The CDC Center for HIV, STD, and TB Prevention provides the following
information as a public service only. Providing synopses of key scientific
articles and lay media reports on HIV/AIDS, other sexually transmitted
diseases and tuberculosis does not constitute CDC endorsement. This update
may also include information from CDC and other government agencies, such as
background on Morbidity and Mortality Weekly Report (MMWR) articles, fact
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Prevention News Update should be cited as the source of the information.

TEXAS: "Tuberculosis: Deadly Disease Can Be Cheaply and Easily Defeated";
   Houston Chronicle (09.22.01).

"Every year, tuberculosis kills 2 million people worldwide, more people than
die from AIDS. But unlike the costly anti-viral cocktails doctors must give
patients to fight AIDS, a full course of TB drugs costs as little as $10 in
developing countries and cures up to 95 percent of cases. The Chronicle
urges the US Senate to provide adequate funding in the 2002 foreign aid
appropriations bill to combat TB around the globe. "Health experts say they
are worried about the possibility that unless TB is wiped out in the near
future, dangerous drug-resistant strains may become prevalent and make TB an
untreatable plague. Like the car repair man used to say on television: Pay
me now or pay me later. "If the United States does not lead the battle in
fighting TB while it can be beaten relatively inexpensively, the world could
find itself in a war with strains of TB that are terribly difficult to
defeat. The House already has approved its version of the foreign assistance
bill. The smart thing for the Senate to do is pay now, so the nation doesn't
have to pay later."

Britain: TB Cases at Ten Year High in City"; Evening Mail (United Kingdom)  (09.24.01):Paula Marsh.

A report by Birmingham Health Authority reveals new
cases of TB reached 356 last year -a 44 percent rise since 1998. Dr.
Surinder Bakhshi, director of communicable diseases at Birmingham Health
Authority, said the number of health professionals qualified to treat the
disease in the city was among the lowest in the country. "Most patients can
be treated in the community but the increasing complexity and number of
reported cases requires a much strengthened response from both primary care
and the City Central Chest Clinic," Bakhshi said. An additional two staff
members would enable the Chest Clinic at Heartlands Hospital to train more
professionals to administer simple treatment and follow-up care as well as
improve public and patient education about the disease, he said.

OTHER NEWS:
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Global AIDS Fund to Start Disbursing Money Late 2001; September 27, 2001; UN
Integrated Regional Information Network/All Africa Global Media via COMTEX .

The Global AIDS and Health Fund - an initiative of UN Secretary-General Kofi
Annan, would become operational by the end of this year, a UN statement said
on Wednesday..... The fund's ultimate goal would be to mobilize additional
resources, and to channel them to developing countries to ensure rapid
progress in addressing the huge challenges caused by HIV/AIDS, malaria and
tuberculosis, said the statement.

JOURNALS:
*********************************

Proceedings of the National Academy of Sciences USA, Vol. 98, Issue 20,
11497-11502, September 25, 2001; Immunology: Divergent effect of bacillus
Calmette-Guérin (BCG) vaccination on Mycobacterium tuberculosis infection in
highly related macaque species: Implications for primate models in
tuberculosis vaccine research; Jan A. M. Langermans, Peter Andersen, Dick
van Soolingen, Richard A. W. Vervenne, Patrice A. Frost, Tridia van der
Laan, Laurens A. H. van Pinxteren, Jan van den Hombergh, Saskia Kroon, Inge
Peekel, Sandrine Florquin, and Alan W. Thomas.

Article notes that despite the widespread use of bacillus Calmette-Guérin
(BCG) vaccination, tuberculosis infection remains globally the leading cause
of death from a single infectious disease and the complicated and often
protracted dynamics of infection and disease make clinical trials to test
new tuberculosis vaccines extremely complex.; for this reason, preclinical
selection of only the most promising candidates is therefore essential.
These investigators noted that since macaque monkeys develop a disease very
similar to humans, they have potential to provide important information in
addition to small animal models. In order to assess the relative merits of
rhesus and cynomolgus monkeys as screens for tuberculosis vaccines, they
compared the efficacy of BCG vaccination and the course of infection in both
species. They report that both unvaccinated rhesus and cynomolgus monkeys
developed progressive disease with high levels of C-reactive protein, M.
tuberculosis-specific IgG, and extensive pathology including cavitation and
caseous necrosis. They say BCG vaccination protected cynomolgus almost
completely toward the development of pathology, reflected in a striking
2-log reduction in viable bacteria in the lungs compared with nonvaccinated
animals. However they also found that the Rhesus were not protected
efficiently by BCG and the vaccinated animals developed substantial
pathology and had negligible reductions of colony-forming units in the
lungs. They believe comparative studies in these closely related species are
likely to provide insight into mechanisms involved in protection against
tuberculosis.

