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Residual Brain Infection in Relapsing-Fever Borreliosis
The Journal of Infectious Diseases,
Volume 193, Issue 10,
15 May 2006, Pages 1451–1458
"Abstract
Background:
Neurological involvement is common in the spirochetal infection relapsing fever (RF) in both humans and experimental animals. RF is best known for antigenic variation caused by the sequential expression of variable outer membrane lipoproteins of 2 sizes, variable small (Vsp) and variable large (Vlp) proteins. Less understood is the persistence of RF borreliae in the brain after they are cleared from the blood, referred to as residual brain infection (RBI). Our goal was to investigate the phenomenon of RBI in RF
Methods:
We studied RBI in immunocompetent mice by culturing blood and perfused brain samples 1 month after intraperitoneal inoculation with Borrelia turicatae serotype 1 (Bt1). Mice deficient in Toll-like receptor 2 (TLR2−/−) or in B and T cells (scid) were included for comparison
Results:
All scid mice had persistent infection in blood and brain. RBI was found in 3 (19%) of 16 immunocompetent and TLR2−/− mice. RBI was caused by either persistence of the original serotype (Bt1) or newly emerged Vsp (n=1, renamed Bt3) or Vlp serotypes. The Vsp of Bt1 (Vsp1) and Bt3 (Vsp3) were 75% identical
Conclusions:
RBI in RF is relatively frequent and can occur by persistence of the original or newly emerged serotypes."
"Discussion
The major findings of the present study were as follows.
(1) RBI occurs in close to 20% of immunocompetent mice inoculated with a neurotropic strain of B. turicatae.
(2) TLR2 deficiency does not increase susceptibility to RBI.
(3) The scid mutation confers 100% susceptibility to RF neuroborreliosis, independently of background genes.
(4) Vestibular dysfunction is the main clinical manifestation of RF neuroborreliosis in mice.
(5) RBI can be caused by persistence of the original infecting serotype or by newly emerged serotypes that spontaneously arise in the population.
Interest in the phenomenon of neurological involvement by Borrelia species dates to the early twentieth century, when neurological complications were frequent in patients with RF; however, research was almost abandoned after effective treatment with penicillin became available. Earlier investigators in the field were especially interested in the ability of some RF spirochetes to persist in the brain for long time after they disappear from the blood, referred to as RBI. RBI was the subject of many investigations during the last century. It was shown to occur not only in experimental animals but also in nature. RBI was documented in experimental animals for up to 3 years after inoculation. Borreliae causing RBI are susceptible to the serum from the animal from which they are recovered, and they cannot reenter the blood from the brain. In contrast to RF, RBI has not been documented in animal models of Lyme borreliosis. In a recent study, we did not find a single case of RBI in 40 outbred mice 1 month after inoculation with several different strains of LD borreliae, most of which were isolated from human cerebrospinal fluid [40]. In contrast, brain involvement is a frequent occurrence with many species of RF borreliae. A major recent advance in the field of RF has been the elucidation by Barbour et al. that a switch in the expression of VMP proteins due to spontaneous gene conversion of silent vmp genes to a single expression locus in a linear plasmid is the underlying mechanism of antigenic variation in RF. However, whether the VMP switch influences brain infection remains to be determined.
The results reported in the present article reveal that the main determinant of susceptibility to brain infection in RF is the ability to mount a specific immune response. This is in agreement with previous studies that showed that the ability to mount a specific antibody response is the main determinant of susceptibility to RF. Recent studies have shown that these antibodies are produced by B1b lymphocytes and that they can be bactericidal in the absence of complement. Although scid mice are deficient in both B and T cells, B cell deficiency is likely responsible for their increased susceptibility to RF borreliosis. In support of this is our recent finding that Igh6-deficient mice, which are deficient only in B cells, are also highly susceptible to neuroborreliosis after inoculation with Bt1 (D.C. and H. Gelderblom, data not shown). In contrast to the scid mutation, we did not find any evidence that TLR2 deficiency increases susceptibility to RF neuroborreliosis: the frequency of RBI, cerebral microgliosis, and vestibular dysfunction was similar in wild-type and TLR2-deficient mice. This is in contrast to the case in Lyme borreliosis, in which TLR2 deficiency increases the severity of arthritis and the spirochetal load in some tissues.
Previous studies of scid mice inoculated with B. turicatae and Balb/c mice inoculated with Borrelia hermsii showed significant differences in the ability of the individual serotypes to enter the brain. Because the only difference between isogenic Borrelia serotypes is their VMPs, this suggests that expressing certain VMPs (like Vsp1) may facilitate brain invasion. In other words, some RF VMPs may function as spirochetal “neuroinvasins.” This suggests that another consequence of VMP variation in RF may be a gain or loss of function with regard to brain infection. Sequence analysis of Vsp3 showed that it is closely related to Vsp1 (table 3 and figure 4). This suggests that a VMP switch from Vsp1 to Vsp3 may have allowed B. turicatae to escape killing while still preserving its ability to infect the brain. Sequence alignment of B. turicatae Vsp1, 2, and 3 showed they are very similar in the proximal and distal regions, with most of the variability concentrated in the middle third (figure 4). Localized polymorphisms in this middle region of Vsp may account for differences of individual Borrelia serotypes in the ability to infect the brain.
