Mpex Pharmaceuticals, Inc. today
announced the initiation of a Phase 1b clinical trial with its lead
compound, MP-376, in patients with cystic fibrosis (CF). MP-376 is a
proprietary aerosolized formulation of the antibiotic levofloxacin that is
being developed for the treatment of chronic lung infections due to
Pseudomonas aeruginosa in CF patients. Preclinical and early clinical
studies indicate that active levofloxacin concentrations in pulmonary
tissues after MP-376 administration are markedly increased compared to
those achieved when the antibiotic is delivered by other routes of
administration. The trial is being conducted under an open Investigational
New Drug Application (IND) that has been filed with the U.S. Food and Drug
Administration (FDA).

MP-376 employs a number of formulation enhancements and has been
designed for use in conjunction with a high efficiency nebulizer to rapidly
deliver high pulmonary concentrations of levofloxacin to the lung. Compared
to other treatment options, regimens of MP-376 are projected to have
powerful activity against key bacterial pathogens resident in the CF lung
and provide exposures that reduce the selection of bacterial resistance.

The current clinical trial is a randomized, placebo-controlled,
multi-center study in the U.S. that will evaluate the safety, tolerability,
pharmacokinetics, and microbiological effects of multiple daily doses of
MP-376 in stable cystic fibrosis patients with chronic infections due to
Pseudomonas aeruginosa. A total of 39 patients are planned to be enrolled,
and several dose levels will be evaluated.

This study complements a single dose, dose escalation study of MP-376
that was recently completed in healthy volunteers and CF patients in
Denmark. Together, the single and multiple dose trials are expected to
support a larger Phase 2 study that the company plans to initiate in 2008.

“We are collaborating with numerous CF physicians who are enthusiastic
about the potential for MP-376 in treating difficult chronic lung
infections,” stated Dr. Michael Dudley, Senior Vice President of Research
and Development for Mpex. “Based on our work to date, we believe MP-376 has
the potential to provide doctors and patients with a convenient, powerful
and well-tolerated new treatment option that addresses key pathogens in CF
and minimizes the potential for drug resistance. We look forward to working
with the CF community to rapidly advance MP-376 through clinical
development.”

About Mpex Pharmaceuticals:

Mpex Pharmaceuticals is a clinical stage biopharmaceutical company
whose mission is to develop critical new therapies to combat the growing
issue of antibiotic resistance. The company’s initial focus is on the
treatment of gram-negative bacterial pathogens such as Pseudomonas
aeruginosa, for which limited effective treatment options exist. Mpex’s
lead product candidate, MP-376, is currently in Phase 1b clinical trials
and is being developed for the treatment of chronic lung infections due to
Pseudomonas aeruginosa in cystic fibrosis patients. The company is also
pursuing applications related to its extensive intellectual property estate
around inhibitors of bacterial multi-drug resistant (MDR) efflux pumps
(EPIs). Efflux pumps have been shown to be a primary source of drug
resistance in gram-negative organisms. Mpex has identified a number of
promising lead EPI compounds that, when combined with existing antibiotics,
have been shown to restore the potency of these existing antibiotics
against previously resistant gram-negative organisms. These compounds are
being profiled in further preclinical studies and may be candidates for
clinical development. Additional information about Mpex can be obtained
from the company’s website at mpexpharma.

Mpex Pharmaceuticals, Inc.
mpexpharma Continue reading →

Three of the five candidates running for the job of the next Executive Director of the Global Fund to Fight AIDS, Tuberculosis and Malaria lead the field, with the edge going to one, according to an Editorial in this week’s issue of The Lancet.

On Nov 1, the next Executive Director of the Global Fund will be announced. The five candidates are: Hilde Johnson, senior adviser to the President of the African Development Bank; Michel Kazatchkine, France’s ambassador against HIV/AIDS and communicable diseases; Jim Kolbe, a Republican Congressman for Arizona; Bill Roedy, Vice Chairman of MTV Networks and President of MTV Networks International and an ambassador for UNAIDS; and Michel Sidibe, Director of the Country and Regional Support Department at UNAIDS.

