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Volume: 5
Issue: 12
Date: 17-Dec-97


Table of Contents:

I.    NY TIMES: Researchers Decode DNA Of Lyme Disease Bacterium
II.   WALL STREET JOURNAL: Scientists Make Lyme Disease
      Breakthrough
III.  CLIN INFEC DIS: Why is chronic Lyme borreliosis chronic?
IV.   CLIN INFECT DIS:  Functional brain imaging and
      neuropsychological testing in Lyme disease.
V.    CLIN INFECT DIS: Invasion and cytopathic killing of human
      lymphocytes by spirochetes causing Lyme disease.
VI.   J CLIN INVEST: Simultaneous expression of Borrelia OspA and
      OspC and IgM response in cerebrospinal fluid in early
      neurologic Lyme disease.
VII.  About The LymeNet Newsletter


Newsletter:

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IDX#                Volume 5 / Number 12 / 17-DEC-97
IDX#                            INDEX
IDX#
IDX#  I.    NY TIMES: Researchers Decode DNA Of Lyme Disease Bacterium
IDX#  II.   WALL STREET JOURNAL: Scientists Make Lyme Disease
IDX#        Breakthrough
IDX#  III.  CLIN INFEC DIS: Why is chronic Lyme borreliosis chronic?
IDX#  IV.   CLIN INFECT DIS:  Functional brain imaging and
IDX#        neuropsychological testing in Lyme disease.
IDX#  V.    CLIN INFECT DIS: Invasion and cytopathic killing of human
IDX#        lymphocytes by spirochetes causing Lyme disease.
IDX#  VI.   J CLIN INVEST: Simultaneous expression of Borrelia OspA and
IDX#        OspC and IgM response in cerebrospinal fluid in early
IDX#        neurologic Lyme disease.
IDX#  VII.  About The LymeNet Newsletter
IDX#



     "We took on this project because Lyme disease is very
      difficult to diagnose and in many instances difficult
      to treat.  We hoped that by sequencing the bacterium's
      genome we could begin answering a lot of important
      questions."


      -- Dr. Claire Fraser, the Institute of Genomic Research


I.    NY TIMES: Researchers Decode DNA Of Lyme Disease Bacterium
----------------------------------------------------------------
DATE:  December 10, 1997
AUTHOR: NICHOLAS WADE
SOURCE: N.Y. Times News Service


Gaining a major new insight into the nature of Lyme disease, biologists
have decoded the entire DNA of the bacterium that causes the infection.


Somewhat like obtaining the enemy's order of battle, the achievement
yields the genetic instructions for every survival stratagem the
organism has developed in the course of evolution.  Biologists have a
new starting point from which to develop diagnostic tests and vaccines,
even though they are far from understanding all the information they
have obtained.


``It is certainly very useful to have the whole book in your hand, even
though you can't yet read it,'' said Dr. Alan G. Barbour of the
University of California at Irvine, who first discovered how to grow
the picky bacterium in the laboratory.


Dr. Benjamin J. Luft, a Lyme disease expert at the State University of
New York at Stony Brook, said the new DNA sequence would be
``invaluable for the development of new therapeutics and for
understanding the development of the disease.''


The DNA of the organism, known as Borrelia burgdorferi, was sequenced
by Dr. Claire M. Fraser and a team of biologists at the Institute for
Genomic Research in Rockville, Md., and other institutions.  Their
report is being published Thursday in the journal Nature.


Lyme disease, which is particularly prevalent in New York State and
New England, is spread by a tick that feeds on such animals as mice,
deer, dogs and humans at various stages of its life cycle.  Though the
disease is easily treated if antibiotics are given promptly, it can
cause serious symptoms if unrecognized.  A vaccine is now undergoing
clinical trials, but no accurate diagnostic test is available.


Knowledge of the bacterium's full DNA sequence should help toward
developing second generation vaccines, if needed, and accurate
diagnostic tests.  From its genetic repertoire biologists should also
be able to gain a better understanding of Borrelia's complicated life
cycle.


``It's very exciting for us, given the amount of money we have put
into the field and the spotty progress in terms of the research,'' said
James H. Handelman, executive director of the Mathers Charitable Trust
of Mount Kisco, N.Y., which financed the research.  The trust, which
supports basic biomedical research, became interested in Lyme disease
10 years ago, in part because many of its board members had been
exposed to it.


