Early invasion of the brain

Topics with information and discussion about published studies related to Lyme disease and other tick-borne diseases.
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Joe Ham
Posts: 489
Joined: Fri 27 Jul 2007 6:15
Location: New Mexico, USA

Early invasion of the brain

Post by Joe Ham » Tue 2 Oct 2007 18:18

Infect Immun. 1997 Aug;65(8):3352-60.

Immunologic and genetic analyses of VmpA of a neurotropic strain of Borrelia turicatae.
Cadavid D, Pennington PM, Kerentseva TA, Bergström S, Barbour AG.
Department of Microbiology, University of Texas Health Science Center at San Antonio, 78284, USA.

In mice infected with serotype A but not serotype B of the relapsing fever spirochete Borrelia turicatae, early invasion of the brain occurs.

Serotypes A and B are further distinguished by the abundant surface protein they produce: VmpA and VmpB, respectively. Western blotting with monoclonal antibodies, one-dimensional peptide mapping, and partial amino acid sequencing demonstrated regions of the VmpA protein that differed from VmpB.
Oligonucleotide primers based on the partial amino acid sequences of unique regions were used to amplify a portion of the VmpA gene (vmpA) by PCR, and the product was used as a probe in Southern blot and Northern blot analyses.
These experiments showed that (i) expression of the vmpA sequence was determined at the level of transcription and (ii) the vmpA sequence was in two locations in serotype A and one location in serotype B.
The vmpA gene at the expression-linked locus of serotype A was cloned and sequenced. An open reading frame would encode a polypeptide of 214 amino acids.
The polypeptide expressed by Escherichia coli was bound by VmA-specific but not VmpB-specific antibody.
Primer extension analysis identified a consensus sigma70-type promoter for vmpA at the expression locus. Phylogenetic analysis revealed that VmpA is homologous to small Vmp (Vsp) proteins of B. hermsii and to OspC proteins of B. burgdorferi.

These findings indicate that a function of the Vsp-OspC family of proteins of Borrelia spp. may be differential localization in organs, including the brain, during infection.

PMID: 9234797 [PubMed - indexed for MEDLINE]

cave76
Posts: 3182
Joined: Sun 12 Aug 2007 2:27

Re: Early invasion of the brain

Post by cave76 » Tue 2 Oct 2007 23:51

early invasion of the brain occurs.

Now, I (or somebody) need(s) to find that reference in an article I saw years ago, about just how fast the infection will get into the CNS. :)

It was minutes, but it would be nice to have the citation.

Calif.Lyme? :)

Joe Ham
Posts: 489
Joined: Fri 27 Jul 2007 6:15
Location: New Mexico, USA

Re: Early invasion of the brain

Post by Joe Ham » Mon 16 Jun 2008 22:03

Antimicrob Agents Chemother. 1996 Nov;40(11):2632-6.

In vivo activities of ceftriaxone and vancomycin against Borrelia spp. in the mouse brain and other sites.

Kazragis RJ, Dever LL, Jorgensen JH, Barbour AG.
Department of Medicine (Infectious Diseases), University of Texas Health Science Center at San Antonio 78284, USA.

ABSTRACT
Borrelia burgdorferi, the agent of Lyme disease, and B. turicatae, a neurotropic agent of relapsing fever, are susceptible to vancomycin in vitro, with an MIC of 0.5 microgram/ml. To determine the activity of vancomycin in vivo, particularly in the brain, we infected adult immunocompetent BALB/c and immunodeficient CB-17 scid mice with B. burgdorferi or B. turicatae. The mice were then treated with vancomycin, ceftriaxone as a positive control, or normal saline as a negative control. The effectiveness of treatment was assessed by cultures of blood and brain and other tissues. Ceftriaxone at a dose of 25 mg/kg of body weight administered every 12 h for 7 to 10 days eliminated cultivable B. burgdorferi or B. turicatae from all BALB/c or scid mice in the study.

Vancomycin at 30 mg/kg administered every 12 h was effective in eliminating infection from immunodeficient mice if treatment was started within 3 days of the onset of infection.

If treatment with vancomycin was delayed for 7 days or more, vancomycin failed to eradicate infection with B. burgdorferi or B. turicatae from immunodeficient mice.

The failure of vancomycin in eradicating established infections in immunodeficient mice was associated with the persistence of viable spirochetes in the brain during antibiotic treatment.

PMID: 8913478 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/pubmed/8913478

Full PDF
http://aac.asm.org/cgi/reprint/40/11/2632.pdf
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Some excerpts from the full text:

Why did vancomycin fail in situations in which ceftriaxone was effective? Both vancomycin and ceftriaxone are bactericidal for borrelias (14, 15) and thus do not differ with respect to one determinant of antibiotic efficacy in immunodeficient individuals. Neither antibiotic effectively penetrates mammalian cells (12, 30), and, consequently, the possibility of intracellular persistence of the spirochetes is not a compelling explanation for the two outcomes.


Once some spirochetes had reached the brain, it appears that they survived the treatment of the mice with vancomycin.


When vancomycin treatment was stopped and concentrations declined below the MIC, the spirochetes could invade the blood from the brain (10). This phenomenon may have occurred in other tissues, such as the eye (10), into which vancomycin penetrates relatively poorly.
There are implications of these findings for treatment of humans with either Lyme disease or relapsing fever. It is likely that most patients with Lyme disease or relapsing fever would present for diagnosis and treatment more than 1 week after exposure to the infectious agent (4, 36).
This is beyond the time window of vancomycin’s effectiveness in the animal models.
[And beyond the time window of any antibiotic that does not have good brain penetration.]
Although invasion of the central nervous system is not invariable in either infection, it is common enough that effective therapy may depend on eliminating the organism from the brain or cerebrospinal fluid.


More generally, the study shows the importance of examining the brain in studies of antibiotics in animals experimentally infected with Borrelia spp. Treatment recommendations that are based on experimental studies in which the endpoints for success are clearance of the organisms from blood or tissues outside the central nervous system may not provide for optimum therapy of Lyme disease and relapsing fever.

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They never learn:
This paper was published in a well distributed peer reviewed journal 12 years before Hodzic and Barthold published a study in the same journal, March 2008, that did not look at the the brain. It was debated on this forum:
http://www.lymeneteurope.org/forum/view ... &sk=t&sd=a

I can send a copy of the full PDF by email if you want to see all the details.

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LymeEnigma
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Joined: Sun 28 Oct 2007 18:26
Location: The Nevada Desert, USA
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Re: Early invasion of the brain

Post by LymeEnigma » Tue 17 Jun 2008 19:52

How are we supposed to move forward with this disease, when it seems even research is just going around in circles...?

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