Research Update: Battling Infection With Microbes

A relationship between gut bacteria and blood cell development helps the immune system fight infection, Caltech researchers say.

The human relationship with microbial life is complicated. At almost any supermarket, you can pick up both antibacterial soap and probiotic yogurt during the same shopping trip. Although there are types of bacteria that can make us sick, Caltech professor of biology and biological engineering Sarkis Mazmanian and his team are most interested in the thousands of other bacteria—many already living inside our bodies—that actually keep us healthy. His past work in mice has shown that restoring populations of beneficial bacteria can help alleviate the symptoms of inflammatory bowel disease, multiple sclerosis, and even autism. Now, he and his team have found that these good bugs might also prepare the immune cells in our blood to fight infections from harmful bacteria.

In the recent study, published on March 12 in the journal Cell Host & Microbe, the researchers found that beneficial gut bacteria were necessary for the development of innate immune cells—specialized types of white blood cells that serve as the body's first line of defense against invading pathogens.

In addition to circulating in the blood, reserve stores of immune cells are also kept in the spleen and in the bone marrow. When the researchers looked at the immune cell populations in these areas in so-called germ-free mice, born without gut bacteria, and in healthy mice with a normal population of microbes in the gut, they found that germ-free mice had fewer immune cells—specifically macrophages, monocytes, and neutrophils—than healthy mice.

Germ-free mice also had fewer granulocyte and monocyte progenitor cells, stemlike cells that can eventually differentiate into a few types of mature immune cells. And the innate immune cells that were in the spleen were defective—never fully reaching the proportions found in healthy mice with a diverse population of gut microbes.

"It's interesting to see that these microbes are having an immune effect beyond where they live in the gut," says Arya Khosravi, a graduate student in Mazmanian's lab, and first author on the recent study. "They're affecting places like your blood, spleen, and bone marrow—places where there shouldn't be any bacteria."

Khosravi and his colleagues next wanted to see if the reduction in immune cells in the blood would make the germ-free mice less able to fight off an infection by the harmful bacterium Listeria monocytogenes—a well-studied human pathogen often used to study immune responses in mice. While the healthy mice were able to bounce back after being injected with Listeria, the infection was fatal to germ-free mice. When gut microbes that would normally be present were introduced into germ-free mice, the immune cell population increased and the mice were able to survive the Listeria infection.

The researchers also gave injections of Listeria to healthy mice after those mice were dosed with broad-spectrum antibiotics that killed off both harmful and beneficial bacteria. Interestingly, these mice also had trouble fighting the Listeria infection. "We didn't look at clinical data in this study, but we hypothesize that this might also happen in the clinic," says Mazmanian. "For example, when patients are put on antibiotics for something like hip surgery, are you damaging their gut microbe population and making them more susceptible to an infection that had nothing to do with their hip surgery?"

More importantly, the research also suggests that a healthy population of gut microbes can actually provide a preventative alternative to antibiotics, Khosravi says. "Today there are more and more antibiotic resistant superbugs out there, and we're running out of ways to treat them. Limiting our susceptibility to infection could be a good protective strategy."

These results appear in a paper titled "Gut Microbiota Promote Hematopoiesis to Control Bacterial Infection."

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A Changing View of Bone Marrow Cells

Caltech researchers show that the cells are actively involved in sensing infection

In the battle against infection, immune cells are the body's offense and defense—some cells go on the attack while others block invading pathogens. It has long been known that a population of blood stem cells that resides in the bone marrow generates all of these immune cells. But most scientists have believed that blood stem cells participate in battles against infection in a delayed way, replenishing immune cells on the front line only after they become depleted.

Now, using a novel microfluidic technique, researchers at Caltech have shown that these stem cells might be more actively involved, sensing danger signals directly and quickly producing new immune cells to join the fight.

"It has been most people's belief that the bone marrow has the function of making these cells but that the response to infection is something that happens locally, at the infection site," says David Baltimore, president emeritus and the Robert Andrews Millikan Professor of Biology at Caltech. "We've shown that these bone marrow cells themselves are sensitive to infection-related molecules and that they respond very rapidly. So the bone marrow is actually set up to respond to infection."

The study, led by Jimmy Zhao, a graduate student in the UCLA-Caltech Medical Scientist Training Program, will appear in the April 3 issue of the journal Cell Stem Cell.

In the work, the researchers show that blood stem cells have all the components needed to detect an invasion and to mount an inflammatory response. They show, as others have previously, that these cells have on their surface a type of receptor called a toll-like receptor. The researchers then identify an entire internal response pathway that can translate activation of those receptors by infection-related molecules, or danger signals, into the production of cytokines, signaling molecules that can crank up immune-cell production. Interestingly, they show for the first time that the transcription factor NF-κB, known to be the central organizer of the immune response to infection, is part of that response pathway.