The genome of the Lyme disease organism turns out to consist of some
1,444,000 base pairs of DNA, the hereditary material.  Most bacteria
have genomes in the form of a single circular chromosome.  Borrelia's
is very unusual because it has a single linear chromosome and numerous
small strips of DNA known as plasmids.  Exchange of plasmids is the
usual way by which bacteria transfer antibiotic resistance genes among
one another.


Though few of Borrelia's genes have been directly studied, biologists
can assign likely roles to many through their similarity to genes of
known function from other organisms.  Of the 853 genes on Borrelia's
main chromosome, the roles of 59 percent have been identified.  
But only 16 percent of the 430 plasmid genes are familiar, Fraser's
team reported.


Borrelia seems to have most of its basic housekeeping genes lined up
on its main chromosome, while the plasmids carry numerous genes for
making lipoproteins, substances that form the bacterium's coat.  
The parasite has to survive attacks by the immune systems of all its
different hosts, and may do so by rapidly switching between its
repertoire of lipoprotein genes so as to change the composition of its
coat.


Borrelia also has many genes thought to be involved in responding to
chemical cues in its environment.  This is not surprising, given that
the bacterium must move at the right time from the tick's stomach to
its mouth parts, and that once inside its new host it must seek out
various organs to lay low and avoid the immune system's attack.


Fraser said she expected that the bacterium was able to switch on one
set of genes for living in its insect host and another set for living
in mammals.  But to her disappointment, she has not yet managed to
identify any such master gene.


Fraser's team was not alone in sequencing the Borrelia genome.
Biologists at the Brookhaven National Laboratory started to decode the
organism's DNA in January 1996, in part to test a novel sequencing
method.  Fraser's team started in March 1996, using a method developed
at the Institute for Genomic Research.


``It's like going jogging - you both jog faster if someone else is
with you,''  Dr. John J. Dunn of the Brookhaven group said.


But Brookhaven's new method turned out not to be competitive, and
Fraser's team finished first by a considerable margin.


The Lyme vaccine now being tested is based on a component of
Borrelia's coat known as OspA, for outside protein A.  The protein
was chosen because it was the most common in laboratory cultures of
Borrelia.


Biologists now know that OspA is produced only when the bacterium is
living inside its insect host.  As soon as Borrelia senses that it is
being transferred to a mammal bitten by the tick, it switches to
making another protein, OspC.  By sheer luck, the OspA-based vaccine
seems to be effective because it starts attacking the bacteria the
instant they emerge from the tick, and before they have been able to
switch coats.


Borrelia is the 11th bacterium to have its genome sequenced, and the
sixth to be sequenced by the Institute for Genomic Research, which
pioneered in this field in 1995.



=======*======


II.   WALL STREET JOURNAL: Scientists Make Lyme Disease Breakthrough
--------------------------------------------------------------------
DATE: December 11, 1997
AUTHOR: MICHAEL WALDHOLZ
SOURCE: THE WALL STREET JOURNAL


Researchers have deciphered the genetic blueprint of the microbe that
causes Lyme disease, a formidable achievement that scientists hope will
someday lead to new treatments.


But the research has also uncovered new mysteries about the gene's
makeup that ensure the search for a Lyme vaccine will still take many
years of research.


Still, the discovery highlighted new techniques that are speeding up the
process of cracking the genetic code of infectious agents.  A gene-
hunting process that until recently took several years is now taking a
matter of months, offering hope for more genetic breakthroughs soon.


A Lyme disease infection, if not caught early and treated aggressively
with antibiotics, can cause painful nerve damage and progressive
arthritis.  The ailment, most common in the Northeast and Midwest, as
well as parts of California and Oregon, is caused by a tick bite,
which transports the bacterium from infected deer to humans.


Lyme disease is particularly troublesome because many people miss the
early signs of infection, a round skin rash and flu-like symptoms.
Once the bug spreads throughout the body, it is difficult to eradicate
with drugs.  That's why scientists have been racing to find vaccines to
protect people against the bacterium infection in the first place.


"Lyme disease has been a real enigma," said Claire Fraser, a biologist
at the Institute of Genomic Research in Rockville, Md.  Dr. Fraser led a
large team of 38 scientists in a relatively swift 18 month effort to
decode the genome, the microbe's entire set of 1,300 or so genes.


"We took on this project because Lyme disease is very difficult to
diagnose and in many instances difficult to treat," she said.  
"We hoped that by sequencing the bacterium's genome we could begin
answering a lot of important questions."


But Dr. Fraser said that identifying the genes that constitute Borrelia
burgdorferi, the germ that causes Lyme disease, produced more new
questions than answers.  Indeed, Dr. Fraser says, many of the genes
uncovered appear to produce a kind of chemical protean that scientists
have never seen.