In the Editorial, The Lancet assesses each candidate and comments: “The key criteria for this post are to optimise the Global Fund’s grant performance, to accelerate results, and to mobilise resources, including getting donors to honour their pledges. Most importantly, the appointee needs to understand the importance of evaluation, and to break down the dependencies that can arise from being a donor or a recipient, ensuring that the relationship is one of true partnership. From the five candidates, Johnson, Kazatchkine, and Sidibe lead the field, with the edge going to Sidibe because of his strong first-hand experience of Africa.”

###

Contact: Lancet press office

Lancet Continue reading →

Allan Hubbard, director of the National Economic Council, on Tuesday said that the largest factor behind increased health care costs is the public “perception that health care is free,” CQ HealthBeat reports. At a breakfast with reporters, Hubbard said that U.S. residents overuse health care services because health insurance covers most of the cost. He added that a proposal by President Bush to expand health savings accounts, which seek to make individuals more responsible for their health care spending, would help reduce costs. Hubbard did not estimate the amount of the savings that would result from the proposal, which would cost $29 billion over five years, but said, “We’ll know its working when growth starts to slow.” According to CQ HealthBeat, the “idea is that once patients are forced to pay more costs out-of-pocket, they will begin to comparison shop and request quality data, eventually driving down the costs of health care.” Hubbard also addressed concerns that only higher-income individuals will enroll in HSAs. According to Hubbard, the high-deductible health plans associated with HSAs are less expensive than traditional health insurance. About three million U.S. residents have enrolled in HSAs, and the Bush proposal would increase enrollment to 21 million by 2010, Hubbard said (Schuler, CQ HealthBeat, 2/14). Hubbard on Tuesday answered questions about HSAs in an “Ask the White House” online chat. The complete transcript is available online.

Related Broadcast Coverage
NPR’s “Morning Edition” on Wednesday reported on the Bush health care agenda. The segment includes comments from Drew Altman, president and CEO of the Kaiser Family Foundation; HHS Secretary Mike Leavitt; and Theodore Marmor, a public policy professor at Yale University (Rovner, “Morning Edition,” NPR, 2/15).

The complete segment is available online in RealPlayer.

“Reprinted with permission from kaisernetwork. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at kaisernetwork/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork, a free service of The Henry J. Kaiser Family Foundation . © 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved. Continue reading →

Egrifta has been approved by the Food and Drug Administration (FDA) for the treatment of lipodystrophy in HIV positive patients, known as HIV-associated lipodystrophy. Fat is lost under the skin and accumulates in other parts of the body, such as the liver, stomach, and the upper back; the patient typically loses fat in the face, buttocks arms and legs. Breast size in both male and females tends to increase.

Experts believe HIV-associated lipodystrophy is caused by anti-retroviral drugs, specifically HIV-1 protease inhibitors.

Egrifta (tesamorelin), a GRF (growth hormone releasing factor) medication, is taken as an injection once a day. It is the first drug to be approved in the USA for lipodystrophy treatment.

Curtis Rosebraugh, M.D., M.P.H., director of the Office of Drug Evaluation, Center for Drug Evaluation and Research, FDA, said:
“The FDA recognizes the need for therapies to treat patients with HIV-lipodystrophy. The presence of excess fat with this condition may contribute to other health problems as well as affect a patient’s quality of life, so treatments that demonstrate they are safe and effective at treating these symptoms are important.”
Studies have not looked into cardiovascular risk or whether this medication improves adherence to antiretroviral drug regimens, the FDA informs.

Two human trials with 816 men and women who were HIV positive, had lipodystrophy and excess abdominal fat demonstrated that Egrifta reduced abdominal fat significantly more than a placebo. Some of the participants commented that their self-image improved too.

