A naturally occurring molecule made by symbiotic gut bacteria may offer a new type of treatment for inflammatory bowel disease, according to scientists at the California Institute of Technology.”Most people tend to think of bacteria as insidious organisms that only make us sick,” says Sarkis K. Mazmanian, an assistant professor of biology at Caltech, whose laboratory examines the symbiotic relationship between “good” bacteria and their mammalian hosts. Instead, he says, “bacteria can be beneficial and actively promote health.”

For example, the 100 trillion bacteria occupying the human gut have evolved along with the human digestive and immune systems for millions of years. Some harmful microbes are responsible for infection and acute disease, while “other bacteria, the more intelligent ones, have taken the evolutionary route of shaping their environment by positively interacting with the host immune system to promote health, which gives them an improved place to live; it’s like creating bacterial nirvana,” says Mazmanian.

If bacteria are actively modifying the gut, their work would have to be mediated by molecules. In their recent work, Mazmanian and his colleagues have identified one such molecule, a sugar called polysaccharide A, or PSA, which is produced by the symbiotic gut bacterium Bacteroides fragilis. They have termed this molecule a “symbiosis factor,” and predict that many other bacterial compounds with diverse beneficial activities await discovery.

To identify the molecule and its action, the scientists used experimental mice and induced changes to their intestinal bacteria by exposing them to a pathogenic bacterium called Helicobacter hepaticus. This microbe causes a disease in the mice that is similar to Crohn’s disease and ulcerative colitis. However, when the animals were co-colonized with B. fragilis, they were protected from the disease–as were animals that were given oral doses of just the PSA molecule.

In particular, Mazmanian and his colleagues found that PSA induced particular immune-system cells called CD4+ T cells to produce interleukin-10 (IL-10), a molecule that has previously been shown to suppress inflammation–and offer protection from inflammatory bowel disease. “Thus, bacteria help reprogram our own immune system to promote health,” he says.

“The most immediate and obvious implication is that PSA may potentially be developed as a natural therapeutic for inflammatory bowel disease,” says Mazmanian.

Inflammatory bowel disease, a constellation of illnesses that cause inflammation in the intestines, including ulcerative colitis and Crohn’s disease, is estimated to affect one million Americans. The rates of inflammatory bowel diseases have skyrocketed in recent years; for example, the incidence of Crohn’s disease, a condition that causes debilitating pain, diarrhea, and other gastrointestinal symptoms, has increased by 400 percent over the past 20 years.

The current research, along with other work by Mazmanian and June L. Round, a Caltech postdoctoral researcher, suggests that the interplay between various groups of bacteria living in the intestines has profound effects on human health.

This notion gels with the so-called “hygiene hypothesis.” The hypothesis, first proposed two decades ago, links modern practices like sanitation, vaccination, a Western diet, and antibiotic use, which reduce bacterial infections, to the increased prevalence of a variety of illnesses in the developed world, including inflammatory bowel disease, asthma, multiple sclerosis, and Type 1 diabetes. However, it is now clear that increased living standards and antibacterial drugs affect not only infectious microbes, but all of the beneficial ones that we may depend on for our well-being.

“Through societal measures we have changed our association with the microbial world in a very short time span. We don’t have the same contact with microbes as we have for millions of years–we just live too clean now,” Mazmanian says. So while it is useful to eliminate disease-causing organisms, “perhaps disease results from the absence of beneficial bacteria and their good effects,” he suggests. “This study is the first demonstration of that. What it hopefully will do is allow people to re-evaluate our opinions of bacteria. Not all are bad and some, maybe many, are beneficial.”

The protein MAEBL is critical for completing the life cycle of malaria parasites in mosquitoes, allowing the insects to transmit the potentially deadly infection to humans, a University of South Florida study has shown. The research may ultimately help provide a way to better control malaria by blocking development of the malaria parasite in the mosquito.

John Adams, PhD, and his team study the complex life cycle of the malaria parasite (on computer screen) to try to find ways to block transmission of the deadly infection.

