TB-Related News and Journal Items: Week of May 30, 2000

>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
>also includes information from CDC and other government agencies, such as
>background on Morbidity and Mortality Weekly Report (MMWR) articles, fact
>sheets, press releases, and announcements. Reproduction of this text is
>encouraged; however, copies may not be sold, and the CDC HIV/STD/TB
>Prevention News Update should be cited as the source of the information.
>*************************************************************
>President Touts Positive Role of Portugal in World Affairs"; Washington
>Times; Cain, Andrew; May 31,2000.
>
>During his visit to Portugal on Tuesday, President Clinton called on the
>European Union (EU) to "address challenges beyond our borders," including
>the AIDS epidemic in Africa. The president also plans to ask leaders at the
>EU meeting in Lisbon today to intensify the fight against AIDS,
>tuberculosis, and malaria. He stated, "I hope we will come out of that
>meeting with a common approach to the global health crisis" that will boost
>scientific research, facilitate the distribution of drugs and vaccines, and
>save more lives.
>*************************
>"Isolation, Purification and Immunological Characterization of Novel Low
>Molecular Weight Protein Antigen CFP 6 From Culture Filtrate of M.
>Tuberculosis"; Vaccine Online ; (06/15/00) Vol. 18, No. 25, P. 2856;
>Bhaskar, Sangeeta; Khanna, S. P.; Mukherjee, Rama
>
> Researchers from India purified a novel immunogenic antigen, CFP 6,
>using a culture filtrate of Mycobacterium tuberculosis. The purified CFP 6
>was studied for its ability to encourage responses in the peripheral blood
>lymphocytes of five groups of people: those who were not treated, active
>pulmonary tuberculosis patients, patients after two to three months of
>chemotherapy, vaccinated professional contacts, and vaccinated/nonvaccinated
>healthy controls. According to the authors, from the National Institute of
>Immunology in New Delhi and the New Delhi TB Center, the protein generated
>high proliferative responses in both healthy individuals and those
>recovering from infection. The researchers also noted that the protein
>caused an potent immune response in vitro and in an in vivo animal model.
>**************************
> BALTIMORE: "Key Health Data for City Show Improvement; Trends Include
>Decline in Teen Birth Rate"; Baltimore Sun (www.sunspot.net) (05/31/00) P.
>2B; Sugg, Diana K.
>
> New statistics show that Baltimore's rates of teenage birth and
>sexually transmitted diseases have decreased. Dr. Peter Beilenson, the
>city's health commissioner, said that medical advances and lifestyle changes
>have helped save more babies and improve overall health....... In 1999, the
>number of tuberculosis cases recorded in Baltimore hit a low for the third
>straight year, and AIDS cases have decreased 46 percent in the last several
>years.
>**************************
>OTHER NEWS:
>*******************************
>MEMPHIS, TENNESSEE: MSNBC: TB scare shakes Maury County business.
>
>June 1, 2000, A case of tuberculosis raised a lot of concern in Maury County
>last week, but is there any reason for people to be worried? Human Resources
>Manager Mike Hagan at the Columbia Specialties plant says there were some
>tense moments last week. "Everything is back to normal, and we have very
>very little absenteeism during this period of time, because we communicated,
>the department of health kept us very aware and involved with what's going
>on." But about this time last week, the phones were lighting up here at
>the plant, and across town at the regional health department. Alarmist
>reports, one from a Nashville TV station spread fear about a case of
>tuberculosis at the plant. "The employees and their family members have
>obviously been very concerned with the reports that have come out."
>Tuberculosis is an infection of the lungs. It used to be the leading killer
>of adults in the U.S. but that was a long time ago. The number of cases drop
>every year and in the U.S. deaths are rare. Still, says Tennessee Department
>of health infectious diseases expert Donna Gibbs says the disease still
>shows up. "Well, with it being 382 cases last year, and there being
>22-thousand in the United States last year, it is still definitely out
>there." Six more workers at the Columbia Specialties plant had positive
>skin tests, but health officials say those numbers can seem much more
>alarming than they really are. "Having a positive skin test does not mean
>that anyone has disease or is in any way contagious to anyone. It only means
>that some
>time in their lifetime, and we don't know when, they breathed in a TB germ."
>Preventive medications were given to those people with positive skin tests.
>Most of the people tested in this case were foreign born. "The immigrants
>may have a higher risk of a positive skin test just because the prevalence
>of the disease is much higher where they came from." Even the worker who
>actually had TB is back at work. "Once we have determined that they're not
>contagious, they can go out, back out into the public and do their every day
>duties." At the plant, Mike Hagan says everyone involved in the case is back
>at work today. "Far as we're concerned it's over with."
>********************************
>CANADA: CTV Television, Inc.; SHOW: CANADA AM; May 24, 2000 8:08:15 -
>8:12:15 Eastern Time; Tuberculosis May Be Making A Comeback; ANCHOR: Dan
>Matheson; GUEST: Dr. Howard Njoo, Health Canada
>
>The host noted that TB is the most infectious disease in the world and it is
>making a comeback in this country and he mentioned the new warning connected
>with a Greyhound bus that went from Vancouver to Nelson, BC on March 6 and
>then from Nelson to Calgary on March 15, where one of the passengers on
>board had tuberculosis. The host introduced Dr. Howard Njoo, the director
>of Health Canada's Infectious Disease Centre. MATHESON asked if it would be
>pretty fair to say that until recently in Canadians' general consciousness
>was that tuberculosis had just dropped off the face of the map and thought
>this disease was gone. Dr. NJOO agreed Canadians may have forgotten about
>tuberculosis and it might be surprising for them to learn that tuberculosis
>is still the number-one infectious disease in the world. He noted
>approximately one-third of the world's entire population is infected by the
>TB bacteria and, from that pool approximately seven to eight million new
>cases of active TB will develop each year and two to three million people
>will die from the disease. Dr. NJOO explained TB is a disease that mainly
>affects the lungs, and essentially, if it's untreated it eats away at your
>lungs and you eventually die from it. MATHESON: said we thought we had a
>cure -- 1940 --Sixty years ago and he asked "What happened? " Dr. NJOO
>said "Well, we did find a cure. The cure right now for TB is antibiotics.