Side effects, if they do occur may include arthralgia (pain in the joints), injection site rash, skin redness, swelling, myalgia (muscle pain) and stomach pain. More patients on Egrifta had worsening blood sugar control than those on the placebo.

Dr. Morris Schambelan, Professor of Medicine, University of California, San Francisco, said:
“As HIV-infected patients are living longer, a substantial number may develop metabolic complications associated with HIV, such as abdominal lipohypertrophy. With the approval of Egrifta, doctors are now able to provide appropriately selected patients with a treatment option shown to reduce visceral adipose tissue.”
Fereydoun Firouz, President and CEO, EMD Serono, Inc., the marketers of Egrifta, said:
“While antiretroviral therapy is extremely important in the management of patients with HIV
infection, some patients are experiencing excess abdominal fat associated with lipodystrophy,
which can be difficult to manage. EMD Serono has maintained a commitment to advancing science and medicine in this area of unmet medical need, and it will continue to remain a focus for the organization. We are committed to making a difference in people’s lives, and look forward to making Egrifta
available for patients as soon as possible.”
Mr. Yves Rosconi, President and CEO of Theratechnologies, the creators of Egrifta, said:
“Theratechnologies is very pleased to receive marketing approval for Egrifta from the
FDA. We are one of very few Canadian biotechnology companies to have successfully
discovered, developed and brought a drug to the market on our own. This milestone
represents a significant achievement which will benefit both patients and our shareholders.”
Sources: EMB-Serono, FDA

View drug information on Egrifta.

Continue reading →

GlaxoSmithKline (NYSE: GSK)
announced new study results that indicate that Rotarix(R), an oral
candidate vaccine for infants to prevent rotavirus gastroenteritis, could
be co-administered with routine infant vaccines recommended in the U.S. at
the two and four month old immunization visits, if approved by the U.S.
Food and Drug Administration (FDA).

The data show that co-administration of GSK’s rotavirus candidate
vaccine does not impair the immune responses to vaccines currently included
in the Centers for Disease Control and Prevention’s (CDC) schedule of
recommended immunizations for infants. These data are results from a Phase
III clinical trial presented today at the 47th Annual Interscience
Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Chicago,
Illinois.

Severe, dehydrating gastroenteritis occurs primarily among children
aged three to 35 months. Of children hospitalized with rotavirus,
approximately 17 percent are younger than six months old. The candidate
vaccine contains a live, weakened form of natural human rotavirus derived
from the most common human rotavirus strain. Published data show that
immunity resulting from natural human rotavirus infection provides
significant protection against moderate to severe disease, regardless of
rotavirus strain.

“These co-administration data indicate that GSK’s rotavirus candidate
vaccine could be integrated into the current infant immunization schedule
in the U.S.,” said Remon Abu-Elyazeed, M.D., Ph.D., Director, Clinical
Development, Vaccines for Virus Diseases, GlaxoSmithKline Biologicals. “If
the candidate vaccine is approved, infants could complete the rotavirus
vaccine series by four months of age.”

The CDC Advisory Committee on Immunization Practices (ACIP), the
American Academy of Pediatrics (AAP), and the American Academy of Family
Physicians (AAFP) recommend that infants receive routine vaccination with
the vaccine currently licensed by the FDA at two, four, and six months of
age in order to prevent rotavirus gastroenteritis.

About the Rotarix(R) Co-Administration Study

This Phase III study was conducted to confirm that two doses of the
rotavirus candidate vaccine do not impair the immune response to routine
infant vaccines currently used in the U.S. In the study, 484 healthy
infants ranging from six to 12 weeks of age were randomized (1:1) into two
groups. One group received three doses of the currently recommended infant
vaccines, Pediarix(R) (Diphtheria and Tetanus Toxoids and Acellular
Pertussis, Hepatitis B and Inactivated Poliovirus Vaccine), Prevnar(R)
(Pneumococcal 7-valent Conjugate Vaccine) and ActHIB(R) (Haemophilus b
Conjugate Vaccine), at two, four, and six months of age with the rotavirus
candidate vaccine co-administered at two and four months of age (n=249).
The second group received the rotavirus candidate vaccine administered
separately at three and five months of age (n=235) as well as three doses
of the currently recommended infant vaccines at two, four and six months of
age.

