Небольшая зарисовка к ближайшей дискуссии
Есть те, которые лечатся травами , брт, бвт и правильным питанием, чтобы не навредить иммунитету
(и не только к ней, разумеется, и ранее было много подобных, например почти все отсюда
Дебаты )
Извините, но сделать небольшую зарисовку короче у меня не получилось..
Resurgence of Persisting Non-Cultivable Borrelia burgdorferi following Antibiotic Treatment in Mice
Introduction
The agent of Lyme borreliosis,
Borrelia burgdorferi, evades host immunity and establishes persistent infections in its varied mammalian hosts. This persistent biology may pose challenges to effective antibiotic treatment.
Experimental studies in dogs, mice, and non-human primates have found persistence of B. burgdorferi DNA following treatment with a variety of antibiotics, but persisting spirochetes are non-cultivable. Persistence of
B. burgdorferi DNA has been documented in humans following treatment, but the significance remains unknown. The present study utilized a ceftriaxone treatment regimen in the C3H mouse model that resulted in persistence of non-cultivable
B. burgdorferi in order to determine their long-term fate, and to examine their effects on the host. Results confirmed previous studies, in which
B. burgdorferi could not be cultured from tissues, but low copy numbers of
B. burgdorferi flaB DNA were detectable in tissues at 2, 4 and 8 months after completion of treatment, and the rate of PCR-positive tissues appeared to progressively decline over time.
However, there was resurgence of spirochete flaB DNA in multiple tissues at 12 months, with flaB DNA copy levels nearly equivalent to those found in saline-treated mice. Despite the continued non-cultivable state, RNA transcription of multiple B. burgdorferi genes was detected in host tissues, flaB DNA was acquired by xenodiagnostic ticks, and spirochetal forms could be visualized within ticks and mouse tissues by immunofluorescence and immunohistochemistry, respectively. A number of host cytokines were up- or down-regulated in tissues of both saline- and antibiotic-treated mice in the absence of histopathology, indicating host response to the presence of non-cultivable, despite the lack of inflammation in tissues.
...
Non-cultivable B. burgdorferi Resurge in Tissues of Mice at 12 Months Following Antibiotic Treatment
A number of studies by different research groups have shown that C3H mice infected by either syringe or tick, and treated with doxycycline, tigecycline, or ceftriaxone contained persisting non-cultivable
B. burgdorferi in tissues for at least 90 days after completion of treatment
[14],
[15],
[16],
[17],
[18],
[19],
[20]. Others
[28] have speculated that the persisting non-cultivable spirochetes did not induce inflammation and would eventually die out following treatment. Thus, a ceftriaxone treatment regimen was used to treat C3H mice similar to previous studies that consistently resulted in persistence of non-cultivable
B. burgdorferi following treatment
[14],
[15],
[16],
[17] to determine the long-term outcome of treatment, including persistence or demise of non-cultivable spirochetes, and returning of cultivability.
...
Discussion
This study validates a mouse model that can be used for investigation of post-antibiotic persistence of non-cultivable
B. burgdorferi. We utilized syringe-inoculation of cultured
B. burgdorferi, which is not the natural route of infection, but others
[15],
[16] have shown persistence of non-cultivable
B. burgdorferi with tick-borne infection as well...
..Furthermore, the short serum half-life of ceftriaxone in mice as an explanation for persistence of non-cultivable
B. burgdorferi was negated with a study that utilized tigecycline
[14], which has a half-life of 11.6 hours in mice and achieved a serum maximum level 70 times greater than the
B. burgdorferi N40 MBC
[43]. Treatment with ceftriaxone, and high or low doses of tigecycline resulted in the same outcome: persistence of non-cultivable
B. burgdorferi in tissues of treated mice at 90 days after completion of treatment
[14].
Results of this study demonstrated not only persistence, but also resurgence of non-cultivable
B. burgdorferi in tissues of mice at up to 12 months following antibiotic treatment, despite the continued inability to culture spirochetes from tissues. In the absence of the ability to culture spirochetes from tissues of treated mice, this study endeavored to determine the physiologic state of persisting non-cultivable
B. burgdorferi. Non-cultivable
B. burgdorferi DNA acquisition was demonstrated by xenodiagnosis (including transstadial persistence from larva to nymph),
B. burgdorferi spirochetal forms were visualized by immunofluorescence in xenodiagnostic ticks, RNA transcription of multiple
B. burgdorferi-specific genes was detected in the tissues of antibiotic-treated mice at 12 months after antibiotic treatment, and spirochetal forms were visualized in the tissue of an antibiotic-treated mouse by immunohistochemistry. It has been speculated that following antibiotic treatment, persisting non-cultivable spirochetes were non-viable and would eventually be eliminated
[15],
[28],
[44]. Results of the current study suggested a similar trend if the experiment were to be stopped at 8 months, as the prevalence of PCR-positive tissue sites declined with time through 8 months. However, there was resurgence of
B. burgdorferi DNA in tissues at 12 months to levels nearly equivalent to those in untreated persistently infected mice. These findings underscore the difficulty of detecting non-cultivable
B. burgdorferi following antibiotic treatment, as interpretation of xenodiagnosis depends upon timing and number of ticks tested, and the outcome of infection must be measured by analysis of multiple tissues at appropriate intervals. Non-cultivability of persisting
B. burgdorferi is likely a reflection of their limited replication kinetics. In a recent study involving antibiotic-treated macaques, small numbers of spirochetes were found in culture after several weeks of incubation
[22], and others have demonstrated slow outgrowth of spirochetes in cultures from antibiotic-treated humans after prolonged incubation of up to 10.5 months
[45]. In the present study, we attempted to incubate cultures for several weeks, as in the macaque study, but were unable to grow viable spirochetes.