>The problem with the cure, actually, is the fact that you require three to
>four antibiotics. So we're talking more than one antibiotic. And you have
>to take it for quite a substantial period of time -- six months minimum.
>Sometimes even more -- up to a year or so. And I can easily admit that even
>myself I have trouble taking antibiotics when I'm prescribed a course for
>two weeks. So you can imagine someone having to take three or four drugs for
>six months or more. Dr. NJOO said if TB is untreated there's about a
>50-percent case fatality rate, but if it is treated then usually there's no
>problems whatsoever. In response to a question from MATHESON about the
>Greyhound bus incident, Dr. NJOO isaid it is difficult in this particular
>situation and, usually when cases are involved with public transportation
>such as long-distance, international flights they are able to get manifests
>and therefore can do follow up investigations in a more low-key fashion --
>and can actually identify the individuals who were maybe fellow passengers
>at risk and actually take steps to notify them. However, in this particular
>case, he noted, because it's a bus there are no passenger lists --
>therefore, the only action the public health authorities could take was to
>issue a public advisory. Dr. NJOO explained TB is an airborne disease and
>compared to other airborne diseases, it's far less contagious -- compared
>to, measles, influenza, chicken pox. He explained you usually need prolonged
>exposure on the level of several hours or more. He understands that
>individual who had active TB on this bus was there for 12 or 13 hours -- and
>there was a fellow passenger who was seated beside that person for quite a
>substantial period of time and that person may be at risk of having been
>exposed. MATHESON asked about the reported new strain of TB which is
>resistant to drug treatment. Dr. NJOO said this is a growing concern
>worldwide. He noted the problem is that it results from poor treatment of TB
>cases and, since TB treatment requires multiple drugs for such a long period
>of time, if someone doesn't complete their treatment fully it certainly sets
>up a situation where a drug-resistant strain can emerge. Dr. NJOO pointed
>out if that strain is transmitted to someone else unfortunately that second
>person who gets the strain will now have a drug-resistant strain.
>*********************************
>TEXAS: OSHA REGION 6 NEWS RELEASE: Mon, May 8, 2000; OSHA ISSUES WILLFUL
>CITATIONS TO TWO INS FACILITIES IN HOUSTON FOR TUBERCULOSIS EXPOSURE.
>
>The Occupational Safety and Health Administration has issued willful
>citations to the U. S. Justice Department, Immigration and Naturalization
>Services (INS) for two immigration detention facilities in Houston,
>announced the U.S. Department of Labor. The alleged violations were
>discovered during an investigation of two INS detention facilities at 15850
>Export Drive and 126 Northpoint Drive in Houston. An employee complained
>that employees were being exposed to active tuberculosis from individuals
>brought into the INS facilities. Thousands of undocumented individuals are
>processed through the INS detention facilities and stay an average of 48 to
>72 hours. INS employees come into close contact with the individuals during
>apprehension, pat downs, transportation and interrogation. During
>transportation of the individuals, INS employees are enclosed in the
>confined space of the vehicle without personal protective equipment such as
>respirators or masks. Additionally, at the INS facilities, INS employees
>must stay with the individuals in 10'X10' rooms again without personal
>protective equipment. OSHA found that since 1996, INS employees, at the
>above mentioned facilities, have not been provided with personal protective
>equipment or received training on the hazards associated with tuberculosis.
>The Centers for Disease Control (CDC) has categorized this type of work as
>high hazard for exposure to tuberculosis. INS has been aware of the hazards
>of exposing employees to tuberculosis and other airborne viral agents from
>other OSHA investigations. A willful violation is defined as a violation
>in which the employer knew that a hazardous condition existed but made no
>reasonable effort to eliminate it; and in which the hazardous condition
>violated a standard, regulation or the OSH Act. The willful violations for
>each facility are as follows: 1. The employer failed to furnish employment
>and a place of employment which are free from recognized hazards that were
>causing or likely to cause death or serious physical harm to employees -
>29CFR1960.8(a). 2. The employer did not establish and implement a written
>respiratory protection program with worksite specific procedures where
>respirators are necessary to protect the health of employees -
>29CFR1910.139(a)(2). 3. The employer did not provide annual training for
>employees with occupational exposure to bloodborne materials, within one
>year of their previous training - 29CFR1910.1030(g)(2) VI). The
>other-than-serious violations for each facility are as follows: 1. A log of
>all recordable occupational injuries and illnesses was not maintained at
>each establishment - 29CFR1960.67. 2. A supplemental record for each
>occupational injury and illness was not available for inspection at the
>establishment with 6 working days after receiving after receiving that a
>recordable case had occurred. Federal agencies are not assessed penalties
>by OSHA. The private sector equivalent total penalty would be $390,000.00
>for the two federal facilities.
>*********************************************
>The Wall Street Transcript publishes Outlook for Biotechnology Issue;
>Tuesday, May 30, 2000.
>
>PRNewswire via COMTEX/ -This business report notes that InterMune
>Pharmaceuticals has a lead product named "Actimmune" which is about to begin
>a Phase III clinical trial in idiopathic pulmonary fibrosis as well as
>multi-drug resistant tuberculosis.