Serum antibodies were measured one month after the third dose of
routine vaccines (Pediarix, Prevnar and ActHIB). Antibody responses to
routine vaccines were similar in both groups, indicating that the rotavirus
candidate vaccine can be co-administered with other routine vaccinations
without interfering with the immune response to any of the administered
vaccines.

Results from the active phase of this study were included in GSK’s
Biologics License Application (BLA) for the rotavirus candidate vaccine,
which was recently accepted for review by the FDA.

About Rotarix(R)

The GSK rotavirus candidate vaccine is a live-attenuated oral rotavirus
vaccine licensed in 99 countries around the world. The vaccine is designed
to prevent rotavirus gastroenteritis by mimicking natural rotavirus
infection. Studies have shown that natural rotavirus infection provides
significant protection from moderate to severe disease, regardless of
rotavirus strain. In the BLA currently under review by the FDA, it is
proposed that the vaccine would be given in two oral doses beginning at six
weeks of age and completed by 24 weeks of age, with a minimum four-week
interval between the doses. If approved, the vaccine could be integrated
into the two and four month immunization visits.

About Rotavirus

Rotavirus infects virtually every child worldwide by age five and is
the leading cause of severe acute gastroenteritis in infants and young
children in the U.S. and worldwide. Severe diarrhea and dehydration occurs
from as young as three months of age.

In the U.S. each year, 2.7 million children younger than five years of
age suffer from rotavirus disease, resulting in 410,000 clinic visits and
up to 272,000 emergency room visits. In addition, between 55,000 and 70,000
children are hospitalized each year and 20-60 die.

GlaxoSmithKline: A Leader in Vaccines

GlaxoSmithKline, with U.S. operations in Philadelphia, PA, and Research
Triangle Park, NC, is one of the world’s leading research-based
pharmaceutical and healthcare companies and is committed to improving the
quality of human life by enabling people to do more, feel better and live
longer.

GSK Biologicals (GSK Bio), one of the world’s leading vaccine
manufacturers, is headquartered in Rixensart, Belgium, where the majority
of GlaxoSmithKline’s activities in the field of vaccine research,
development and production are conducted.

GSK Bio employs more than 1,500 scientists, who are devoted to
discovering new vaccines and developing more cost-effective and convenient
combination products to prevent infections that cause serious medical
problems worldwide. In 2006, GSK Bio distributed more than 1.1 billion
doses of vaccines to 169 countries in both the developed and the developing
world – an average of 3 million doses a day. Of those vaccine doses,
approximately 136 million were doses of combination pediatric vaccines
which protect the world’s children from up to six diseases in one vaccine.

Cautionary statement regarding forward-looking statements

Under the safe harbor provisions of the U.S. Private Securities
Litigation Reform Act of 1995, the company cautions investors that any
forward-looking statements or projections made by the company, including
those made in this Announcement, are subject to risks and uncertainties
that may cause actual results to differ materially from those projected.
Factors that may affect the Group’s operations are described under ‘Risk
Factors’ in the ‘Business Review’ in the company’s Annual Report on Form
20-F for 2006.

Prevnar(R) is a registered trademark of Wyeth Pharmaceuticals.

ActHib(R) is a registered trademark of sanofi pasteur, the vaccines
business of sanofi-aventis Group.

References

1. Abu-Elyazeed R, et al. Co-Administration of RIX4414 Oral Human
Rotavirus Vaccine, does not Impact the Immune response to Antigens
Contained in Routine Infant Vaccines in the United States.