In previous studies of Balb/c mice inoculated with B. hermsii serotype 7, we found that it had been cleared not only from the blood but also from the brain by the time of the first relapse. In this study, we also found that an established serotype 7 brain infection was cleared from the brain of irradiated Balb/c mice by the intravenous administration of anti-Vsp7 monoclonal antibodies of the IgG but not of the IgM isotype. This demonstrated that some antibodies are better than others at clearing spirochetes from the brain. However, we have now found Bt1 in the brain of an immunocompetent mouse that had been inoculated with Bt1 1 month earlier. This is, to our knowledge, the first demonstration that the original infecting serotype can somehow escape the host’s antibody response and survive in the brain. The implication is that, occasionally, immunocompetent hosts fail to clear spirochetes from the brain, resulting in RBI. The mechanism that allowed Bt1 to survive in the brain but not in the blood remains to be determined. Because the spirochetes cultured from the brain were expressing Vsp1, it is more likely that the antibody response of this particular C3H/HeJ mouse had difficulty reaching or killing the spirochetes that had entered the brain. Although the number of mice was small, it was also interesting that one of the outbred mice developed vestibular dysfunction as severe as that of scid mice. This also implies that some hosts, who apparently are immunocompetent, fail to control RF borreliosis, resulting in neurological complications. Contrary to the case in humans, in whom neuroborreliosis involves predominantly the seventh cranial nerve both in RF and LD, in mice, RF neuroborreliosis predominantly affects the vestibular system.
The present results reveal that persistent brain infection in RF borreliosis is not only a feature of antibody-deficient mice but that it also occurs in a significant percentage of immunocompetent mice. RBI can be caused by the persistence in the brain of the original or relapse serotypes after they had been eliminated from the blood. Future studies may elucidate how variations in VMPs modulate the ability of RF borreliae to enter the brain."
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Trav here - note that the authors state: "The present results reveal that persistent brain infection in RF borreliosis is not only a feature of antibody-deficient mice but that it also occurs in a significant percentage of immunocompetent mice. RBI can be caused by the persistence in the brain of the original or relapse serotypes after they had been eliminated from the blood. "
So, why are the 'powers that be' fighting with chronic Lyme patients so much and denying that we even exist?? Remember, this article was in print since 2006 - for 12 years this has been known!
The Journal of Infectious Diseases,
Volume 193, Issue 10,
15 May 2006, Pages 1451–1458
"Abstract
Background:
Neurological involvement is common in the spirochetal infection relapsing fever (RF) in both humans and experimental animals. RF is best known for antigenic variation caused by the sequential expression of variable outer membrane lipoproteins of 2 sizes, variable small (Vsp) and variable large (Vlp) proteins. Less understood is the persistence of RF borreliae in the brain after they are cleared from the blood, referred to as residual brain infection (RBI). Our goal was to investigate the phenomenon of RBI in RF
Methods:
We studied RBI in immunocompetent mice by culturing blood and perfused brain samples 1 month after intraperitoneal inoculation with Borrelia turicatae serotype 1 (Bt1). Mice deficient in Toll-like receptor 2 (TLR2−/−) or in B and T cells (scid) were included for comparison
Results:
All scid mice had persistent infection in blood and brain. RBI was found in 3 (19%) of 16 immunocompetent and TLR2−/− mice. RBI was caused by either persistence of the original serotype (Bt1) or newly emerged Vsp (n=1, renamed Bt3) or Vlp serotypes. The Vsp of Bt1 (Vsp1) and Bt3 (Vsp3) were 75% identical
Conclusions:
RBI in RF is relatively frequent and can occur by persistence of the original or newly emerged serotypes."
"Discussion
The major findings of the present study were as follows.
(1) RBI occurs in close to 20% of immunocompetent mice inoculated with a neurotropic strain of B. turicatae.
(2) TLR2 deficiency does not increase susceptibility to RBI.
(3) The scid mutation confers 100% susceptibility to RF neuroborreliosis, independently of background genes.
(4) Vestibular dysfunction is the main clinical manifestation of RF neuroborreliosis in mice.
(5) RBI can be caused by persistence of the original infecting serotype or by newly emerged serotypes that spontaneously arise in the population.