>*******************************
>White House Fact Sheet: U.S.-Portugal Bilateral Issues; Tuesday, May 30,
>2000; WASHINGTON, May 30 /U.S. Newswire/
>
>The following was released today by the White House: The United States and
>Portugal have enjoyed close and friendly relations for two centuries.....The
>science and technology cooperation between the United States and Portugal
>includes extensive research collaboration in infectious diseases, ocean and
>atmospheric sciences, and archeology, as well as cooperative work to help
>train the next generation of scientists. Under a new cooperative project,
>health experts in the United States and Portugal will work together to
>combat malaria in Sao Tome and Principe..............U.S. and Portuguese
>researchers also collaborate on other infectious diseases, particularly
>HIV/AIDS and tuberculosis. The U.S. National Institutes of Health (NIH) and
>a number of Portuguese institutions are supporting a cooperative effort to
>develop state-of-the-art AIDS treatments, with potential benefit for all
>nations. Other NIH-supported collaborative teams are studying the immunology
>of tuberculosis, new drug-resistant disease threats, and an unusual pathogen
>that could strike down those already suffering from AIDS......
>********************************
>Africa News; WorldSpace, Satellite Create First Public Health Channel; May
>22, 2000.
>Washington, DC (WorldSpace Foundation, May 22, 2000) - WorldSpace Foundation
>and SATELLIFE have announced the launch of a new health service that will
>provide a steady stream of material to assist medical professionals in
>Africa in the diagnosis, prevention and treatment of diseases that are
>ravaging the continent. This unique new service, called the Public Health
>Channel, will overcome the barriers of poverty, geography, and unreliable
>communications infrastructures to help stop the decimation and maiming of
>Africa's population from such diseases as HIV/AIDS, malaria, and
>tuberculosis....... The goal of SATELLIFE's information services is to
>connect the health practitioner in the developing world with a range of
>high-quality information resources in a cost-effective manner, by making use
>of the most affordable, efficient and appropriate technology," stated
>SATELLIFE executive director, Holly Ladd. "The Public Health Channel will
>employ the technology of the WorldSpace system to exponentially increase the
>amount of information health practitioners throughout Africa can access -
>information that most health practitioners in the United States and Europe
>take for granted." The Public Health Channel will be launched in four
>countries: Zimbabwe, Kenya, Uganda and Ethiopia. After an initial testing
>period, the project will expand to other African countries as funding
>becomes available. "We are limited only by our resources," said Ms. Ladd.
>"We envision a time in the near future when the Public Health Channel is
>available to every doctor and nurse throughout Africa, no matter how remote
>their location." WorldSpace receivers will be placed in hospitals, medical
>schools, medical libraries, health clinics, health ministries and research
>settings. WorldSpace receivers provide crystal clear digital audio channels,
>and can also serve as a modem, downloading text-based material and dynamic
>images from the AfriStar satellite directly to computers..... SATELLIFE is
>an international not-for-profit humanitarian organization whose mission is
>to improve health by enhancing connectivity among professionals in the field
>via electronic communications and exchanges of information in the areas of
>public health, medicine, and the environment..... WorldSpace Foundation is
>a 501(c)(3) nonprofit organization created in 1997. Headquartered in
>Washington, DC, its work encompasses Africa, Asia-Pacific, Latin America and
>the Caribbean. The WorldSpace homepage is at: www.worldspace.org
>**********************************
>Main priorities of the G8 Summit, from the G8 Summit Home Page: Statement by
>Then Prime Minister Keizo Obuchi Discussion Group on the Kyushu-Okinawa
>Summit; Keizo Obuchi; Former Prime Minister; February 28, 2000
>
>I would like to begin by expressing my heartfelt appreciation to all of you
>for taking time out of your busy schedules to participate in this meeting
>today. In October last year, I had an opportunity to hear the opinions of
>experts from a variety of fields on what perspectives we should consider in
>our approach to the Kyushu-Okinawa Summit. Soon after, Japan officially
>assumed the G8 Presidency and has begun the process of consultation among
>the G8........ In discussions related to development the G8 have once again
>acknowledged that the issue of infectious diseases is of great importance.
>Although great strides have been achieved in the battle against such
>diseases as polio, the problem of HIV/AIDS is one that continues to
>increase, with an estimated 33 million people infected worldwide, and every
>year it is estimated that more than 300 million people contract malaria.
>Also, it is thought that tuberculosis, once thought of as a disease that had
>been conquered, is now the primary cause of fatalities among patients who
>have contracted HIV in developing countries. Tuberculosis is reappearing in
>the countries of the G8 and around the world. On such issues surrounding
>infectious diseases, the G8 will have to discuss toward the Kyushu-Okinawa
>Summit......
>**********************************
>MICHIGAN: State gets $6 million to fight bovine TB; Federal aid will help
>rid dairy herd of deadly disease; Gebe Martinez; Detroit News.
>
>Michigan won $6 million in special federal aid Thursday to help fight bovine
>tuberculosis, a deadly disease that is contaminating the state's cows. The
>bovine TB aid is urgently needed because the U.S. Department of Agriculture
>announced recently that the federal government plans to take away Michigan
>state's tuberculosis-free status next month. In response, Michigan will
>test all 12.2 million dairy cows and beef cattle for tuberculosis and
>Michigan's cattle and dairy farmers will find it tougher to sell their
>products. The testing program is likely to sharply reduce the marketability
>of Michigan cattle as states place greater restrictions on cattle coming
>from Michigan. The loss of the TB- free status could cost Michigan farmers
>up to $156 million over 10 years. "This money is critical in order to
>develop a comprehensive strategy to help Michigan's farm families fight
>bovine tuberculosis," said Rep. Dave Camp, R-Midland, who lobbied heavily
>for the money in the House. "This money will help eradicate the disease,
>compensate farmers for their losses and research the bovine tuberculosis
>problem," he added. Sen. Spencer Abraham lobbied for the aid in the Senate.
>"I know these funds will quickly be put to use in our state." Camp and
>Abraham worked to get the money into the crop insurance bill, which was part
>of the emergency bill passed by the House on Thursday.