2. Centers for Disease Control and Prevention. Prevention of Rotavirus
Gastroenteritis Among Infants and Children. MMWR. 2006; 55(RR12); 1-13.
Available at cdc/mmwr/preview/mmwrhtml/rr5512a1.htm

3. Green KY, et al. Homotypic and Heterotypic Epitope-Specific Antibody
Responses in Adult and Infant Rotavirus Vaccines: Implications for Vaccine
Development. The Journal of Infectious Diseases. 1990;161:667-679.

4 Centers for Disease Control and Prevention. Recommended Immunization
Schedule for Ages 0-6 Years – United States 2007.

GlaxoSmithKline
gsk

View drug information on Pediarix Vaccine; Prevnar 13. Continue reading →

A technique developed by U.S. Department of Agriculture (USDA) scientists for tracking pathogens has helped confirm that Escherichia coli is not likely to contaminate the internal vascular structure of field-grown leafy greens and thus increase the incidence of foodborne illness.

Agricultural Research Service (ARS) microbiologist Manan Sharma wanted to find out if plant roots could draw in E. coli pathogens from the soil when taking in nutrients and water. He and colleagues modified several types of E. coli – including some highly pathogenic strains that cause foodborne illness – by adding a gene for fluorescence. This allowed them to track the pathogen’s journey from the field to the produce.

ARS is USDA’s chief intramural scientific research agency, and this work supports the USDA priority of ensuring food safety.

The team, which is located at the ARS Environmental Microbial and Food Safety Laboratory in Beltsville, Md., confirmed that the pathogenic E. coli could survive in the soil for up to 28 days. They also observed that the fluorescent E. coli cells were capable of migrating into the roots of spinach plants.

The researchers also examined baby spinach plants over the course of 28 days after germination to see if any of the E. coli strains were taken up past the roots and into the plant’s interior structures. For this part of the study, they grew baby spinach in pasteurized soil and hydroponic media.

At day 28, there was no evidence that the E. coli had become “internalized” in leaves or shoots of baby spinach plants grown in the pasteurized soil. E. coli could be detected in hydroponically-grown spinach samples, but its survival in shoot tissue was sporadic 28 days after the plants had germinated.

These findings strongly suggest that although E. coli can survive in soils, it’s highly unlikely that foodborne illness would result from the bacterium becoming “internalized” through roots in leafy produce.

Results from this work were published in the Journal of Food Protection.

Source:
Ann Perry
United States Department of Agriculture – Research, Education and Economics Continue reading →

HIV prevention has “seen two breakthroughs this month” in data indicating that male circumcision might reduce a man’s risk of HIV infection, as well as the publication of a study that found “AIDS and malaria feed on each other with disastrous effects,” a New York Times editorial says (New York Times, 12/18). Laith Abu-Raddad of the University of Washington and the Fred Hutchinson Cancer Research Center and colleagues used a mathematical model to examine HIV and malaria coinfection data gathered in Malawi by James Kublin, a study co-author from FHCRC. HIV transmission occurs most easily when a person has high viral load. The study — funded in part by the University of Washington Center for AIDS and STD and FHCRC — found that malaria causes a sevenfold increase in viral load that lasts six to eight weeks. In addition, the study found that HIV-positive people are more susceptible to malaria because their immune systems are weakened. In regions where both diseases are common, HIV might be responsible for almost 10% of malaria cases, and malaria might be responsible for about 5% of HIV cases, according to Abu-Raddad. The researchers focused their work in Kisumu, Kenya, where they applied the mathematical model to determine that 8,500 additional HIV cases and 980,000 extra malaria cases during a 20-year period were the result of coinfection, Abu-Raddad said (Kaiser Daily HIV/AIDS Report, 12/8). One “important lesson of the study is that protecting HIV-positive people from malaria would also limit the spread” of HIV, the editorial says, adding that the study’s findings also “should add extra urgency to the fight against malaria, which has always lagged far behind AIDS in both money and attention.” President Bush last week hosted the White House Summit on Malaria, but the “fact that more than a million people, most of them under five, die each year from a disease that is easily preventable and curable speaks volumes,” according to the Times. In addition, the study “sheds new light on why Africa’s AIDS rates are so much higher than elsewhere” — “Africans’ health is poor, and they are more likely to suffer from diseases,” including malaria and genital herpes, that “make HIV more transmissible,” the editorial says. It concludes, “Donors eager to fight AIDS have shown less interest in improving Africa’s health systems, training health workers and equipping clinics. The biggest lesson of the new study is that it is all one fight” (New York Times, 12/18).