Interest in the phenomenon of neurological involvement by Borrelia species dates to the early twentieth century, when neurological complications were frequent in patients with RF; however, research was almost abandoned after effective treatment with penicillin became available. Earlier investigators in the field were especially interested in the ability of some RF spirochetes to persist in the brain for long time after they disappear from the blood, referred to as RBI. RBI was the subject of many investigations during the last century. It was shown to occur not only in experimental animals but also in nature. RBI was documented in experimental animals for up to 3 years after inoculation. Borreliae causing RBI are susceptible to the serum from the animal from which they are recovered, and they cannot reenter the blood from the brain. In contrast to RF, RBI has not been documented in animal models of Lyme borreliosis. In a recent study, we did not find a single case of RBI in 40 outbred mice 1 month after inoculation with several different strains of LD borreliae, most of which were isolated from human cerebrospinal fluid [40]. In contrast, brain involvement is a frequent occurrence with many species of RF borreliae. A major recent advance in the field of RF has been the elucidation by Barbour et al. that a switch in the expression of VMP proteins due to spontaneous gene conversion of silent vmp genes to a single expression locus in a linear plasmid is the underlying mechanism of antigenic variation in RF. However, whether the VMP switch influences brain infection remains to be determined.
The results reported in the present article reveal that the main determinant of susceptibility to brain infection in RF is the ability to mount a specific immune response. This is in agreement with previous studies that showed that the ability to mount a specific antibody response is the main determinant of susceptibility to RF. Recent studies have shown that these antibodies are produced by B1b lymphocytes and that they can be bactericidal in the absence of complement. Although scid mice are deficient in both B and T cells, B cell deficiency is likely responsible for their increased susceptibility to RF borreliosis. In support of this is our recent finding that Igh6-deficient mice, which are deficient only in B cells, are also highly susceptible to neuroborreliosis after inoculation with Bt1 (D.C. and H. Gelderblom, data not shown). In contrast to the scid mutation, we did not find any evidence that TLR2 deficiency increases susceptibility to RF neuroborreliosis: the frequency of RBI, cerebral microgliosis, and vestibular dysfunction was similar in wild-type and TLR2-deficient mice. This is in contrast to the case in Lyme borreliosis, in which TLR2 deficiency increases the severity of arthritis and the spirochetal load in some tissues.
Previous studies of scid mice inoculated with B. turicatae and Balb/c mice inoculated with Borrelia hermsii showed significant differences in the ability of the individual serotypes to enter the brain. Because the only difference between isogenic Borrelia serotypes is their VMPs, this suggests that expressing certain VMPs (like Vsp1) may facilitate brain invasion. In other words, some RF VMPs may function as spirochetal “neuroinvasins.” This suggests that another consequence of VMP variation in RF may be a gain or loss of function with regard to brain infection. Sequence analysis of Vsp3 showed that it is closely related to Vsp1 (table 3 and figure 4). This suggests that a VMP switch from Vsp1 to Vsp3 may have allowed B. turicatae to escape killing while still preserving its ability to infect the brain. Sequence alignment of B. turicatae Vsp1, 2, and 3 showed they are very similar in the proximal and distal regions, with most of the variability concentrated in the middle third (figure 4). Localized polymorphisms in this middle region of Vsp may account for differences of individual Borrelia serotypes in the ability to infect the brain.
In previous studies of Balb/c mice inoculated with B. hermsii serotype 7, we found that it had been cleared not only from the blood but also from the brain by the time of the first relapse. In this study, we also found that an established serotype 7 brain infection was cleared from the brain of irradiated Balb/c mice by the intravenous administration of anti-Vsp7 monoclonal antibodies of the IgG but not of the IgM isotype. This demonstrated that some antibodies are better than others at clearing spirochetes from the brain. However, we have now found Bt1 in the brain of an immunocompetent mouse that had been inoculated with Bt1 1 month earlier. This is, to our knowledge, the first demonstration that the original infecting serotype can somehow escape the host’s antibody response and survive in the brain. The implication is that, occasionally, immunocompetent hosts fail to clear spirochetes from the brain, resulting in RBI. The mechanism that allowed Bt1 to survive in the brain but not in the blood remains to be determined. Because the spirochetes cultured from the brain were expressing Vsp1, it is more likely that the antibody response of this particular C3H/HeJ mouse had difficulty reaching or killing the spirochetes that had entered the brain. Although the number of mice was small, it was also interesting that one of the outbred mice developed vestibular dysfunction as severe as that of scid mice. This also implies that some hosts, who apparently are immunocompetent, fail to control RF borreliosis, resulting in neurological complications. Contrary to the case in humans, in whom neuroborreliosis involves predominantly the seventh cranial nerve both in RF and LD, in mice, RF neuroborreliosis predominantly affects the vestibular system.
The present results reveal that persistent brain infection in RF borreliosis is not only a feature of antibody-deficient mice but that it also occurs in a significant percentage of immunocompetent mice. RBI can be caused by the persistence in the brain of the original or relapse serotypes after they had been eliminated from the blood. Future studies may elucidate how variations in VMPs modulate the ability of RF borreliae to enter the brain."
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Trav here - note that the authors state: "The present results reveal that persistent brain infection in RF borreliosis is not only a feature of antibody-deficient mice but that it also occurs in a significant percentage of immunocompetent mice. RBI can be caused by the persistence in the brain of the original or relapse serotypes after they had been eliminated from the blood. "
So, why are the 'powers that be' fighting with chronic Lyme patients so much and denying that we even exist?? Remember, this article was in print since 2006 - for 12 years this has been known!