Typhoid fever is a serious threat in many parts of the world, infecting 11-20 million and killing as many as 161,000 people each year, with many multidrug resistant strains. Dr. Jeongmin Song, assistant professor of microbiology and immunology, has discovered a new potential defense against this bacterial disease — one of its closest relatives.

Song studies the bacteria that cause typhoid fever, Salmonella typhi, and how it invades and infects host cells. In a study published May 11 in Cell Host & Microbe, Song and her team discovered that typhoid’s close cousin, Salmonella Javiana, invades and infects hosts cells in almost the same way, but with much less harmful results. “We found that one of the important differences in deadliness between these two bacteria came down to a handful tiny molecular changes which dictate what host cells they attack,” says Song. This family resemblance could potentially be leveraged as a potential vaccine against typhoid fever.

In previous studies, Song discovered that Salmonella typhi produce a toxin that is responsible for most of the symptoms of typhoid fever. The toxin does the heavy lifting in the disease process, using a specific protein one-two punch technique when attacking its prey, white blood cells. First, toxin protein ‘B’ zeroes in on specific sugars adorning the outer membrane of immune cells, helping the toxin find its victim. Then, two toxin ‘A’ proteins, which are enzymes, enter the cell and disrupt the white blood cells’ immune response. The bacteria’s special method of binding its toxin to immune cells is the “secret key” behind its deadliness, Song explains.

Song knew that Salmonella Javiana had the same type of search-and-destroy proteins in its molecular toolkit. However, Javiana toxin only causes short-lived food poisoning. “Surprisingly, we found that two toxins play different roles despite the high similarity between the two,” she says.

Indeed, Javiana toxins differ from typhoid toxins by only six amino acids. The researchers found that those tiny differences were in fact the critical reason why typhoid bacteria can be deadly, while Javiana just cause a sick stomach. “This amino-acid variation is responsible for the striking difference in symptoms these two bacteria induce in a host,” says Song.

The researchers took a deeper dive into understanding how those different amino acids affected the toxins’ behavior on a molecular level. Both toxins had three binding sites, but the difference in their amino-acid make up enabled typhoid toxins to attack a broader range of cellular targets and induce deadly systemic infections throughout the body, while Javiana could only attach to cells in the intestinal tract.

Song and her team also wondered if the similarity could also be a form of protection. “We wondered if exposure to Javiana bacteria or their toxin might provide some protection against typhoid-related illnesses,” she says.

The team exposed mice first to Javiana toxins, and then a lethal dose of typhoid toxins, and found that the Javiana exposure protected the mice dying from typhoid infection. “We found that exposure to Javiana is protective against lethal doses of typhoid toxins,” Song says. “This finding may be the key to designing improved typhoid fever vaccines and therapeutics.”

With luck, Song’s discovery may pave the way to making typhoid fever finally a disease of the past.

-By Lauren Cahoon Roberts