To examine what happens to a blood stem cell once it is activated by a danger signal, the Baltimore lab teamed up with chemists from the lab of James Heath, the Elizabeth W. Gilloon Professor and professor of chemistry at Caltech. They devised a microfluidic chip—printed in flexible silicon on a glass slide, complete with input and output ports, control valves, and thousands of tiny wells—that would enable single-cell analysis. At the bottom of each well, they attached DNA molecules in strips and introduced a flow of antibodies—pathogen-targeting proteins of the immune system—that had complementary DNA. They then added the stem cells along with infection-related molecules and incubated the whole sample. Since the antibodies were selected based on their ability to bind to certain cytokines, they specifically captured any of those cytokines released by the cells after activation. When the researchers added a secondary antibody and a dye, the cytokines lit up. "They all light up the same color, but you can tell which is which because you've attached the DNA in an orderly fashion," explains Baltimore. "So you've got both visualization and localization that tells you which molecule was secreted." In this way, they were able to measure, for example, that the cytokine IL-6 was secreted most frequently—by 21.9 percent of the cells tested.

"The experimental challenges here were significant—we needed to isolate what are actually quite rare cells, and then measure the levels of a dozen secreted proteins from each of those cells," says Heath. "The end result was sort of like putting on a new pair of glasses—we were able to observe functional properties of these stem cells that were totally unexpected."

The team found that blood stem cells produce a surprising number and variety of cytokines very rapidly. In fact, the stem cells are even more potent generators of cytokines than other previously known cytokine producers of the immune system. Once the cytokines are released, it appears that they are able to bind to their own cytokine receptors or those on other nearby blood stem cells. This stimulates the bound cells to differentiate into the immune cells needed at the site of infection.

"This does now change the view of the potential of bone marrow cells to be involved in inflammatory reactions," says Baltimore.

Heath notes that the collaboration benefited greatly from Caltech's support of interdisciplinary work. "It is a unique and fertile environment," he says, "one that encourages scientists from different disciplines to harness their disparate areas of expertise to solve tough problems like this one."

Additional coauthors on the paper, "Conversion of danger signals into cytokine signals by hematopoietic stem and progenitor cells for regulation of stress-induced hematopoiesis," are Chao Ma, Ryan O'Connell, Arnav Mehta, and Race DiLoreto. The work was supported by grants from the National Institute of Allergy and Infectious Diseases, the National Institutes of Health, a National Research Service Award, the UCLA-Caltech Medical Scientist Training Program, a Rosen Fellowship, a Pathway to Independence Award, and an American Cancer Society Research Grant.

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Kimm Fesenmaier
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Friday, March 14, 2014
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Caltech-Developed Method for Delivering HIV-Fighting Antibodies Proven Even More Promising

In 2011, biologists at the California Institute of Technology (Caltech) demonstrated a highly effective method for delivering HIV-fighting antibodies to mice—a treatment that protected the mice from infection by a laboratory strain of HIV delivered intravenously. Now the researchers, led by Nobel Laureate David Baltimore, have shown that the same procedure is just as effective against a strain of HIV found in the real world, even when transmitted across mucosal surfaces.

The findings, which appear in the February 9 advance online publication of the journal Nature Medicine, suggest that the delivery method might be effective in preventing vaginal transmission of HIV between humans.

"The method that we developed has now been validated in the most natural possible setting in a mouse," says Baltimore, president emeritus and the Robert Andrews Millikan Professor of Biology at Caltech. "This procedure is extremely effective against a naturally transmitted strain and by an intravaginal infection route, which is a model of how HIV is transmitted in most of the infections that occur in the world."

The new delivery method—called Vectored ImmunoProphylaxis, or VIP for short—is not exactly a vaccine. Vaccines introduce substances such as antigens into the body to try to get the immune system to mount an appropriate attack—to generate antibodies that can block an infection or T cells that can attack infected cells. In the case of VIP, a small, harmless virus is injected and delivers genes to the muscle tissue, instructing it to generate specific antibodies.  

The researchers emphasize that the work was done in mice and that the leap from mice to humans is large. The team is now working with the Vaccine Research Center at the National Institutes of Health to begin clinical evaluation.

The study, "Vectored immunoprophylaxis protects humanized mice from mucosal HIV transmission," was supported by the UCLA Center for AIDS Research, the National Institutes of Health, and the Caltech-UCLA Joint Center for Translational Medicine. Caltech biology researchers Alejandro B. Balazs, Yong Ouyang, Christin H. Hong, Joyce Chen, and Steven M. Nguyen also contributed to the study, as well as Dinesh S. Rao of the David Geffen School of Medicine at UCLA and Dong Sung An of the UCLA AIDS Institute.

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