University of California, Irvine and MIT researchers
have developed a new strategy to immunize against microbes that invade the
gastrointestinal tract, including Salmonella, which causes more foodborne
illness in the United States than any other bacteria.
Source: University
of California, Irvine
The researchers
targeted a molecule that Salmonella and other bacteria secrete to scavenge
iron, which is essential to many cellular functions. Immunization against this
molecule led to the production of antibodies that reduced Salmonella growth,
and to much lower levels of the bacteria. This approach could offer an
alternative to antibiotics, which can cause side effects because they also kill
beneficial bacteria. Using too many antibiotics can also lead to drug
resistance. "Enteric infections are difficult to treat, because
antibiotics also disrupt the body's beneficial microbes that can provide a
defense against these pathogens," said Manuela Raffatellu, a UCI associate
professor of microbiology & molecular genetics. "Our strategy is
narrow-spectrum and augments the host's existing defenses." Raffatellu and
MIT's Elizabeth Nolan are the senior authors of the study, which appears in the
Proceedings of the National Academy of Sciences the week of Nov. 7. The
paper's lead authors are Martina Sassone-Corsi, a UCI postdoctoral scholar, and
Phoom Chairatana, who recently received a doctorate in chemistry at MIT.
Iron-clad
defenses
Most bacteria,
as well as some fungi, use molecules known as siderophores to obtain iron, a
metal that is critical for cellular processes including metabolism and DNA
synthesis. Bacteria that live in the intestinal tract secrete siderophores into
the gut and then reabsorb them after they have grabbed onto iron. There are
hundreds of different types of siderophores, and in this study, the researchers
focused on a subset of siderophores that are produced by Salmonella and a few
other types of pathogenic bacteria that can live in the gut. The researchers
were inspired by the way that some organisms naturally combat microbes by
blocking their iron uptake. Humans have a defense protein known as lipocalin 2,
which can capture some siderophores and prevent these molecules from carrying
iron into bacterial cells. However, lipocalin 2 is not effective against
certain types of siderophores, including one type used by Salmonella. "There's
no identified human defense mechanism against some of these molecules. That's
how we got thinking about how we could boost this metal-withholding response
via an immunization," Nolan said.
The siderophore
molecules are too small to induce an immune response from a host organism, so
the researchers decided to attach it to a protein that does induce an immune
response -- cholera toxin subunit B (CTB). The siderophore-CTB complex is
delivered nasally or injected into the abdomen and makes its way to the lining
of the GI tract, where the body begins producing antibodies against both CTB
and the siderophore. The researchers gave mice the immunization twice, two
weeks apart, and then infected them with Salmonella 36 to 51 days after the
first immunization. They found that antibodies against the siderophores peaked
around 21 days after the first immunization and then remained at high levels.
The immunized mice also had much smaller numbers of Salmonella in their gut and
did not experience the weight loss seen in mice that were infected but not
immunized. In a paper appearing in the same issue of PNAS, researchers
at the University of Michigan used a similar approach to generate an immune
response against E. coli that can cause urinary tract infections.
Bacterial
benefits
The researchers
also found that immunization not only reduced the Salmonella population but also
led to the expansion of the population of a beneficial bacteria known as
Lactobacillus -- the probiotic bacteria found in yogurt, which help to inhibit
the growth of pathogenic microbes. "We think that the expansion of
Lactobacillus may be conferring additional benefit to the host," Nolan
says. This immunization strategy could be useful to protect people at high risk
for certain kinds of infections, such as people who have compromised immune
systems or cancer patients receiving chemotherapy, Nolan says. This approach
could also be used to generate antibodies to treat people after they become
infected with certain pathogens, such as Salmonella. The researchers are now
working to isolate and analyze the antibodies that the mice produced in this
study, and they are developing immunization strategies against other types of
siderophores found in other organisms.
By
Dr. G. Saravanan
Associate Professor & Head
Department of Biochemistry
No comments:
Post a Comment