>****************************
>GEORGIA: Atlanta Journal Constitution: Judge wants details on Fulton jail
>Crowded conditions: County officials say they have data; Alfred Charles;
>Saturday, May 27, 2000.
>
>A federal judge has ordered Fulton County to give a detailed snapshot of its
>jail population when the county submits its plan next month to reduce
>crowding.... . The information the judge has asked for includes:...... the
>number of inmates who are HIV positive or have tuberculosis.......... Fulton
>is trying to comply with a ruling by Shoob to reduce chronic crowding at its
>jail, an order prompted by a class-action lawsuit filed by HIV-positive
>inmates who insisted they were not receiving adequate health care. The
>county expects to submit a detailed plan on June 19 on how it will reduce
>overcrowding at the jail, which usually has about 1,000 more prisoners than
>the 2,500 it was designed to hold.
>***********************************
>Frogs Help Unlock Secrets of Tuberculosis; May 25, 2000.
>
> STANFORD (BW HealthWire) - Frogs get tuberculosis too, and by studying the
>amphibian version of this disease, Stanford researchers have pinpointed two
>genes that may enable the TB bacterium to survive for decades within the
>human body. The findings may help clear up the mystery of how the TB
>bacterium sets up house within the very immune system cells that are
>supposed to destroy it. The bacterium that causes human TB belongs to a
>notorious family of killers that victimizes many other animals, said Lalita
>Ramakrishnan, MD, PhD, a senior research scientist in the lab of Stanley
>Falkow, PhD, professor of microbiology and immunology. One species of
>bacterium sickens cattle, for example, while another attacks frogs, fishes,
>and other cold-blooded animals. But like 90 percent of the 2 billion people
>infected by the human TB bacterium, most infected frogs don't get sick.
>Instead they develop a lifelong "silent" infection in which the bacteria
>linger within the body without causing symptoms. However, if the frogs'
>immune system is weakened, "they will get rip-roaring disease and die,"
>Ramakrishnan said. The same thing can happen in people with silent
>tuberculosis infection whose immune system is then throttled by the AIDS
>virus, for example. During this clinically silent or latent period, the
>bacteria bed down inside the immune system cells known as macrophages, which
>normally annihilate bacteria and other interlopers. Responding to the
>invasion, macrophages may huddle with other immune cells to form little
>nodules called granulomas, or tubercles. Tubercles gave the disease its name
>and may represent a standoff between the immune system's attempts to wall in
>the organism and the bacterium's efforts to make a snug home for itself,
>Ramakrishnan said. Because of the difficulties of working with human TB,
>scientists know little about how the bacterium alters its biochemistry to
>persist within macrophages and tubercles. Ramakrishnan, Falkow and Nancy A.
>Federspiel, PhD, associate director of the Stanford Center for DNA Sequence
>and Technology, decided to address the question by finding out which genes
>were activated in the frog bacterium when it dwells in macrophages or
>tubercles. To identify the active genes, the team manipulated the bacteria
>so that some of their genetic on-off switches were attached to a gene that
>codes for a glowing green protein. Then they used a machine to pick out the
>macrophages that contained luminous bacteria. By determining which on-off
>switches had been turned on, they could identify which genes the bacteria
>had activated to cope with the hostile environment within a macrophage or
>tubercle. They found that the bacterium switches on six genes when
>inhabiting a macrophage that are not turned on when the bacterium is growing
>in a laboratory culture. When living in a tubercle, the bacterium switches
>on an additional four genes. All of the genes are similar to genes in the
>human TB bacterium -- no surprise, since the two species of bacteria are
>close relatives. Two of the genes were particularly interesting,
>Ramakrishnan said, because they belong to "a family of mystery genes" whose
>function is unknown, even though they constitute about 5 to 10 percent of
>the bacterium's genetic material. When the researchers disrupted either of
>these two genes, they found that the bacteria could no longer reproduce
>inside macrophages. Disruption of one of the genes also handicapped the
>bacterium's ability to live within tubercles. "At least some members of this
>gene family play a role in virulence in this bacterium," Ramakrishnan said.
>"It's very likely that the genes we found using this system will be
>important in human TB as well," she added. She and her colleagues report
>their findings in the May 26 issue of Science. The results also demonstrate
>that frog TB makes a good model system for studying the human disease,
>Ramakrishnan said. The amphibian bacterium is safer to work with. Because it
>doesn't travel through the air like the human TB bacterium, no elaborate
>facilities to prevent infection are required. And the frog bacterium grows
>five times as fast as its human counterpart. Although the frog bacterium is
>not a danger to humans, it can cause mild illness. Reflecting its penchant
>for cold-blooded hosts, when it invades the human body it seeks the coolest
>region -- the skin - producing granulomas there. These infections, which can
>easily be treated with antibiotics, are common among people who handle fish
>and among swimmers, Ramakrishnan said. The work was supported by a grant
>from the National Institutes of Health.
>***********************************
>U.S., Europe Step Up War on Third World Disease; May 31, 2000.
>
>LISBON (Reuters) - The U.S. and the European Union said Wednesday they would
>work together to fight diseases such as AIDS, malaria and tuberculosis that
>kill over five million people each year, mainly in the Third World. A
>one-day summit attended by President Clinton, Portugal's Prime Minister
>Antonio Guterres and EU Commission chief Romano Prodi agreed to seek funds
>from both governments and the private sector to combat the spread of
>disease."Infectious diseases are the leading cause of death worldwide,
>causing nearly half of all deaths among people under age 45," they said in a
>statement. "The developing world, especially Africa, bears an enormous
>burden from these diseases, which not only destroy lives but also perpetuate
>the cycle of sickness and poverty," they added. Amongst joint steps agreed
>at the summit, held in the former royal palace of Queluz outside Lisbon,
>were new financial investment incentives and public/private partnerships to
>make drugs and vaccines more available and affordable. They also said that
>they would "encourage" the G-8, the world's seven richest states plus
>Russia, to address the issue at an upcoming summit in Okinawa, Japan.
