strains globally (10), and may survive in forms other than spirals (11), with tropisms for cells, organs, or the central nervous system.
The 1950s even saw a movement to change the taxonomy of T. pallidum to account for the animal and laboratory phenomena and latency and relapse in humans (12). At the 1962 WHO symposium on treponemes, Herman Beerman's opening address emphasized the need to continue exploring all these phenomena (13). The two principal controversies centered around 1) whether a latency mechanism exists, be it facultative or obligative, and 2) whether some altered form of T. pallidum - whether buds, cysts, gemmae, etc. - is propagative or "germinative" for new treponemes.
Unfortunately, these research issues were eclipsed by the overwhelming success of penicillin in the treatment of early syphilis in the post-war period, subsequently followed by the diversion of most STD funding into HIV/AIDS research starting in the early 1980s. These still-unanswered questions about syphilis are not even referred to in more recent textbooks dedicated to syphilis research (14).
The deficient cell wall mechanism may be the only way to explain the relapsing phenomena in syphilis and persistence of T. pallida, treatment notwithstanding (15).
HIV research: many hypotheses, few results
Establishing a new gold standard for the diagnosis of syphilis may also help answer long-standing questions over whether co-factors are necessary for the progression of HIV disease, in light of the numerous inconsistencies with current theories of pathogenesis:
The mechanism behind CD4 cell depletion in AIDS still remains unproven. Leading investigators disagree over whether the syndrome is induced by a direct cell-killing mechanism (16), i.e., HIV actually infecting enough CD4 cells to cause AIDS, or is the result of an immunologic mechanism that leads to depletion/apoptosis of the functional CD4-bearing cell (17).
No virulent strains have been demonstrated at the molecular level (18). It is unreasonable to assume a thousand mutations of pathogenic HIV. HIV isolation techniques have been seriously questioned (19) - finding genetic sequences is one thing, but isolating whole infectious virus is quite another. There is still no quantitatively and qualitatively comparable animal model for HIV-1, in contrast to SIV disease in primates, in which many cells are infected, antibody is lost before clinical decline, and anti-retroviral therapy or vaccination often proves beneficial.
Anti-HIV treatment is toxic, only marginally effective, and expensive. The initiation of HAART admittedly causes HIV viral load to drop sharply - in many cases to levels undetectable by genetic analysis - but whereas in most other infectious diseases this would signal complete recovery, this seems not to be the case with HIV, with no sustained recovery after effective viral clearance, following either the initial seroconversion, or subsequent protease inhibitor (HAART) combination therapy. Despite earlier optimistic and anecdotal reports, HAART is proving clinically far less effective than first hoped, complicated by a host of drug interactions and toxicities, and remaining completely unaffordable for the majority of the world's HIV populations.
There is still no HIV vaccine, despite billions in research dollars spent over the last 15 years, and amidst growing confusion over what constitutes protective immunity against AIDS.
Most healthy people may naturally resist HIV. Strong, seemingly protective, HIV-specific Th1 type responses - and even virus isolation - have been documented in many exposed individuals who do not subsequently seroconvert by such laboratory measures as IL-2 secretion (20), CTL activity (often up to 10 times stronger than in healthy HIV-seropositives) (21), PCR , PBMC production of anti-gp120 antibodies (22), and anti-idiotypic antibodies (23).
HIV may be centuries-old among humans. Debates persist over the origin of HIV-1 (24). Despite recent speculations (25), the global phylogenetics of HIV-1 suggest the virus has been in human populations for centuries, perhaps millennia (26), possibly an obligate human retrovirus activated out of latency by the AIDS-inducing co-factors (27). Indeed, evidence from hemophiliac (28) and IVDU cohorts (29) suggests that the control of non-HIV-related factors has a greater impact on disease progression than antiviral strategies.
An impaired host immune status appears necessary for HIV activation (i.e., seroconversion) (30), likely involving a Th1 à Th2 immunologic switch (31), increasingly recognized as the mechanism behind chronic bacterial diseases (32). It is therefore possible that most people exposed to HIV develop effective Th1 type cell-mediated immune responses and will not seroconvert to HIV surface proteins (i.e., develop chronic active disease) in the absence of co-factors intrinsic to their AIDS risk group.