Infection and Immunity, October 2001, p. 6348-6363, Vol. 69, No. 10;
American Society for Microbiology; High Extracellular Levels of
Mycobacterium tuberculosis Glutamine Synthetase and Superoxide Dismutase in
Actively Growing Cultures Are Due to High Expression and Extracellular
Stability Rather than to a Protein-Specific Export Mechanism; Michael V.
Tullius, Günter Harth, and Marcus A. Horwitz.

Article notes that glutamine synthetase (GS) and superoxide dismutase (SOD),
large multimeric enzymes that are thought to play important roles in the
pathogenicity of Mycobacterium tuberculosis, are among the bacterium's major
culture filtrate proteins in actively growing cultures and, although these
proteins lack a leader peptide, their presence in the extracellular medium
during early stages of growth suggests that they might be actively secreted.
In order to understand their mechanism of export, these investigators cloned
the homologous genes (glnA1 and sodA) from the rapid-growing, nonpathogenic
Mycobacterium smegmatis, generated glnA1 and sodA mutants of M. smegmatis by
allelic exchange, and quantitated expression and export of both
mycobacterial and nonmycobacterial GSs and SODs in these mutants. They also
quantitated expression and export of homologous and heterologous SODs from
M. tuberculosis. They say when each of the genes was expressed from a
multicopy plasmid, M. smegmatis exported comparable proportions of both the
M. tuberculosis and M. smegmatis GSs (in the glnA1 strain) or SODs (in the
sodA strain), in contrast to previous observations in wild-type strains.
They were surprised to find that recombinant M. smegmatis and M.
tuberculosis strains even exported nonmycobacterial SODs. So in order to
determine the extent to which export of these large, leaderless proteins is
expression dependent, they constructed a recombinant M. tuberculosis strain
expressing green fluorescent protein (GFP) at high levels and a recombinant
M. smegmatis strain coexpressing the M. smegmatis GS, M. smegmatis SOD, and
M. tuberculosis BfrB (bacterioferritin) at high levels. They report the
recombinant M. tuberculosis strain exported GFP even in early stages of
growth and at proportions very similar to those of the endogenous M.
tuberculosis GS and SOD. Similarly, they noted the recombinant M. smegmatis
strain exported bacterioferritin, a large (~500-kDa), leaderless, multimeric
protein, in proportions comparable to GS and SOD. In contrast, they say
high-level expression of the large, leaderless, multimeric protein malate
dehydrogenase did not lead to extracellular accumulation because the protein
was highly unstable extracellularly. They sum up noting their findings
indicate that, contrary to expectations, export of M. tuberculosis GS and
SOD in actively growing cultures is not due to a protein-specific export
mechanism, but rather to bacterial leakage or autolysis, and that the
extracellular abundance of these enzymes is simply due to their high level
of expression and extracellular stability. They comment that the same
determinants likely explain the presence of other leaderless proteins in the
extracellular medium of actively growing M. tuberculosis cultures.

Journal of Clinical Microbiology, October 2001, p. 3603-3608, Vol. 39, No.
10; American Society for Microbiology; Clinical Evaluation of
Anti-Tuberculous Glycolipid Immunoglobulin G Antibody Assay for Rapid
Serodiagnosis of Pulmonary Tuberculosis; Ryoji Maekura, Yoshinari Okuda,
Masaru Nakagawa, Touru Hiraga, Souichirou Yokota, Masami Ito, Ikuya Yano,
Hiroaki Kohno, Masako Wada, Chiyoji Abe, Takeo Toyoda, Toshio Kishimoto, and
Takeshi Ogura.