>********************************************
>United Press International; June 1, 2000, Thursday; Japan want talks on
>infectious disease; MOTOKO NAITO.
>
>TOKYO, June 1: The Japanese government is having final negotiations with
>other G-8 countries to set up a foundation during the July Kyushu-Okinawa
>summit for rooting out any infectious diseases such as AIDS and
>tuberculosis, the Kyodo News Agency reported Thursday. The government is
>mapping out a $92-million foundation to back up activities of
>non-governmental organizations to fight against infectious diseases, the
>news agency said. The purpose of creating the foundation is to eliminate
>gaps in every region and every country by bringing together the members of
>the G-8, and to establish a network for their activities by strengthening
>cooperative relations between non-governmental organizations and private
>enterprises. The foundation is going to call for financial cooperation from
>private firms worldwide, along with donations from the G-8 countries, it
>said. The office of the foundation is scheduled to be set up within an
>international organization, the news agency said.
>****************************************************************
>OTHER JOURNAL ARTICLES:
>*********************************************
>Antimicrobial Agents and Chemotherapy, June 2000, p. 1458-1462, Vol. 44, No.
>6; American Society for Microbiology; Evaluation of Rifalazil in Long-Term
>Treatment Regimens for Tuberculosis in Mice; Carolyn M. Shoen, Sharon E.
>Chase, Michelle S. DeStefano, Tami S.Harpster, Alex J. Chmielewski, and
>Michael H. Cynamon.
>
>Report notes that previous experiments with rifalazil (RLZ) (also known as
>KRM-1648) in combination with isoniazid (INH) demonstrated its potential for
>short-course treatment of Mycobacterium tuberculosis infection. In this
>study, the authors investigated the minimum RLZ-INH treatment time required
>to eradicate M. tuberculosis in a murine model. RLZ-INH treatment for 6
>weeks or longer led to a nonculturable state. They killed groups of mice
>treated in parallel following an observation period to evaluate regrowth.
>They report RLZ-INH treatment for a minimum of 10 weeks was necessary to
>maintain a nonculturable state through the observation period. They added
>pyrazinamide (PZA) to this regimen to determine whether the treatment
>duration could be further reduced. They found in this model, the addition of
>PZA did not shorten the duration of RLZ-INH treatment required to eradicate
>M. tuberculosis from mice. They report the addition of PZA did reduce the
>number of mice in which regrowth occurred, but the reduction was not
>statistically significant.
>**********************
>Infection and Immunity, June 2000, p. 3097-3102, Vol. 68, No. 6; DNA
>Vaccination against Tuberculosis: Expression of a Ubiquitin-Conjugated
>Tuberculosis Protein Enhances Antimycobacterial Immunity; Giovanni Delogu,
>Angela Howard, Frank M. Collins, and Sheldon L. Morris.
>
>Report notes that genetic immunization is a promising new technology for
>developing vaccines against tuberculosis that are more effective. In the
>present study, authors evaluated the effects of intracellular turnover of
>antigens expressed by DNA vaccines on the immune response induced by these
>vaccines in a mouse model of pulmonary tuberculosis. They report the
>mycobacterial culture filtrate protein MPT64 was expressed as a chimeric
>protein fused to one of three variants of the ubiquitin protein (UbG, UbA,
>and UbGR) known to differentially affect the intracellular processing of the
>coexpressed antigens. They found that immunoblot analysis of cell lysates of
>in vitro-transfected cells showed substantial differences in the degradation
>rate of ubiquinated MPT64 (i.e., UbG64 < UbA64 < UbGR64). They report the
>specific immune response generated in mice correlated with the stability of
>the ubiquitin-conjugated antigen and the UbA64 DNA vaccine induced a weak
>humoral response compared to UbG64, and a mixed population of interleukin-4
>(IL-4)- and gamma interferon (IFN-)-secreting cells. They say vaccination
>with the UbGR64 plasmid generated a strong Th1 cell response (high IFN-, low
>IL-4) in the absence of a detectable humoral response; aerogenic challenge
>of vaccinated mice with Mycobacterium tuberculosis indicated that
>immunization with both the UbA64- and UbGR64-expressing plasmids evoked an
>enhanced protective response compared to the vector control. They observed
>that expression of mycobacterial antigens from DNA vaccines as fusion
>proteins with a destabilizing ubiquitin molecule (UbA or UbGR) shifted the
>host response toward a stronger Th1-type immunity which was characterized by
>low specific antibody levels, high numbers of IFN--secreting cells, and
>significant resistance to a tuberculous challenge.
>********************************
>Infection and Immunity, June 2000, p. 3269-3274, Vol. 68, No. 6; American
>Society for Microbiology; Identification and Characterization of Murine
>Cytotoxic T Cells That Kill Mycobacterium tuberculosis; Celio L. Silva, and
>Douglas B. Lowrie.
>
>Report notes that as researchers seek to develop and evaluate new vaccines
>against tuberculosis, it is desirable to understand the mechanisms of
>protective immunity in available models. Authors point out that adoptive
>transfer of protection with hsp65-specific T-cell clones from infected or
>vaccinated mice into naïve mice had indicated that cytotoxic T cells can
>make a major contribution to protection. The authors characterized 28 CD4+
>CD8 and 28 CD4 CD8+ hsp65-specific T-cell clones derived from infected or
>vaccinated mice. They report half of the CD4+ CD8 and 64% of the CD4 CD8+
>clones were cytotoxic and cytotoxicity was associated with high expression
>of CD44 and gamma interferon production. They observed that most (86%) of
>the cytotoxic CD4+ CD8 clones lysed target cells via the Fas-FasL pathway,
>and most (83%) of the cytotoxic CD4 CD8+ clones lysed target cells via
>cytotoxic granules. They say only the clones using the granule-mediated
>pathway caused substantial loss of viability of virulent Mycobacterium
>tuberculosis during lysis of infected macrophages, and the degree of killing
>closely correlated with the availability of granule marker enzyme activity.