Syphilis in the AIDS era: questions remain
Chief among co-factors for susceptibility to HIV/AIDS may be syphilis, a chronic, systemic sexually-transmitted bacterial disease, rampant among homosexual cohorts immediately preceding the current AIDS epidemic. Among the STDs, a history of syphilis has been found to be the best predictor for both HIV seroconversion and progression to AIDS (33).
While most investigators point to syphilis and other ulcerative STDs as co-factors only for HIV transmission, these infections may play a systemic immuno-regulatory role as well, perhaps activating an otherwise latent HIV infection (34).
Immunoregulatory molecules from chronic syphilitics survived in the plasma used for years to prepare many blood products for the hemoglobinopathies, globulinopathies, and the coagulopathies.
The available evidence suggests immunologic memory in syphilis is poor: while untreated infection results in somewhat effective Th1 type responses in early syphilis, immune deviation away from protective cellular immunity (perhaps in part because of Th2 predominance) is the norm in post-secondary disease. The lack of serologic and clinical anamnesis in later syphilis is demonstrated by asymptomatic re-infection of rabbits (35), guinea pigs (36), primates (37) and humans (38).
Clinical experience from earlier this century suggests infection with syphilis induces a state of immunologic tolerance over time. As Evan Thomas stated, "Within 2 years after infection, untreated syphilis produces immune changes in the host which, with rare exceptions, are permanent and make it impossible for tissues to react to subsequent infection with development of early syphilitic lesions" (39). Other investigators found that this loss of cellular memory is not reversible by any amount of therapy, be it penicillin or older arsenicals (40).
Serum factors in syphilitics may cancel lymphoproliferation (i.e., type IV DTH) and the cytokine production needed for immune upregulation (41), but cells perform normally when they are isolated in vitro, findings which suggest a peripheral inhibition mechanism may operate in vivo after a few months of natural infection with T. pallidum.
The human immune response to both syphilis and now Lyme puts most untreated patients at the anergic, or tolerized end of the spectrum. This is in contrast to HIV, where many display antibodies to core proteins (as in other infections such as hepatitis B), and do not fall ill or seroconvert unless they continue to take AIDS risks.
Neither vaccination, passive immune transfer nor natural infection have ever demonstrated protective immunity to T. pallidum, except for the vaccine work of Miller in 1973 (42). American public health authorities state that there is no natural immunity to syphilis and past infection offers no protection to the patient (43).
Admittedly, some degree of immunity develops during both early syphilis and early Lyme disease, as spirochetes are cleared from lesions by T-helper mechanisms, but in the absence of prompt and aggressive early treatment, this immunity seems to wane, and an intractable latent stage seems to be the normal consequence for the vast majority of patients. Symptomatic late syphilis and late Lyme only occur in a minority of latent cases. It may have been a mistake to characterize the late latent stages of these conditions as a benign condition, and late symptomatic forms as the only morbid or mortal sequelae - these sensitized and more easily diagnosed and treated presentations may only be the tip of the syphilis/Lyme iceberg.
During the first half of the 20th century, there was considerable debate over whether there was excess mortality associated with a history of syphilis (44). Several major investigators, actuaries, and the Oslo (45) and Tuskegee natural history studies all found decreased life expectancy among syphilitics, independent of classical symptoms of late syphilis. The chief causes of death were usually reactivation TB, pneumonias, and cancers.
In animal models, including mice (46) and primates (47), similar outcomes from silent syphilis occurred, but the observers lacked proper immunologic tools, e.g., CD4 cell counts, to measure the extent and type of immune suppression, nor even a reproducible treponemal test until 1949. Laboratory workers demonstrated FTA-ABS negative syphilis in primates in the 1960s and 1970s; many of the animals died prematurely of secondary infections. This may be where to look for an AIDS animal model.