These investigators previously reported the development of a highly
sensitive enzyme-linked immunosorbent assay specific for anti-tuberculous
glycolipid (anti-TBGL) for the rapid serodiagnosis of tuberculosis. In this
study, they evaluated the usefulness of an anti-TBGL antibody assay kit for
rapid serodiagnosis in a controlled multicenter study and they analyzed
antibody titers in sera from 318 patients with active pulmonary tuberculosis
(216 positive for Mycobacterium tuberculosis in smear and/or culture tests
and 102 smear and culture negative and clinically diagnosed), 58 patients
with old tuberculosis, 177 patients with other respiratory diseases, 156
patients with nonrespiratory diseases, and 454 healthy subjects. They also
examined sera from 256 younger healthy subjects from among the 454 healthy
subjects as a control. When they determined the cutoff point of anti-TBGL
antibody titer as 2.0 U/ml, the sensitivity for active tuberculosis patients
was 81.1% and the specificity was 95.7%. They found sensitivity in patients
with smear-negative and culture-negative active pulmonary tuberculosis was
73.5%. They noted that even in patients with noncavitary minimally advanced
lesions, the positivity rate (60.0%) and the antibody titer (4.6 ± 9.4 U/ml)
were significantly higher than those in the healthy group. They sum up
noting their results indicate that this assay using anti-TBGL antibody is
useful for the rapid serodiagnosis of active pulmonary tuberculosis.

Journal of Clinical Microbiology, October 2001, p. 3563-3571, Vol. 39, No.
10; American Society for Microbiology; Automated High-Throughput Genotyping
for Study of Global Epidemiology of Mycobacterium tuberculosis Based on
Mycobacterial Interspersed Repetitive Units; Philip Supply, Sarah Lesjean,
Evgueni Savine, Kristin Kremer, Dick van Soolingen, and Camille Locht.

Article notes that large-scale genotyping of Mycobacterium tuberculosis is
especially challenging, since the current typing methods are labor-intensive
and the results are difficult to compare among laboratories. In this
article, an automated typing based on variable-number tandem repeats (VNTRs)
of genetic elements named mycobacterial interspersed repetitive units
(MIRUs) in 12 mammalian minisatellite-like loci of M. tuberculosis is
presented; this system combines analysis of multiplex PCRs on a
fluorescence-based DNA analyzer with computerized automation of the
genotyping. Investigators note that analysis of a blinded reference set of
90 strains from 38 countries (K. Kremer et al., J. Clin. Microbiol.
37:2607-2618, 1999) demonstrated that it is 100% reproducible, sensitive,
and specific for M. tuberculosis complex isolates, a performance that has
not been achieved by any other typing method tested in the same conditions.
These investigators point out that MIRU-VNTRs can be used for analysis of
the global genetic diversity of M. tuberculosis complex strains at different
levels of evolutionary divergence. They report that a website has been set
up for the analysis of M. tuberculosis MIRU-VNTR genotypes via the Internet
in order to fully exploit the portability of this typing system. They say
this opens the way for global epidemiological surveillance of tuberculosis
and should lead to novel insights into the evolutionary and population
genetics of this major pathogen.

Journal of Clinical Microbiology, October 2001, p. 3499-3504, Vol. 39, No.
10; American Society for Microbiology; Phospholipase Region of Mycobacterium
tuberculosis Is a Preferential Locus for IS6110 Transposition; Lucio
Vera-Cabrera, Marco A. Hernández-Vera, Oliverio Welsh, Wendy M. Johnson, and
Jorge Castro-Garza.

Article notes that enzymes with phospholipase C activity in Mycobacterium
tuberculosis have been recently described; the three genes encoding these
proteins, plcA, plcB, and plcC, are located at position 2351 of the genomic
map of M. tuberculosis H37Rv and are arranged in tandem. These investigators
previously described the presence of variations in the restriction fragment
length polymorphism patterns of the plcA and plcB genes in M. tuberculosis
clinical isolates. They have now investigated the origin of this
polymorphism by sequence analysis of the phospholipase-encoding regions of
11 polymorphic M. tuberculosis clinical isolates. They used a long-PCR assay
to amplify a 5,131-bp fragment that contains the plcA and plcB genes and
part of the plcC gene. They observed the production of an amplicon ~1,400 bp
larger than anticipated in the M. tuberculosis strains and sequence analysis
of the PCR products indicated the presence of a foreign sequence that
corresponded to an IS6110 element. They observed insertion elements in the
plcA, plcB, and plcC genes; one site in plcB had the highest incidence of
transposition (5 out of 11 strains); and in two strains the insertion
element was found in plcA in the same nucleotide position; and in all the
cases, IS6110 was transposed in the same direction. They point out the high
level of transposition in the phospholipase region can lead to the excision
of fragments of genomic DNA by recombination of neighboring IS6110 elements,
as demonstrated by finding the deletion, in two strains, of a 2,837-bp
fragment that included plcA and most of plcB. They comment that this can
explain the negative results obtained by some authors when detecting the
mtp40 sequence (plcA) by PCR. They say the use of the mtp40 sequence as a
genetic marker for M. tuberculosis sensu stricto is very restricted given
the high polymorphism in this region.