>They conclude granule-mediated cytotoxicity may have a key role in
>protection against tuberculosis by delivering mycobactericidal granule
>contents.
>*****************************
>Infection and Immunity, June 2000, p. 3674-3679, Vol. 68, No. 6; American
>Society for Microbiology; Lack of Protection in Mice and Necrotizing
>Bronchointerstitial Pneumonia with Bronchiolitis in Guinea Pigs Immunized
>with Vaccines Directed against the hsp60 Molecule of Mycobacterium
>tuberculosis; Oliver C. Turner, Alan D. Roberts, Anthony A. Frank, Susan W.
>Phalen, David M. McMurray, Jean Content, Olivier Denis, Sushila D'Souza,
>Audrey Tanghe, Kris Huygen, and Ian M. Orme.
>
>Authors say the hsp60 and hsp70 heat shock protein antigens of Mycobacterium
>tuberculosis were tested as potential vaccine candidates, using purified
>recombinant protein antigens or antigens encoded in the form of a DNA
>plasmid vaccine. They report vaccinated guinea pigs with a mixture of the
>two proteins showed no evidence of resistance to low-dose aerosol challenge
>infection and quickly developed severe lung damage characterized by
>necrotizing bronchointerstitial pneumonia and bronchiolitis. As a result,
>they turned instead to a DNA vaccination approach using a plasmid encoding
>the hsp60 antigen of M. tuberculosis. Authors report that, while immunogenic
>in mice, vaccination with plasmid DNA encoding hsp60 was not protective in
>that model or in the guinea pig model and again gave rise to similar severe
>lung damage. They conclude their results seriously questions the safety of
>vaccines against tuberculosis that target highly conserved heat shock
>proteins.
>*******************************
>Infection and Immunity, June 2000, p. 3322-3326, Vol. 68; American Society
>for Microbiology; Interleukin-6 Induces Early Gamma Interferon Production in
>the Infected Lung but Is Not Required for Generation of Specific Immunity to
>Mycobacterium tuberculosis Infection; Bernadette M. Saunders, Anthony A.
>Frank, Ian M. Orme, and Andrea M. Cooper.
>
>Report notes that immunity to Mycobacterium tuberculosis is dependent upon
>the generation of a protective gamma interferon (IFN-)-producing T-cell
>response and recent studies have suggested that interleukin-6 (IL-6) is
>required for the induction of a protective T-cell response and that IL-4 may
>suppress the induction of IFN-. To evaluate the role of the cytokines IL-6
>and IL-4 in the generation of pulmonary immunity to M. tuberculosis, these
>investigators infected IL-6 and IL-4 knockout mice with M. tuberculosis via
>aerosol. They observed the absence of IL-6 led to an early increase in
>bacterial load with a concurrent delay in the induction of IFN-. However,
>they report the mice were able to contain and control bacterial growth and
>developed a protective memory response to secondary infection. They point
>out this demonstrates that while IL-6 is involved in stimulating early IFN-
>production, it is not essential for the development of protective immunity
>against M. tuberculosis. And in contrast, while the absence of IL-4 resulted
>in increased IFN- production, this had no significant effect upon bacterial
>growth.
>********************************
>Infection and Immunity, June 2000, p. 3314-3321, Vol. 68, No. 6; American
>Society for Microbiology; Antigenic Equivalence of Human T-Cell Responses to
>Mycobacterium tuberculosis-Specific RD1-Encoded Protein Antigens ESAT-6 and
>Culture Filtrate Protein 10 and to Mixtures of Synthetic Peptides; Sandra M.
>Arend, Annemieke Geluk, Krista E. van Meijgaarden, Jaap T. van Dissel,
>Michael Theisen, Peter Andersen, and Tom H. M. Ottenhoff.
>
>This report notes that the early secreted antigenic target 6-kDa protein
>(ESAT-6) and culture filtrate protein 10 (CFP-10) are promising antigens for
>reliable immunodiagnosis of tuberculosis; both antigens are encoded by RD1,
>a genomic region present in all strains of Mycobacterium tuberculosis and M.
>bovis but lacking in all M. bovis bacillus Calmette-Guérin vaccine strains.
>Also, production and purification of recombinant antigens are laborious and
>costly, precluding rapid and large-scale testing. These authors aimed to
>develop alternative diagnostic reagents, and they investigated whether
>recombinant ESAT-6 (rESAT-6) and recombinant CFP-10 (rCFP-10) can be
>replaced with corresponding mixtures of overlapping peptides spanning the
>complete amino acid sequence of each antigen. They report proliferation of
>M. tuberculosis-specific human T-cell lines in response to rESAT-6 and
>rCFP-10 and that in response to the corresponding peptide mixtures were
>almost completely correlated ® = 0.96, P < 0.0001 for ESAT-6; r = 0.98, P <
>0.0001 for CFP-10). More importantly, they say, the same was found when
>gamma interferon production by peripheral blood mononuclear cells in
>response to these stimuli was analyzed ® = 0.89, P < 0.0001 for ESAT-6; r =
>0.89, P < 0.0001 for CFP-10). They report whole protein antigens and the
>peptide mixtures resulted in identical sensitivity and specificity for
>detection of infection with M. tuberculosis. They observe that peptides in
>each mixture contributing to the overall response varied between individuals
>with different HLA-DR types and responses to CFP-10 were significantly
>higher in the presence of HLA-DR15, which is the major subtype of DR2. They
>sum up that their results show that mixtures of synthetic overlapping
>peptides have potency equivalent to that of whole ESAT-6 and CFP-10 for
>sensitive and specific detection of infection with M. tuberculosis, and
>peptides have the advantage of faster production at lower cost.