An earlier reference consistent with this thinking comes from J. Earle Moore, head of the syphilis clinic (then known as "Medicine One") at JHU School of Medicine, who asked in 1939 "Is it justifiable to assume, as did Osler, that syphilis actually ranks first, as opposed to its apparent tenth, among killing infections?" (48) The advent of penicillin greatly reduced the dangers of syphilis, but most homosexual cases in the AIDS era were not early cases. The diagnosis, when made in these men, was usually serologic, as the typical signs and symptoms of early syphilis were repeatedly observed to be disappearing in this population (49).
In addition, although the serologic tests for syphilis have existed since the early 1900s, these tests and their modern counterparts are insensitive in the diagnosis of congenital syphilis, reinfections with T. pallidum, neurosyphilis, and more recently, in HIV-infected individuals (50). Among 500 such patients, consecutively examined between 1988 and 1993, none reacted on the VDRL/RPR screen test, and only 11% showed evidence of exposure to T. pallidum by reactive treponemal test - a suspiciously low rate, considering rates of other STDs and the highly infectious nature of syphilis compared to HIV (51).
Anomalies in syphilis serology have been documented in several HIV cohorts since 1988 (52), most importantly the selective loss of treponemal antibody, a phenomenon noted in Toronto (53) and elsewhere (54). The window of investigation is typically only a few months, or at the most 2 years, whereas the typical AIDS patient has been sexually active for an average of 15 to 20 years. Therefore, with rates of antibody loss such as those observed in Toronto, treponemal tests may well be insensitive as an indicator of the interaction/synergy of T. pallidum and HIV at an immunologic level (55).
Many patients in Toronto who still had treponemal antibody were IgM-positive in some bands, as was also documented by Musher’s lab in Houston (56). Detection of T. pallidum among multi-partner individuals at high risk of re-exposure, including homosexual men, is a pressing issue, given estimates of untreated syphilis in this population ranging up to half a million cases at the advent of the modern AIDS epidemic.
Yet syphilis is paradoxically absent as an AIDS-related opportunistic infection, despite the critical importance of cell-mediated immunity in the control of the infection. But, as Musher and colleagues noted in 1990, "a substantial proportion of HIV-infected men may have unrecognized, latent, inadequately treated syphilis. These findings support more aggressive treatment of T. pallidum infection in this patient population" (56). Such treatment was attempted in Toronto, where it was found that presumptive penicillin therapy caused return of treponemal antibody in some cases, if given shortly after seroreversion (57).
There may be an extensive problem with false negative syphilis serology when HIV antibody is present. The question remains: how can we test HIV patients for syphilis, given these serologic problems? To date, the culture of T. pallidum at the binary fission stage on artificial media has not been quantitatively useful, in contrast to B. burgdorferi. The polymerase chain reaction (PCR), which has proven insensitive in the diagnosis of Lyme disease, seems insensitive in syphilis diagnosis as well (58), and is often negative in frank cases involving secondary lesions and neurosyphilis, even in the presence of positive antibody tests (59).
In light of the recent culturing of B. burgdorferi from the blood of patients with late Lyme, it may now be incumbent upon the syphilis research community to attempt a variation of this technique in the blood, CSF and lymph nodes of sexually-acquired AIDS cases, regardless of syphilis antibody test results or clinical history. Applying this technique to T. pallidum could be problematic, however, because the organism only survives in vitro for a few days and a few divisions, and then loses virulence, so it may be more difficult to coax the putative L-forms back into pathogenic spirochetes. But the mere isolation of T. pallidum in seronegative patients without a history of syphilis would be quite hard to explain.
Some prominent AIDS researchers, including Luc Montagnier (27), have repeatedly called for co-factor research to explain why some HIV-infected persons develop AIDS, while others with seemingly identical strains do not. If the diagnosis of syphilis is insensitive, as the Lyme work suggests, then it may be impossible to rule out a role for silent infection (and re-infection) with virulent treponemes in the pathogenesis of AIDS, in light of the already-documented isolation of T. pallidum in HIV-positive individuals without appropriate syphilis antibody (60), and the numerous immuno-regulatory (4) symptomatic (61) and epidemiologic (33) overlaps between the two conditions.
This paper is dedicated to the memory of Stephen Caiazza, M. D., Bernard Fields, Ph. D, and John Hinchman Stokes, M.D. Many thanks to Maria Nunes for research assistance.