The mechanism for resurgence of non-cultivable
B. burgdorferi at 12 months after treatment remains to be determined, but may be
related to declining antibody response.
Antibody is critical for resolution of arthritis and carditis, as well as global reduction of spirochete burdens in tissues [40],
[46],
[47]. Disease resolution can be maintained and reduced tissue burdens can be sustained in infected severe combined immunodeficient mice by passive immunization with immune serum from persistently infected immunocompetent mice, but disease recurs and resurgence of spirochete burdens occurs as the passive antibody decays
[48]. The antigenic target for maintaining reduced tissue burdens has not been determined, so cause and effect in the current study could not be confirmed
. Antibody titers against several in vivo-expressed N40 recombinant proteins (DbpA, OspC, Arp, BmpA) [49], similar to antibody against B. burgdorferi lysates, were also diminished at all intervals following antibiotic treatment (data not shown). In a related study, recrudescence of non-cultivable
B. burgdorferi following antibiotic treatment was attempted by transient immunosuppression of the mice with corticosteroids without apparent consequence
[15], but that outcome would be expected when spirochete burdens in tissues are under control of antibody.
The current study builds upon similar evidence of non-cultivable
B. burgdorferi persistence in studies involving dogs, mice and macaques.
While it has been concluded that non-cultivable B. burgdorferi is not infectious [16],
we previously demonstrated transmission of B. burgdorferi DNA by ticks that fed upon antibiotic-treated mice to naïve mice, as well as transmission of B. burgdorferi DNA by transplantation of B. burgdorferi DNA-positive heart base and tibiotarsus tissue allografts from treated mice into recipient mice, with dissemination of the DNA in the recipient mice [14]. Transtadial transmission of
B. burgdorferi DNA from larvae that fed upon treated mice to nymphs and then to adults was also demonstrated
[14]. RNA transcription of a limited number of
B. burgdorferi genes by persisting non-cultivable spirochetes was shown after antibiotic treatment of both mice
[14] and macaques
[22],
but analyses were limited to only a few target genes.
In the current study, the LDA approach allowed simultaneous analysis of multiple gene targets, indicating more global transcription activity of persisting non-cultivable B. burgdorferi at 12 months. Added to earlier studies that demonstrated persistence of
B. burgdorferi DNA in tissues of antibiotic-treated dogs
[9],
[21],
[50], the collective conclusion is persistence of non-cultivable spirochetes following treatment of mice, macaques and dogs with various antibiotics. The limited infectivity of persisting non-cultivable
B. burgdorferi has no biological significance for the natural enzootic cycle of
B. burgdorferi, but it remains to be determined if they have significance in the post-treatment host. Thus, validation of a reproducible animal model for study of this phenomenon is important.
It has been suggested that persisting non-cultivable
B. burgdorferi may be irrelevant, in that they are non-pathogenic and do not cause disease
[28]. This is difficult to prove, since
in the normal course of events, fully virulent B. burgdorferi infects multiple tissues without inflammation. Experimental animal studies have shown that arthritis and carditis are more severe in animals that are genetically susceptible, immature or immunodeficient, or in animals inoculated with high doses of spirochetes that can replicate to high enough titer to colonize specific tissue sites before immune-mediated disease remission [30]. Inflammation is related to colonization of specific tissue sites that are prone to inflammation, including synovium and vascular media, resulting in acute arthritis (synovitis), arteritis and carditis.
The host antibody response eliminates or prevents colonization of these sites, so that the normal course of infection in adult, immunocompetent animals is minimal or none. The lack of inflammation, therefore, in tissues of antibiotic-treated mice at 12 months, with resurgence of spirochete DNA burdens equivalent to those found in saline-treated mice, does not prove the argument one way or the other, since there is no or minimal inflammation in tissues of infected saline-treated mice at 12 months with similar or greater spirochete burdens. The only histologic evidence of host response in both groups of mice was segmental lymphoplasmacytic infiltrates in plantar artery adventitia and sparse infiltrates in the epicardium, albeit less obvious in the antibiotic-treated mice.
The lack of morphological evidence of inflammation under normal circumstances, as well as after antibiotic treatment, prompted us to evaluate host response through LDA analysis of host cytokines. Avoiding over-interpretation of specific cytokine responses, our results indicated that mice were responding to the presence of persisting non-cultivable
B. burgdorferi. The LDA approach allows simultaneous analysis of multiple host cytokines relative to age-matched uninfected mouse tissues, but does not measure absolute values.
It is therefore useful for visualizing a “fingerprint” of host response, indicating a pro-inflammatory cytokine state in both persistently infected, saline-treated and antibiotic-treated mice at 12 months after treatment. Recently, it has been shown that spirochete antigens persist in tissues of antibiotic-treated mice, which may be responsible for cytokine activation [16]. The presence of persisting, non-cultivable
B. burgdorferi that transcribe RNA and express antigens in tissues may contribute to this phenomenon.
...
Resurgence of Persisting Non-Cultivable Borrelia burgdorferi following Antibiotic Treatment in Mice