>*****************************
>Journal of Bacteriology, June 2000, p. 3331-3335, Vol. 182, No. 12; American
>Society for Microbiology; Genetic Antagonism and Hypermutability in
>Mycobacterium smegmatis; Ponniah Karunakaran and Julian Davies.
>
>Report notes that multidrug-resistant strains of Mycobacterium tuberculosis
>are a serious and continuing human health problem, and such strains may
>contain as many as four or five different mutations, and M. tuberculosis
>strains that are resistant to both streptomycin and rifampin contain
>mutations in the rpsL and rpoB genes, respectively. Authors observe that
>coexisting mutations of this kind in Escherichia coli have been shown to
>interact negatively (S. L. Chakrabarti and L. Gorini, Proc. Natl. Acad. Sci.
>USA 72:2084-2087, 1975; S. L. Chakrabarti and L. Gorini, Proc. Natl. Acad.
>Sci. USA 74:1157-1161, 1977). They investigated this possibility in
>Mycobacterium smegmatis by analyzing the frequency and nature of spontaneous
>mutants that are resistant to either streptomycin or rifampin or to both
>antibiotics. They isolated mutants resistant to streptomycin from
>characterized rifampin-resistant mutants of M. smegmatis under selection
>either for one or for both antibiotics. Similarly, they isolated from
>streptomycin-resistant strains, mutants resistant to rifampin . They
>observed the second antibiotic resistance mutation occurred at a lower
>frequency in both cases. They comment, in both cases a very high rate of
>reversion of the initial antibiotic resistance allele was detected when
>single antibiotic selection was used; the majority of strains resistant to
>only one antibiotic were isolated by this process. They report
>determinations of rates of mutation to antibiotic resistance in M. smegmatis
>showed that the frequencies were enhanced up to 104-fold during stationary
>phase. They comment that, if such behavior is also typical of slow-growing
>pathogenic mycobacteria, these studies suggest that the generation of
>multiply drug-resistant strains by successive mutations may be a more
>complex genetic phenomenon than suspected.
>*******************************
>Journal of Bacteriology, June 2000, p. 3394-3399, Vol. 182, No. 12;
>American Society for Microbiology;
>A Point Mutation in the mma3 Gene Is Responsible for Impaired Methoxymycolic
>Acid Production in Mycobacterium bovis BCG Strains Obtained after 1927;
>Marcel A. Behr, Benjamin G. Schroeder, Jacquelyn N. Brinkman, Richard A.
>Slayden, and Clifton E. Barry.
>
>This report notes that BCG vaccines are substrains of Mycobacterium bovis
>derived by attenuation in vitro, and after the original attenuation (1908 to
>1921), BCG strains were maintained by serial propagation in different BCG
>laboratories (1921 to 1961). As a result, authors report, various BCG
>substrains developed which are now known to differ in a number of genetic
>and phenotypic properties. Authors comment that, to date, none of these
>differences has permitted a direct phenotype-genotype link and, since BCG
>strains differ in their abilities to synthesize methoxymycolic acids and
>since recent work has shown that the mma3 gene is responsible for
>O-methylation of hydroxymycolate precursors to form methoxymycolic acids,
>they analyzed methoxymycolate production and mma3 gene sequences for a
>genetically defined collection of BCG strains. They found that BCG strains
>obtained from the Pasteur Institute in 1927 and earlier produced
>methoxymycolates in vitro, but that those obtained from the Pasteur
>Institute in 1931 and later all failed to synthesize methoxymycolates.
>Furthermore, authors report the mma3 sequence of the latter strains differs
>from that of Mycobacterium tuberculosis H37Rv by a point mutation at bp 293.
>They say site-specific introduction of this guanine-to-adenine mutation into
>wild-type mma3 (resulting in the replacement of glycine 98 with aspartic
>acid) eliminated the ability of this enzyme to produce O-methylated mycolic
>acids when the mutant was cloned in tandem with mma4 into Mycobacterium
>smegmatis. They conclude their findings indicate that a point mutation in
>mma3 occurred between 1927 and 1931, and that this mutant population became
>the dominant clone of BCG at the Pasteur Institute.
>****************************
>Infection and Immunity, June 2000, p. 3704-3709, Vol. 68, No. 6; American
>Society for Microbiology; In Vivo Administration of Mycobacterial Cord
>Factor (Trehalose 6,6'-Dimycolate) Can Induce Lung and Liver Granulomas and
>Thymic Atrophy in Rabbits; Naoko Hamasaki, Ko-Ichi Isowa, Kohachi Kamada,
>Yoshitake Terano, Takayuki Matsumoto, Tetsuo Arakawa, Kazuo Kobayashi, and
>Ikuya Yano.
>
>Report notes that trehalose 6,6'-dimycolate (TDM) is a cell surface molecule
>of Mycobacterium tuberculosis. Authors report that TDM induced a loss of
>body weight and prominent granulomas in the liver and lungs by the
>intravenous injection of TDM into rabbits. They observe that TDM also
>induced atrophy of the thymus and spleen due to apoptosis. By contrast, they
>say sulfolipid (2,3,6,6'-tetraacyl trehalose 2'-sulfate) induced neither
>toxicity, nor granuloma formation, nor atrophy of the thymus and spleen.
>They say the histopathological changes in rabbits were more dramatic than in
>mice and they speculate the rabbit model may be more sensitive and may
>provide more information on the beneficial or pathological effects of TDM.
