Researchers discover molecular target for the bacterial infection brucellosis

Main Category: Infectious Diseases / Bacteria / Viruses
Article Date: 19 Aug 2013 - 1:00 PDT Current ratings for:
Researchers discover molecular target for the bacterial infection brucellosis

UC Davis scientists have uncovered a potential drug target for the development of an effective therapy against the debilitating, chronic form of the bacterial disease brucellosis, which primarily afflicts people in Mediterranean and Middle Eastern countries.

Brucellosis, which affects about 500,000 people worldwide each year, typically is caused by ingestion of unsterilized milk or close contact with body secretions from infected animals. Symptoms include intermittent or irregular fever of variable duration, headache, weakness, profuse sweating, chills, weight loss and generalized aching. It can also cause long-lasting or chronic symptoms such as recurrent fevers, joint pain and fatigue.

In a paper published online in the journal Cell Host & Microbe, the researchers reported that they have identified the cells that harbor the B. abortus bacteria during the persistent phase of the brucellosis. The cells, known as alternatively activated macrophages (AAMs), are a recently identified category of immune defense cells.

The researchers also determined that the biological pathway peroxisome proliferator activated receptor ?, abbreviated as PPAR?, is responsible for altering the metabolism of AAMs so that they supply B. abortus with the energy in the form of glucose that enables bacteria to survive and replicate and thereby sustain the chronic phase of the infectious disease. Other labs also have shown that PPAR? control a cell's metabolism.

"We found that PPAR? induces a metabolic shift in these cells that causes them to generate glucose," said Renee Tsolis, associate professor of medical microbiology and immunology at UC Davis who led the study.

"Starving the B. abortus bacteria by inhibiting the PPAR? pathway may be a new approach to eradicating the chronic, difficult-to-treat form of Brucellosis infection that usually occurs because antibiotic therapy was not used during the acute, or early, phase of the infection," said Tsolis.

Tsolis and her collaborators were the first to discover PPAR?'s role in brucellosis and to determine that AAMs harbor the bacteria during the chronic stage of the disease. The identification of the bacteria's niche is another important clue for the development of a more effective treatment, she said.

In a series of experiments, Tsolis and collaborators found that the gene encoding PPAR? is very active during chronic Brucellosis infection, but not during acute infection, and that the B. abortus bacteria did not survive in AAMs when deprived of glucose.

When the researchers inactivated the protein that normally transports glucose, the bacteria stopped reproducing, and the infection no longer was chronic, she said.

In mice infected with B. abortus, Tsolis and collaborators treated the animals with GW9662, a PPAR inhibitor. The researchers administered the inhibitor before the infection became chronic, or long lasting. The inhibitor significantly reduced the amount of AAMs and B. abortus bacteria in the mice.

"These results suggested that inhibition of PPARreduced the bacteria's survival by reducing the abundance of AAMs during chronic infection," said Tsolis.

Conversely, when the researchers treated the B. abortus-infected mice with Rosiglitazone, a drug that boosts PPAR activity, the bacteria increased by two-fold during the acute phase and four-fold during the chronic phase of infection. Rosiglitazone and other drugs that boost PPARare used to treat type 2 diabetes because they lower blood glucose by increasing cellular glucose uptake.

In other experiments, the researchers showed that AAMs, one of two categories of macrophages, are abundant in the spleen during chronic brucellosis but not during the acute, or initial, phase of the infection, which is dominated by classically activated macrophages (CAM), the second category of these immune cells.

In addition to profuse sweating, symptoms of brucellosis infection include joint and muscle pain. Among the complications of chronic infection are arthritis and endocarditis, a serious inflammation of one of the four heart valves. Brucellosis rarely occurs in the U.S., with about 100 to 200 cases reported each year, according to the U.S. Centers for Disease Control and Prevention.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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The title of the journal paper is “PPAR?-Mediated Increase in Glucose Availability Sustains Chronic Brucella abortus Infection in Alternatively Activated Macrophages.”

Authors also include: Mariana N. Xavier, Maria G. Winter, Alanna M. Spees, Andreas B. den Hartigh, Kim Nguyen, Christelle M. Roux, Vidya L. Atluri, Tobias Kerrinnes, A. Marijke Keestra and Andreas J. Baumler of UC Davis; Denise M. Monack of Stanford University, Palo Alto, CA; and Paul A. Luciw, Richard A. Eigenheer, Renato L. Santos and Teane M.A. Silva of the Universidade Federal de Minas Gerais in Brazil. Cell Host & Microbe, Volume 14, Issue 2, 159-170, 14 August 2013; 10.1016/j.chom.2013.07.009

University of California - Davis Health System

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How tiny swimmers get around could inform studies of bacterial infection and fertility

Main Category: Infectious Diseases / Bacteria / Viruses
Also Included In: Fertility
Article Date: 15 Aug 2013 - 0:00 PDT Current ratings for:
How tiny swimmers get around could inform studies of bacterial infection and fertility

It's counterintuitive but true: Some microorganisms that use flagella for locomotion are able to swim faster in gel-like fluids such as mucus. Research engineers at Brown University have figured out why. It's the angle of the coil that matters. Findings are reported in Physical Review Letters.

