In a new study the first mouse model of the common bacterial disease typhoid fever is reported. The study is published by Cell Press October 25 in the journal Cell. Because the animals show human-like symptoms and respond positively to immunization, they could be used to develop more effective vaccines against the deadly pathogen.
"Prior to our work, there was no small animal model for studying immune responses to the bacteria that cause typhoid fever," says study author Matthew Hayden of Columbia University. "We hope that the model we have developed will promote rapid progress in developing better vaccines."
Typhoid fever is characterized by rash and severe diarrhea, and it causes more than 220,000 deaths each year, frequently in developing countries lacking clean sources of drinking water. It is caused by the bacterium Salmonella typhi
), which normally infects humans but not mice. Unlike humans, mice express toll-like receptor 11 (TLR11), an immune cell receptor that recognizes molecules found in a range of microbes and triggers immune responses that help to fight infections.
"The two vaccines currently approved for this disease are only modestly effective, so research aimed at improving vaccines is essential," says senior study author Sankar Ghosh of Columbia University.
Because TLR11 is highly expressed in the mouse intestine, Hayden and his colleagues suspected that this receptor might recognize pathogens that cause intestinal diseases and could be responsible for preventing typhoid fever in mice. To answer these questions, the researchers inactivated the tlr11 gene in mice and exposed them to S. Typhi
. These mice developed severe intestinal tissue damage and hallmark symptoms such as fever and diarrhea. But when the mice were first immunized with heat-killed S. Typhi
, they mounted strong immune responses and became impervious to infection.
Moreover, the researchers found that the key component responsible for S. Typhi
's virulence is a protein called flagellin, which is recognized by TLR11. Because other pathogens have flagellin, these mice might also serve as a model system for other important bacterial diseases. "Having an animal model vastly improves our ability to investigate diseases, the immune response and, importantly, can be immensely beneficial for efforts to develop new vaccines and therapies," Hayden says.