A kaisernetwork webcast of the White House malaria summit is available online.

“Reprinted with permission from kaisernetwork. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at kaisernetwork/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork, a free service of The Henry J. Kaiser Family Foundation . © 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved. Continue reading →

The Arkansas Senate on Monday voted 35-0 to approve a bill (HB 1444) that would require state inmates to receive HIV tests before being released, the AP/Pine Bluff Commercial reports (DeMillo, AP/Pine Bluff Commercial, 3/6). Arkansas Rep. Fred Allen (D) in February introduced a version of the bill that would have required inmates to undergo tests for HIV and other sexually transmitted infections before being paroled. The House public health committee previously tabled the bill but endorsed it after Allen amended the proposed legislation to require only HIV tests for all inmates being released, not just those being paroled. Allen also removed a requirement from the original bill that all Arkansas Department of Correction employees receive an HIV test. In addition, the amended version requires inmates who test positive to be provided with counseling on treatment options. Allen said the tests would cost the state about $34,000 annually, adding that the test would not be a condition for parole (Kaiser Daily HIV/AIDS Report, 3/1). The bill returns to the House for members to consider amendments and then will go to Gov. Mike Beebe (D) (AP/Pine Bluff Commercial, 3/6).

“Reprinted with permission from kaisernetwork. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at kaisernetwork/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork, a free service of The Henry J. Kaiser Family Foundation . © 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved. Continue reading →

Some shocking statistics on death and disease rates due to chronic diseases in developing countries are uncovered in the final paper in The Lancet Series on Chronic Disease and Development. Around 23 million deaths occur due to chronic diseases in just 23 high-burden countries, which represent some 60% of all chronic disease-related deaths globally each year. Six in every ten of those chronic disease deaths in the 23 countries are in people aged 70 or younger. In this final paper, Dr Ala Alwan, Non-communicable Diseases and Mental Health, WHO, Geneva, Switzerland, and colleagues take a critical look at progress in these nations over the past decade, and lament the inadequate coverage of basic interventions that could make a massive difference. They suggest a number of key surveillance strategies that are well within the scope of these countries despite their limited resources.

High smoking rates in men across many of these 23 nations (Russia 65%, China 57%) expose the lack of effective tobacco control therein. To review tobacco control progress, authors looked at elements required through WHO’s Framework Convention on Tobacco Control (FCTC). WHO is assisting countries to implement some of the demand reduction measures of the FCTC including monitoring of tobacco use and prevention policies; protecting people from tobacco smoke; offering help to quit; warning about the dangers of tobacco; and, enforcing bans on advertising, promotion, and sponsorship, and raise taxes on tobacco products. Iran was a success here, having achieved all these goals except higher levels of taxation on cigarettes. The only country to increase taxes to at least 75% of the retail price of tobacco was Poland. Overweight and obesity are also big problems in these nations. For example, overweight in men ranged from 4% in Vietnam to 74% in Argentina, and in women from 3% in Ethiopia to 74% in Egypt.

In 14 of these 23 countries that had vital registration data, age-standardised death rates from chronic diseases were 711 per 100000 for men (58% higher than men in high-income countries), and 508 per 100000 for women (69% higher than women in high-income countries).