Researchers with the USF Global Health Infectious Diseases Research team found that the transmembrane protein MAEBL is required for the infective stage of the malaria parasite Plasmodium falciparum to invade the mosquito’s salivary glands. Their findings were published May 28 in the online journal PLoS ONE.

“The mosquito is the messenger of death,” said the study’s principal investigator John Adams, PhD, professor of global health at the USF College of Public Health. “If we could eliminate the parasite from the mosquito, people wouldn’t become infected.”

Plasmodium falciparum causes three-quarters of all malaria cases in Africa, and 95 percent of malaria deaths worldwide. It is transmitted to humans by the bite of an infected mosquito, which injects the worm-like, one-celled malaria parasites from its salivary glands into the person’s bloodstream.

Dr. Adams, center, with his team including, l to r, Steven Maher, Fabian Saenz, PhD, lead author of the PLoS ONE paper, and Sandra Kennedy.

The study was done by genetically modifying the malaria parasites and feeding them in a blood meal to uninfected mosquitoes. Parasites in which MAEBL was deleted were not harbored in the salivary glands of mosquitoes, even though an earlier form of these parasites was observed in the gut of the mosquitoes. The researchers concluded that the transmembrane form of MAEBL is essential for the parasite to enter the mosquito’s salivary glands.

While more studies are needed, lead author Fabian Saenz, PhD, said the finding suggests that silencing the receptor for MAEBL in the mosquito salivary gland might block passage of the parasite through the mosquito, thereby preventing human infection through mosquito bites.

“Our study shows that MAEBL is a weak link in the parasite’s biology,” Dr. Adams said. “This could provide a potential way to block transmission in the mosquito, before the parasite ever has a chance to infect a new person. It is better to prevent the malaria infection from occurring in the first place than having to kill the parasite already inside humans with vaccines or drugs.”

The study was supported by a grant from the National Institute of Allergy and Infectious Diseases. Other study authors were Dr. Bharath Balu, Jonah Smith and Sarita Mendonca.

Microscopic view of an Anopeheles mosquito infected with malaria parasites.

A group of Duke University researchers have made a major advance in understanding how bacteria divide.  These results could lead to new antibiotic treatments that prevent dangerous bacteria from multiplying.

Normally, bacteria divide by forming a ring that pinches the cell in two.  The ring is called a “Z ring” after the protein FtsZ, which forms a ring-shaped scaffold and then squeezes it smaller.  In bacteria, the Z ring also contains a dozen other proteins, all believed to be essential for division.

The Z ring normally pulls in on the cell membrane by binding to another protein, FtsA, which has one end attached to the inner cell membrane and the other end connected to FtsZ.  When the Z ring constricts, it completely pulls in the membrane and nips the bacterium in two.

But cell biology research scientist Masaki Osawa, Ph.D., cut FtsA out of the system by making an FtsZ that could bind directly to the membrane, and called it “membrane targeted FtsZ” or FtsZ-mts.

First, Osawa demonstrated that the new protein, FtsZ-mts, assembled Z rings in bacteria.

Then he constructed a greatly simplified cell-division machine in microscopic oil droplets, called liposomes, that demonstrated the important role of FtsZ in the division process.  He was able to assemble Z rings in this completely artificial system, the liposome, a tiny hollow sphere of fat that mimics natural cell membranes.

To do this, Osawa mixed the liposomes with FtsZ and GTP, a molecule that provides energy.  On a microscope slide the liposomes fused and stretched into tubes that mimicked the shape of E. coli and other rod-shaped bacteria.

“It was a happy coincidence that the size and shape of the liposomes was similar to that of rod-shaped bacteria,” says co-author Harold Erickson, professor of cell biology.  “These tubular liposomes are a new micro-structure, and their formation is still a mystery.”

During the experiment, fluorescently labeled FtsZ-mts was initially on the outside of the liposomes, but some of the tubular liposomes ended up with FtsZ on the inside.  “We don’t know how this happens, but it is a key to the discovery,” Osawa said.

Inside the liposome the FtsZ formed multiple closed rings that aligned perpendicular to the length of the tube, just as Z rings form in bacteria.  They also slid back and forth, and where they collided, they stayed together and formed brighter Z rings.  And as the Z rings grew in brightness, they visibly pulled the wall of the liposome inward.