Infection and Immunity, October 2001, p. 5967-5973, Vol. 69, No. 10;
American Society for Microbiology; Silencing of Oxidative Stress Response in
Mycobacterium tuberculosis: Expression Patterns of ahpC in Virulent and
Avirulent Strains and Effect of ahpC Inactivation; B. Springer, S. Master,
P. Sander, T. Zahrt, M. McFalone, J. Song, K.G. Papavinasasundaram, M. J.
Colston, E. Boettger, and V. Deretic.

Article notes that intracellular pathogens such as Mycobacterium
tuberculosis are able to survive in the face of antimicrobial products
generated by the host cell in response to infection and the product of the
alkyl hydroperoxide reductase gene (ahpC) of M. tuberculosis is thought to
be involved in protecting the organism against both oxidative and
nitrosative stress encountered within the infected macrophage. This report
says, contrary to expectations, that ahpC expression in virulent strains of
M. tuberculosis and Mycobacterium bovis grown in vitro is repressed, often
below the level of detection, whereas expression in the avirulent vaccine
strain M. bovis BCG is constitutively high. These investigators say
repression of the ahpC gene of the virulent strains is independent of the
naturally occurring lesions of central regulator oxyR. Using a green
fluorescence protein vector (gfp)-ahpC reporter construct, they present data
showing that repression of ahpC of virulent M. tuberculosis also occurred
during growth inside macrophages, whereas derepression in BCG was again seen
under identical conditions. They report that inactivation of ahpC on the
chromosome of M. tuberculosis by homologous recombination had no effect on
its growth during acute infection in mice and did not affect in vitro
sensitivity to H2O2. However, they noted consistent with AhpC function in
detoxifying organic peroxides, sensitivity to cumene hydroperoxide exposure
was increased in the ahpC::Kmr mutant strain. They comment that the
preservation of a functional ahpC gene in M. tuberculosis in spite of its
repression under normal growth conditions suggests that, while AhpC does not
play a significant role in establishing infection, it is likely to be
important under certain, as yet undefined conditions. They believe this is
supported by the observation that repression of ahpC expression in vitro was
lifted under conditions of static growth.

Infection and Immunity, October 2001, p. 6022-6029, Vol. 69, No. 10;
American Society for Microbiology; CD85/LIR-1/ILT2 and CD152 (Cytotoxic T
Lymphocyte Antigen 4) Inhibitory Molecules Down-Regulate the Cytolytic
Activity of Human CD4+ T-Cell Clones Specific for Mycobacterium
tuberculosis; Andrea Merlo, Daniele Saverino, Claudya Tenca, Carlo Enrico
Grossi, Silvia Bruno, and Ermanno Ciccone.

Article notes that antigen-specific cytolytic CD4+ T lymphocytes control
Mycobacterium tuberculosis infection by secreting cytokines and by killing
macrophages that have phagocytosed the pathogen. However, the article also
points out that lysis of the latter cells promotes microbial dissemination,
and other macrophages engulf the released bacteria; subsequently, CD4+
T-cell-mediated killing of macrophages goes on, and this persistent process
may hamper control of infection, unless regulatory mechanisms maintain a
subtle balance between lysis of macrophages by cytolytic CD4+ cells and
activation of cytolytic CD4+ cells by infected macrophages. These
investigators sought to find out whether inhibitory molecules expressed by
CD4+ cytolytic T lymphocytes could play a role in such a balance. The report
that human CD4+ T-cell clones specific for M. tuberculosis were produced
that displayed an autologous major histocompatibility complex class
II-restricted lytic ability against purified protein derivative (PPD)-pulsed
antigen-presenting cells. They found that all T-cell clones expressed CD152
(cytotoxic T-lymphocyte antigen 4 [CTLA-4]) and CD85/leukocyte
immunoglobulin-like receptor 1 (LIR-1)/immunoglobulin-like transcript 2
(ILT2) inhibitory receptors, but not CD94 and the killer inhibitory receptor
(or killer immunoglobulin-like receptor [KIR]) p58.2. They report
CD3-mediated activation of the clones was inhibited in a redirected killing
assay in which CD152 and CD85/LIR-1/ILT2 were cross-linked. They noted that
specific antigen-mediated proliferation of the clones was also sharply
reduced when CD152 and CD85/LIR-1/ILT2 were cross-linked by specific
monoclonal antibody (MAb) followed by goat anti-mouse antiserum. In
contrast, they say blockade of the receptors by specific MAb only increased
their proliferation. They noted that production of interleukin 2 (IL-2) and
gamma interferon (IFN-y) by the T-cell clones was also strongly reduced when
CD152 and CD85/LIR-1/ILT2 were cross-linked and the lytic activity of the
T-cell clones against PPD-pulsed autologous monocytes or Epstein-Barr
virus-activated B cells was increased by blockade and decreased by
cross-linking of the receptors. They sum up saying these results indicate
that CD152 and CD85/LIR-1/ILT2 play a role in the regulation of the
antigen-specific activity of CD4+ cytolytic T lymphocytes against
PPD-presenting cells.