Especially disappointing, she says, is that scientists were unable to
identify proteins that explain why burgdorferi can persist in humans for
years even though the human body is able to mount a strong immune-system
response.  Thus, exploiting the new genetic data reported in today's
issue of the British science journal, Nature, will likely require many
more years of research.


Nonetheless, the release of the genetic code is expected to trigger a
flood of research by pharmaceutical companies that have been studying
the disease.  Two companies, SmithKline Beecham PLC of Britain and
Pasteur Merieux Connaught, a unit of Rhone-Poulenc SA, of France,
are expected to market vaccines that, in clinical trials, appear to be
about 80% to 90% effective.  SmithKline and Pasteur Merieux have
applied to the Food and Drug Administration to market the new vaccines
and expect to have them available early in 1998.


Both vaccines are based on a protein that sits on the outer membrane
of the bacterium.  When injected into humans, the protein generates a
strong response against the microbe by the body's disease fighting
immune system.


Some researchers worry, however, that because the vaccine isn't
completely effective in all people studied, any bacterium left in the
body can cause health problems.  The vaccines also don't appear to be
effective in people over 65.


Scientists were impressed by the speed with which the TIGR team of
researchers was able to decipher the organism's complicated genetic
code.  TIGR is led by Craig Venter, a former government researcher
who in the past few years has helped revolutionize gene-hunting
science with the development of several groundbreaking techniques.


With his help, TIGR has completed the genetic sequence of five
infectious agents in the past two years.  These include the sequence
for Hemophilus influenzae, a microbe that can cause meningitis in
children, and Heliobacter pylori, a bacterium that recently was found
to be the cause of many ulcers.


Scientists note that previously only two other infectious microbes had
been sequenced, each requiring about five to 10 years of research.
Using its new techniques, TIGR expects to sequence six microbes next
year and double that number the year after, Dr. Venter said in an
interview.


Indeed, next month TIGR plans to report that it has produced the
genetic code for Treponema pallidum, the bacterium that causes
syphilis.


"By the end of the decade we hope to have [uncovered] the genomes for
5o infectious agents", Dr. Venter said.  "With each new genome, we
understand the history of the organisms, how they evolved, how they
differ and what their relationship is to humans.  It's a very powerful
way to study and attack these pathogens."


Dr. Venter noted, for instance, that one finding from the Lyme disease
research may help explain why the bacterium rides aboard ticks.  The
bacterium needs substances that are found inside the tick.  This
insight suggests that one way to fight the microbe is by blocking its
ability to ingest the shared substance.



=====*=====


III.  CLIN INFEC DIS: Why is chronic Lyme borreliosis chronic?
--------------------------------------------------------------
AUTHORS: Aberer E, Koszik F, Silberer M
ORGANIZATION:  Department of Dermatology, University of Graz Medical
              School, Austria.
REFERENCE:  Clin Infect Dis 1997 Jul;25 Suppl 1:S64-70
ABSTRACT:


Chronic Lyme borreliosis (CLB) can present not only in different
organs but also in different patterns.  Although many theories exist
about the mechanisms leading to CLB, it is known that viable Borrelia
burgdorferi can persist for decades and cause late skin manifestations
of acrodermatitis chronica atrophicans (ACA).  Thus, the
immunopathogenetic findings in ACA can serve as a model for studying
the chronic course of Lyme borreliosis.  Recent findings indicate
that the most important cell for antigen presentation, the epidermal
Langerhans cell (LC), is invaded by B. burgdorferi in early Lyme
borreliosis.  Therefore, LCs were stained immunohistochemically with
different markers to investigate their functional activity.  Numbers of
CD1a+ LCs were reduced in erythema migrans but normal or slightly
elevated in ACA.  In both diseases there was also a marked
downregulation of major histocompatibility complex class II molecules
on LCs, as measured by staining of human leukocyte antigen DR.  This
phenomenon might be a mechanism that protects against the presentation

of autoantigens and may be the cause of the impaired capacity of LCs
to eliminate B. burgdorferi antigens, thus explaining why CLB is
chronic.