“The Z rings are clearly generating force and causing the constriction,” Osawa said.  A movie the team made shows several constrictions in the wall occurring at the sites of the bright Z rings.  When the GTP in the liposome is used up, the tube eases out of its constrictions into its original shape.

“We believe our simple system may recreate the mechanism that the earliest bacteria used to divide.  They probably had FtsZ alone,” Erickson said.  “Osawa’s experiments show that FtsZ, a membrane tether, and the inside surface of a tubular membrane are all that’s needed to assemble the Z ring and generate a constriction force.”

The artificial Z rings were not sufficient to pinch the liposomes in half, “probably because their walls are much thicker than the membrane of a bacterium,” Osawa noted.  “We are now working to make thinner liposomes, so that we can achieve complete division.”

Erickson said that FtsZ is the bacterial ancestor of tubulin, the protein that makes the microtubules in animal cells and is the target of a number of anti-cancer drugs like taxol.  Although FtsZ is not sensitive to taxol, anything learned about the bacterial ancestor will help us understand microtubules, which help animal cells to keep their shape and control their movements, he explained.

According to researchers at Temple University an increase in the CD163+/CD16+ monocyte subset could be a biomarker for the progression of HIV disease.The researchers reported their findings, “CD163/CD16 Coexpression by Circulating Monocytes/Macrophages in HIV: Potential Biomarkers for HIV Infection and AIDS Progression,” in the March issue of AIDS Research and Human Retroviruses (www.liebertonline.com/aid).

A monocyte is a specific white blood cell, a part of the human body’s immune system that protects against blood-borne pathogens and moves quickly to sites of infection within the body’s tissues. As monocytes enter tissue, they undergo a series of changes to become macrophages.

The researchers were investigating alterations in this monocyte subset in patients with HIV infection. As part of this study, they examined a cohort of 18 patients from the Comprehensive HIV Program at Temple University Hospital, under the direction of Ellen Tedaldi, and seven individuals without HIV infection.

“At first, we were just looking at whether or not we saw alterations in this CD163+/CD16+ subset and whether it might be reflective of the amount of virus they have in circulation,” said Tracy Fischer-Smith, an associate scientist in Temple’s Neuroscience Department and the study’s lead author. “We did, indeed, find that patients with detectable virus had an increase of this monocyte subset that correlated with the amount of virus they had in their blood. We were surprised to find that patients with CD4+ T cell counts of less than 450 cells per microliter [200 or less per microliter is defined as AIDS], the increase of this monocyte subset correlates inversely with the number of T cells.”

Fischer-Smith said this finding suggests that as the monocyte cells are increasing, these patients are losing CD4+ T cells, which are critical for the maintenance of immunological competence.

“This may actually provide an earlier window into what is happening with HIV-infected patients where we might be able to see that immune impairment is taking place before we see a dramatic loss of CD4+ T cells,” she said.

“It looks like, based on these correlations, that this particular cell type may be involved in immune impairment and the progression of HIV,” said Jay Rappaport, professor of neuroscience and neurovirology, who oversaw the study. “Is it a good prognostic indicator” If you have a lot of these monocytes, does it mean you are going to progress into AIDS faster” “Right now, all we know is what the correlations are,” he said.

Rappaport added that he believes the CD163+/CD16+ monocyte subset is the first biomarker that correlates with viral load and CD4+ count. “The fact that it actually correlates with both, we think, might make it a key cell type in the pathogenesis of AIDS.” Fischer-Smith said the researchers plan to expand this study by following a cohort of patients longitudinally to see if their findings really can provide doctors with an early warning system and help to design better therapeutic strategies.

“When you are just looking at a single time-point, you don’t know how changes in this monocyte subset might occur over time, and how these changes might relate to the viral load and T cell number in individual patients,” she said. “That is why we want to investigate this further with a longitudinal study of HIV patients.”

The study was supported by the National Institute of Neurological Disorders and Strokes (NINDS) and the National Institute on Drug Abuse (NIDA)