American Society for Microbiology; The Alternative Sigma Factor SigH
Regulates Major Components of Oxidative and Heat Stress Responses in
Mycobacterium tuberculosis; Sahadevan Raman, Taeksun Song, Xiaoling Puyang,
Stoyan Bardarov, William R. Jacobs Jr., and Robert N. Husson.

Article points out that Mycobacterium tuberculosis is a specialized
intracellular pathogen that must regulate gene expression to overcome
stresses produced by host defenses during infection. These investigators
previously demonstrated that SigH is an alternative sigma factor that plays
a role in the response to stress of the saprophyte Mycobacterium smegmatis.
In this work they investigated the role of sigH in the M. tuberculosis
response to heat and oxidative stress and determined that a M. tuberculosis
sigH mutant is more susceptible to oxidative stresses and that the inducible
expression of the thioredoxin reductase/thioredoxin genes trxB2/trxC and a
gene of unknown function, Rv2466c, is regulated by sigH via expression from
promoters directly recognized by SigH. They also determined that the sigH
mutant is more susceptible to heat stress and that inducible expression of
the heat shock genes dnaK and clpB is positively regulated by sigH. They
found the induction of these heat shock gene promoters but not of other
SigH-dependent promoters was markedly greater in response to heat versus
oxidative stress, consistent with their additional regulation by a
heat-labile repressor. To further understand the role of sigH in the M.
tuberculosis stress response, they investigated the regulation of the
stress-responsive sigma factor genes sigE and sig and they determined that
inducible expression of sigE is regulated by sigH and that basal and
inducible expression of sigB is dependent on sigE and sigH. They sum up
noting their findings indicate that sigH plays a central role in a network
that regulates heat and oxidative-stress responses that are likely to be
important in M. tuberculosis pathogenesis.

Infection and Immunity, October 2001, p. 6554-6557, Vol. 69, No. 10;
American Society for Microbiology; Tuberculosis Contacts but Not Patients
Have Higher Gamma Interferon Responses to ESAT-6 than Do Community Controls
in The Gambia; Johan Vekemans, Christian Lienhardt, Jackson S. Sillah,
Jeremy G. Wheeler, George P. Lahai, Mark T. Doherty, Tumani Corrah, Peter
Andersen, Keith P. W. J. McAdam, and Arnaud Marchant.

Article notes that the Mycobacterium tuberculosis antigen ESAT-6 has been
proposed for tuberculosis immunodiagnosis. These authors report that in The
Gambia, 30% of community controls produced gamma interferon (IFN-y) in
response to ESAT-6 and they found increased proportions of responders and
intensities of responses in household contacts. They report that responses
that were initially low in tuberculosis patients increased after treatment.
They believe an ESAT-6 IFN-y assay will be of limited use in the diagnosis
of tuberculosis in countries where tuberculosis is endemic but say its role
in contact tracing should be evaluated further.

OTHER:
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The 33rd World Conference on Lung Health.

Mark your calendars! The 33rd World Conference on Lung Health, will take
place in Montreal, Quebec, Canada, October 6 to 10, 2002 at the Palais des
Congrèès. The preliminary program notes that tuberculosis related topics
will include: Tuberculosis and HIV"; "MDR TB: a real threat?"; "Hope for new
TB drugs?"; and "Better diagnostic tools."

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'Stop TB' - a global movement to accelerate social and political action to 
stop the spread of tuberculosis around the world. 
For further information please contact the Stop TB Secretariat at 
stoptb@who.int