Awardee Profile - Andrew Neish

The Bright Side of Salmonella

Andrew Neish, M.D., has seen more of Salmonella than most people endure in a lifetime.

Salmonella are the bacteria most commonly associated with foodborne illness—a malady commonly, though inaccurately, called food poisoning, which strikes huge numbers of people each year.  But these and other members of the bacterial world still hold his respect.

“Since the very first animals crawled up on land, and even before, they have had to figure out how to deal with bacteria,” he said.  Dr. Neish is an associate professor of pathology and laboratory medicine at the Emory University School of Medicine, and a 2003 recipient of a Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Disease award.

The interactions between bacteria and their human hosts are incredibly complex, Dr. Neish added.  One factor that complicates the picture is that bacteria have been found to exist in tremendous variety and quantity; for instance, many millions of bacteria inhabit the gut of just one healthy human being.  As another factor, relations between the two groups are constantly changing under the pressure to survive.  The coevolution of bacteria and host is often compared to an arms race—but where others see “invasion” and “defense,” Dr. Neish sees a less sinister tale of crossed signals and miscommunication.

“Ninety-nine percent of all interactions between bacteria and their host are beneficial, or at least innocuous,” Dr. Neish said.

When it is working right, he said, this life-sustaining partnership may seem effortless: who remembers to give thanks every day for the Escherichia coli that help every person digest his or her food?  It is this kind of symbiosis that Dr. Neish considers to be like an ongoing conversation.  In his view, disease is a breakdown in the dialogue, with host cells speeding up their own preprogrammed death, a process called apoptosis, in order to get rid of the bacteria.  The very process of infection depends on the transmitting and receiving of signals, with the foreign cells seeking out receptor sites on the surface of the host cells to gain admittance and then co-opting the host’s genetic code to crank out more copies of themselves.

With BWF support, Dr. Neish has been taking a close look at the Salmonella “effector” proteins, which play a crucial role in causing foodborne illness by invading the host’s intestinal epithelia, the membranous lining, and enabling the bacteria to take over some of the epithelial cells’ normal signaling functions.

To study these proteins at work, Dr. Neish and his colleagues developed a technique for inserting the genes for an effector protein known as AvrA into the genome of several animal models.  Both in Drosophila (tiny two-winged flies) and in a mouse model, the effector protein was seen to interfere with the cellular signaling that would trigger an all-out immune response—that is, apoptosis.  This signal-disrupting ability, Dr. Neish said, “is consistent with the natural history of Salmonella in mammalian hosts.”  As anyone who has experienced foodborne illness knows all too well, no matter how strong the gut reaction may be, the infection still has to run its course; Salmonella provokes the endothelial cells of the intestines severely, but it does not kill them.

Dr. Neish didn’t start out worrying about foodborne illnesses.  After receiving his medical degree from the University of North Carolina-Chapel Hill, he focused his research first on the heart and its diseases, and then on the endothelia of various sites in the body.  Along the way, he has studied gene expression and molecular signaling in such diverse conditions as cystic fibrosis, pituitary adenoma, and acute abdominal injury in children.

Today, in addition to his work on Salmonella, Dr. Neish is exploring other signaling pathways of the immune response by means of mammalian cell cultures as well as Drosophila and mouse models.  In addition, he uses microarray technology for large-scale gene expression profiling.

Still, Salmonella hold a special interest bordering on admiration, as Dr. Neish maintains that this ill-famed organism actually has a good side.  After all, many strains of Salmonella coexist with healthy animals and presumably have done so for millions of years.

Even in the human gut, he says, Salmonella may not be all bad, and he is intent on following up evidence that the bacterial surface protein known as flagellin may have a role to play in keeping humans healthy.  In a recent study, published in June 2008 in the Journal of Immunology, Dr. Neish’s research team treated mice with purified flagellin and then challenged their immune system with an assortment of pathogens and potentially damaging chemical compounds.  Not only did the flagellin protect the animals against these immune challenges, it did so without triggering the inflammation, nausea, and other uncomfortable features of an immune response.

To Dr. Neish, that’s not bad for such a maligned organism.

Sandra J. Ackerman writes about science and medicine from Durham, North Carolina.