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(Click on thumbnail image for full-size
version)
Fig. 1 - Drawing showing typical forms of spirochetes from border of aortic focal necrosis, and all stages of transformation to granular forms. (from Warthin, A. S. and Olsen, R . E. The Granular Transformation of Spirocheta Pallida in Aortic Focal Lesions. Am. J. Syph., Gonor., and Ven. Dis. 14 (1930), p. 436)
Fig. 2 - A view of Spirochaeta pallida under the electron microscope showing continuous envelope or membrane; also end-knob. (from Wile, U.J. Picard, R.G. and Kearny, E.B../ The Morphology of Spirochaeta Pallia in the Electron Microscope. J.A.M.A. 119 (1942), p. 880)
Fig.
3 - Spirochaeta pallida as seen with the electron microscope, with two lateral
protrusions, one of which is shown very clearly to be made up of small spherical
bodies. Meierowsky's observation that a stalk often carries more often than
one minute bud led him to conclude that the buds have the property of dividing.
(Strain P126B (88a) X 14,000.) (from Morton, H. E. and Anderson, T. F. Some
Morphologic Features of the Nichols Strain of Treponema Pallidum as Revealed
by the Electron Microscope. Am. J. Syph., Gonor., and Ven. Dis. 26
(1942), p. 565)
Fig. 4 - Plate VI (from DeLamater, E. D. et al. Studies on the Life Cycle of Spirochetes. VIII. Summary and Comparison of Observations on Various Organisms. J. Invest. Dermatol. 16 (1951), p. 245)
Fig. 5 - Plate 14 (from DeLamater, E. D. et al. Studies on the Life Cycle of Spirochetes. III. The Life Cycle of the Nichols Pathogenic Treponema Pallidum in the Rabbit Testis As Seen by Phase Contrast Microscopy. J. Exp. Med. 92 (1950), p. 246)
Fig.
6 - T. pallidum from human chancre. Buds, uni- and multispirochetal cysts,
free commalike bodies, and others with 2 or 3 denser zones. (Original X 900;
enlargement 3 1/2 diameters. (from Coutts, W.E. and W.R. Coutts. Treponema
pallidum buds, granules and cysts as found in human syphilitic chancres and
seen in fixed unstained smears under darkground illumination. Am. J. Syph.,
Gonor., and Ven. Dis. 37 (1953): 29-36.)
Fig.
7 - Treponema from contents of papule in woman suffering from fresh secondary
syphilis; negative stained; magnification X 40 000; b = basal granule; f =
fibrils; s = spore-like structures (from Ovcinnikov, N. M., Delektorskij,
V. V. Morphology of Treponema pallidum. Bull. Wld Hlth Org. 35 (1966)
p. 229)
Fig. 8 - (20) Nichols strain from a 7-day rabbit orchitis. LP - lighter-coloured projections; F - fibrils; (21) Kazan' 2 strain, 14 days' growth. Negative-contrast method. Electron-microscope magnification X 60,000. B-basal granules; F-fibrils; SM-expansion with osmiophilic granules. (22) T. pallidum from a papule from a woman with fresh secondary syphilis; Negative-contrast method. Electron-microscope magnification X 140,000. S=spore-like structure; F=fibrils. (from Ovcinnikov, N. M., Delektorskij V.V. Further Study of Ultrathin Sections of Treponema pallidum under the Electron Microscope. Brit. J. Vener. Dis. 44 (1968), p. 11)
Fig. 9 - Diagrammatic representation of the evolutive life cycle of Treponema pallidum (from Di Virgilio, G. et al. An atlas of the evolutive life cycle of the human pathogen Treponema pallidum. Rieck's Printing Co., Reading, Pa., 1970)
Fig. 10 - Dr. John Hinchman Stokes, who spent 50 years trying to understand syphilis, and was first author of the three editions of Modern Clinical Syphilology (Philadelphia: W.B. Saunders, 1926, 1936, 1944)
Other abstracts and papers by John Scythes and colleagues
Déja
Vu: AIDS in Historical Perspective
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aired January 9 & 10, 1996 (repeated September 5 & 6, 1996) on
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