The authors predict that in these 23 nations, infectious disease rates will fall by 2% per year over the next 40 years, while cancer cases will increase by 1.1% per year and cardiovascular disease cases by 0.7% per year.

Despite these depressing numbers, things are improving, albeit slowly. Comparing assessments of country capacity from 2000 to 2010, many countries that lacked policies for chronic disease in some or most areas have been able to improve their situations. For example, 95% of countries had a dedicated chronic disease office within their Ministry of Health in 2010, compared to 70% in 2000.

The authors’ propose a national surveillance framework for chronic diseases which encompasses key risk factors (consisting of behavioural, dietary, physiological, and metabolic factors), outcomes (mortality and morbidity), health-system response interventions, and health-system capacity. For every component of the proposed surveillance framework, a core and expanded set of indicators was proposed for global and national monitoring. Collection of data necessary to monitor these core indicators are within the capacity of all countries despite limited resources.

In conclusion, the authors say that despite the dearth in resources for and actions on chronic diseases in developing countries, great hope has emerged following the UN General Assembly Resolution on non-communicable diseases, which calls for higher priority to be placed on these conditions in health, national, and global agendas. There will be a high-level meeting of the General Assembly on chronic diseases in September 2011.

The authors say: “The UN resolution provides an unprecedented opportunity for countries, UN agencies, international development organisations, civil society, and the private sector to work jointly around a common vision and a road map to address the enormous chronic-disease
burden that low-income and middle-income countries are increasingly facing. Challenges to prevention of non-communicable diseases, such as strengthened surveillance, more effective intersectoral action, and improved access to basic health care (including essential medicines and technologies), are key issues that are pivotal to include in the discussions over the coming months.”

Source: The Lancet Continue reading →

There are ten microbial cells for every one human cell in the body, and microbiology dogma holds that there is a tight barrier protecting the inside of the body from outside invaders, in this case bacteria. Bacterial pathogens can break this barrier to cause infection and senior author Jeffrey Weiser, MD, professor of Microbiology and Pediatrics from the Perelman School of Medicine at the University of Pennsylvania, and first author Thomas Clarke, PhD, a postdoctoral fellow in the Weiser lab, wondered how microbes get inside the host and circulate in the first place. Weiser and Clarke tested to see if microbes somehow weaken host cell defenses to enter tissues.

In this Cell Host & Microbe study, the investigators found that microbes open and get through the initial cellular barrier — epithelial cells that line the airway — in a programmed and efficient way. They surmise this could be a normal physiological event and the epithelial lining may not be as effective at keeping microbes out as once thought. Microbes that survive once past the epithelial lining tend to be pathogenic, such as Streptococcus pneumoniae and Haemophilus influenzae, two major human pathogens causing invasive infections. Their data support a general mechanism for epithelial opening exploited by invasive pathogens to facilitate movement into tissue to initiate disease.

Using microarray and PCR analysis of the epithelial cells’ response to invasion by S. pneumoniae and H. influenzae, the researchers found a downregulation of genes called claudins that encode proteins key to keeping the spaces between epithelial cells tight. All animals recognize molecules in microbial cell walls. It was detection of these microbial molecules by host molecules called Toll-like receptors that caused the proteins responsible for keeping the cellular barrier tight to fall down on the job.

When modeled in a cell assay, claudin downregulation was preceded by upregulation of another protein called SNAIL1 that suppresses claudins, the cellular components that keep the junctions tight. What’s more, inhibiting claudin expression in a cell assay or stimulating the Toll-like receptors in an animal model loosened the junctions between cells and promoted bacterial movement across the epithelium.

“This study provides an understanding of how microbes gain access into their host to affect its physiology,” concludes Weiser.

This research was funded by the National Institute of Allergy and Infectious Diseases.

Source:
Karen Kreeger

University of Pennsylvania School of Medicine Continue reading →