>***********************************
>Infection and Immunity, June 2000, p. 3090-3096, Vol. 68, No. 6; American
>Society for Microbiology; Protection against Virulent Mycobacterium avium
>Infection following DNA Vaccination with the 35-Kilodalton Antigen Is
>Accompanied by Induction of Gamma Interferon-Secreting CD4+ T Cells; Ela
>Martin, Arun T. Kamath, James A. Triccas, and Warwick J. Britton.
>
>This report notes that Mycobacterium avium is an opportunistic pathogen that
>primarily infects immunocompromised individuals, although the frequency of
>M. avium infection is also increasing in the immunocompetent population; the
>antigen repertoire of M. avium varies from that of Mycobacterium
>tuberculosis, with the immunodominant 35-kDa protein being present in M.
>avium and Mycobacterium leprae but not in members of the M. tuberculosis
>complex. Here authors show that a DNA vector encoding this M. avium 35-kDa
>antigen (DNA-35) induces protective immunity against virulent M. avium
>infection, and this protective effect persists over 14 weeks of infection.
>In C57BL/6 mice, they report DNA vaccines expressing the 35-kDa protein as a
>cytoplasmic or secreted protein, both induced strong T-cell gamma interferon
>(IFN-) and humoral immune responses. They also noted the antibody response
>was to conformational determinants, confirming that the vector-encoded
>protein had adopted the native conformation, and DNA-35 immunization
>resulted in an increased activated/memory CD4+ T-cell response, with an
>accumulation of CD4+ CD44hi CD45RBlo T cells and an increase in
>antigen-specific IFN- production. They report the protective effect of the
>DNA-35 vectors against M. avium infection was comparable to that of
>vaccination with Mycobacterium bovis BCG and significantly greater than that
>for previous treated infection with M. avium. They conclude their results
>illustrate the importance of the 35-kDa protein in the protective response
>to M. avium infection and indicate that DNA vaccination successfully
>promotes a sustained level of protection during chronic M. avium infection.
>***************************
>Journal of Bacteriology, June 2000, p. 3590-3592, Vol. 182, No. 12; American
>Society for Microbiology; In Vivo Splicing and Functional Characterization
>of Mycobacterium leprae RecA; Klaus Frischkorn, Burkhard Springer, Erik C.
>Böttger, Elaine O. Davis, M. Joseph Colston, and Peter Sander.
>
>Report notes the he RecA proteins from Mycobacterium tuberculosis and
>Mycobacterium leprae contain inteins, and in contrast to the M. tuberculosis
>RecA, the M. leprae RecA is not spliced in Escherichia coli. Authors report
>that M. leprae RecA is functionally spliced in Mycobacterium smegmatis and
>produces resistance toward DNA-damaging agents and homologous recombination.
>
>*************************
>Science 2000 May 26; 288: 1436-1439; Granuloma-Specific Expression of
>Mycobacterium Virulence Proteins from the Glycine-Rich PE-PGRS Family;
>Lalita Ramakrishnan, Nancy A. Federspiel, Stanley Falkow.
>
>Report notes that pathogenic mycobacteria, including the agent of
>tuberculosis, Mycobacterium tuberculosis, must replicate in macrophages for
>long-term persistence within their niche during chronic infection: organized
>collections of macrophages and lymphocytes called granulomas. Authors
>identified several genes preferentially expressed when Mycobacterium
>marinum, the cause of fish and amphibian tuberculosis, resides in host
>granulomas and/or macrophages. They found two were homologs of M.
>tuberculosis PE/PE-GRS genes, a family encoding numerous repetitive
>glycine-rich proteins of unknown function. They report mutation of two
>PE-PGRS genes produced M. marinum strains incapable of replication in
>macrophages and with decreased persistence in granulomas. They conclude that
>their results establish a direct role in virulence for some PE-PGRS
>proteins.
>**********************
>Science 2000 May 26; 288: 1314-1315. (in News of the Week) MICROBIOLOGY: New
>Clues to How the TB Bacillus Persists; Ingrid Wickelgren.
>
>Writer notes that how the tuberculosis bacterium manages to persist silently
>in the body for years to decades before exploding in disease has long been a
>mystery--one just now beginning to be solved. She reports that, two groups,
>one of which reports its results in this journal, have identified genes that
>may be required for persistent TB infection. She speculates that if this is
>true, the proteins made by the genes could be good targets for new drugs
>against TB, which are badly needed because the pathogen is becoming
>resistant to current medications.
>*************************
>OTHER:
>**************************
>U.S. DEPARTMENT OF AGRICULTURE Animal and Plant Health Inspection Service 9
>CFR Part 77 Tuberculosis in Cattle, Bison, Goats, and Captive Cervids; State
>and Zone Designations
>
>Wednesday, May 31, 2000 5:28 PM EST Washington, DC, May. 31, 2000 (FedNet
>via COMTEX) - We are reopening and extending the comment period for our
>proposed rule that would amend the bovine tuberculosis regulations to
>establish new levels of tuberculosis risk classifications to be applied to
>States and zones within States. The proposed rule would also classify States
>and zones according to their tuberculosis risk with regard to captive
>cervids. Additionally, it would amend the regulations to specify that the
>regulations apply to goats as well as to cattle, bison, and captive cervids,
>and would increase the amount of testing that must be done before certain
>cattle, bison, and goats may be moved interstate. This action will allow
>interested persons additional time to prepare and submit comments. We are
>also advising the public that we are hosting two public hearings on the
>proposed rule.
>
>DATES: We invite you to comment on Docket No. 99-038-1. We will consider all
>comments that we receive by June 16, 2000. We will also consider comments
>made at public hearings to be held in Albuquerque, NM, on June 14, 2000,
>from 8 a.m. to noon, and in Lansing, MI, on June 15, 2000, from 6 p.m. to 9
>p.m. AGENCY: Animal and Plant Health Inspection Service, USDA. ACTION:
>Proposed rule; reopening and extension of comment period; notice of public
>hearings.
>
>