=====*=====


IV.  CLIN INFECT DIS:  Functional brain imaging and neuropsychological
    testing in Lyme disease.
----------------------------------------------------------------------
AUTHORS: Fallon BA, Das S, Plutchok JJ, Tager F, Liegner K,
        Van Heertum R
ORGANIZATION: The New York State Psychiatric Institute, the Department
             of Psychiatry of Columbia University and Columbia-
             Presbyterian Medical Center, New York 10032, USA.
REFERENCE: Clin Infect Dis 1997 Jul;25 Suppl 1:S57-63
ABSTRACT:


Differentiating neuropsychiatric Lyme disease from a primary
psychiatric disorder can be a daunting task.  This article describes
how functional brain imaging and neuropsychological testing can be
particularly valuable in helping to make diagnostic distinctions.  
In addition to a review of the relevance of functional imaging to
neuropsychiatry in general, recent findings are presented regarding
the use of single photon emission computed tomographic (SPECT) imaging
in Lyme disease.



=====*=====


V.    CLIN INFECT DIS: Invasion and cytopathic killing of human
     lymphocytes by spirochetes causing Lyme disease.
---------------------------------------------------------------
AUTHORS: Dorward DW, Fischer ER, Brooks DM
ORGANIZATION: National Institute of Allergy and Infectious Diseases,
             Rocky Mountain Laboratories, Hamilton, Montana 59840, USA
REFERENCE: Clin Infect Dis 1997 Jul;25 Suppl 1:S2-8
ABSTRACT:


Lyme disease is a persistent low-density spirochetosis caused by
Borrelia burgdorferi sensu lato. Although spirochetes causing Lyme
disease are highly immunogenic in experimental models, the onset of
specific antibody responses to infection is oftendelayed or
undetectable in some patients.  The properties and mechanisms
mediating such immune avoidance remain obscure.  To examine the nature
and consequences of interactions between Lyme disease spirochetes and
immune effector cells, we coincubated B. burgdorferi with primary and
cultured human leukocytes.  We found that B. burgdorferi actively
attaches to, invades, and kills human B and T lymphocytes.  
Significant killing began within 1 hour of mixing.  Cytopathic effects
varied with respect to host cell lineage and the species, viability,
and degree of attenuation of the spirochetes.  Both spirochetal
virulence and lymphocytic susceptibility could be phenotypically
selected, thus indicating that both bacterial and host cell factors
contribute to such interactions.  These results suggest that invasion

and lysis of lymphocytes may constitute previously unrecognized
factors in Lyme disease and bacterial pathogenesis.



=====*=====


VI.   J CLIN INVEST: Simultaneous expression of Borrelia OspA and
     OspC and IgM response in cerebrospinal fluid in early
     neurologic Lyme disease.
-----------------------------------------------------------------
AUTHORS: Schutzer SE, Coyle PK, Krupp LB, Deng Z, Belman AL,
        Dattwyler R, Luft BJ
ORGANIZATION:  Department of Medicine, University of Medicine and
              Dentistry of New Jersey, New Jersey Medical School,
              Newark, New Jersey 07103, USA.  schutzer@umdnj.edu
REFERENCE:  J Clin Invest 1997 Aug 15;100(4):763-7
ABSTRACT:


Lyme disease is the major tick-borne disease, caused by Borrelia
burgdorferi (Bb).  Neurological involvement is common in all stages.
In vivo expression of Bb antigens (Ags) and the immune response to
them has not been well investigated in the cerebrospinal fluid (CSF).
Upregulation of outer surface protein (Osp) C and concomitant
downregulation of OspA before tick inoculation of the spirochete has
been reported in skin and blood in animals.  CSF OspA Ag in early
disease suggests otherwise in CSF.  Early Ag expression and IgM
response in human CSF was investigated here.  Paired CSF and serum
was collected from 16 early, predominantly erythema migrans Lyme
disease patients with neurologic problems, 13 late Lyme disease
patients, and 19 other neurologic disease (OND) controls.  Samples
were examined for IgM reactivity to recombinant Bb-specific Osps
using ELISA and immunoblot. Of 12 early Lyme disease patients with
neurologic involvement with both CSF and serum IgM against OspC, 7
(58%) had IgM to OspA (n = 5) or OspB (n = 2) that was restricted to

the CSF, not serum.  Overall, 12 of 16 (75%) of these early Lyme
disease patients with neurologic involvement had CSF and serum IgM
against OspC.  Only 3 of 13 (23%) late Lyme disease patients and none
of 19 OND controls had CSF IgM directed against OspC.  In conclusion,
in CSF, OspC and OspA can be coexpressed, and IgM response to them
occurs in early Lyme disease patients with neurologic involvement.  
This biologic finding may also provide a discriminating marker for
CNS infection in Lyme disease.



=====*=====


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