A high-angle helix helps microorganisms like sperm and bacteria swim through mucus and other viscoelastic fluids, according to a new study by researchers from Brown University and the University of Wisconsin. The findings help clear up some seemingly conflicting findings about how microorganisms swim using flagella, helical appendages that provide propulsion as they rotate.

Simple as single-celled creatures may be, understanding how they get around requires some complex science. The physics of helical swimming turns out to be "a really interesting fluid dynamics problem," said Thomas Powers, a professor of engineering and physics at Brown and one of the new study's authors.

At the scale of a single cell, fluids become much more viscous than on larger scales. A bacterium swimming through water "would be like us trying to swim in tar," Powers said. That means swimming at the micron scale is a completely different enterprise than it is for fish or people. Counterintuitive as it may sound, tiny helical swimmers rely exclusively on drag to move forward. The turning flagellum creates an apparent wave that propagates out from behind the creature. The drag force against that wave pushes the creature in the opposite direction.

In recent years, there has been some theoretical work aimed at fully understanding the physics of this kind of swimming, much of it done by modeling how helical swimmers behave in water. But bacteria and sperm spend a lot of time in fluids like mucus and cervical fluid - fluids that are not only more viscous than water, but also elastic since they are full of springy polymers. Because a rotating helix might be able to push against the polymers, it could be that a viscoelastic fluid makes swimming easier.

"It's a fairly simple question," Powers said. "Does viscoelasticity make microorganisms swim faster or slower?" Finding the right answer, however, hasn't been so simple.

Early theoretical work suggested viscoelastic fluids should slow helical swimmers down. But some experimental work in the Brown School of Engineering by Powers, postdoctoral associate Bin Liu, and Kenneth Breuer, professor of engineering, suggested that viscoelastic fluids should actually help helical swimmers move faster.

This latest study, published in the journal Physical Review Letters, helps to bridge that apparent gap. Powers and Liu worked with Saverio Spagnolie, a professor of mathematics at the University of Wisconsin and aformer postdoctoral researcher at Brown. Using what Powers described as "some clever numerical methods and a lot of hard work," Spagnolie was able to show computationally that the pitch angle of the helix - the degree to which the helix is coiled - matters in how well it performs in viscoelastic fluids. At a low pitch angle (think of a stretched phone cord), helices move more slowly in viscoelastic fluids. When the pitch angle increases, performance improves.

The findings reconcile the experimental and earlier theoretical work. Much of the theoretical work, which suggested more viscosity would cause slower swimming, assumed a small pitch angle for the sake of keeping the computations manageable. The experimental work, which showed viscosity sped swimming, involved higher pitch angles. By showing numerically that a higher pitch angle increases speed, the researchers were able to explain that apparent discrepancy. "This work shows how you can connect that prior work," Powers said.

While this work was extremely valuable in linking theory and experiment, there's still much more work to be done on this problem, Powers says. "We don't really understand the result because it is so hard to visualize the three-dimensional configuration of all the forces involved. It's actually very frustrating. We're still trying to get an intuitive picture."

That, at this point, is still an upstream swim.

Ultimately, the researchers say, a better understanding how tiny swimmers get around could inform studies of bacterial infection and fertility. It could also help scientists develop artificial swimmers that could deliver medicine inside the body.

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Focus: How Spinning Coils Swim through Gloopy Liquids, Saverio E. Spagnolie, Bin Liu, and Thomas R. Powers, Physical Review Letters, Published August 9, 2013, DOI: 10.1103/Physics.6.89

The work was supported by the National Science Foundation (CBET-0854108).

Brown University

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Tracking variability in a bacterial population means looking beyond averages

Main Category: Genetics
Article Date: 30 Jul 2013 - 1:00 PDT Current ratings for:
Tracking variability in a bacterial population means looking beyond averages

As a result of the variable nature of gene expression, genetically identical cells inhabiting the same environment can vary significantly in their numbers of key enzymes, which in turn results in strikingly different cellular behaviors. This cell-to-cell variability can manifest in the form of anything from differences in growth rate, to the specific biochemical pathways used and the types of metabolic byproducts produced by each cell.

Incorporating data from studies of gene regulation and protein distributions in single cells, the research group of University of Illinois chemistry professor Zaida Luthey-Schulten was able to identify several behavioral subtypes within a modeled population. The researchers' computer model predicts emissions of metabolic byproducts and pathway selection to balance energy (glycolysis pathway) and protein costs (ED pathway) as a function of growth. The research also suggests that tracking the behavior of a few genes "may be sufficient to capture most of the metabolic variability of the entire population," the authors wrote.

"Our investigations provide the first calculations linking variation in specific pathway usages to the growth rate distribution of a microbial population," Luthey-Schulten said. "By looking beyond the average growth rate of a colony, our work provides insight into the different strategies used by bacteria for survival. "

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