Making sense of susceptibility
In their quest to understand infectious diseases, microbiologists and immunologists explore the various tricks that pathogenic bacteria, viruses and parasites use to make us sick, as well as the myriad ways our immune systems try to fight back. On the bug side, it’s well known that genetic factors can affect microbes’ ability to cause disease. What’s less well understood is how the host’s genetic makeup enters in. In other words, to what extent do our genes determine how sick we get when exposed to disease-causing microorganisms?
That’s one of the questions Katherine Spindler is investigating, using a type of adenovirus as a study system. Adenoviruses cause five to ten percent of respiratory illnesses in children and are a particular problem in young transplant patients whose immune systems have been weakened by anti-rejection drugs. Studying human adenoviruses directly is problematic, so Spindler uses a mouse adenovirus called MAV-1, which has many similarities to human adenoviruses and can easily be studied in its natural host in the lab.
Her research group didn’t set out to examine host susceptibility, but the opportunity presented itself when Spindler was a faculty member at the University of Georgia. A worker in her lab was studying persistent infections by infecting mice with doses of MAV-1 that she was sure the mice could survive. But a strange and distressing thing happened with one cohort of mice: they all died from the supposedly mild infection. The researchers went on discover that certain strains of mice were more susceptible to the virus than others and that in fact there was quite a wide range—from highly susceptible to highly resistant.
“So we took off to study that,” says Spindler. Through a series of genetic analyses, the researchers homed in on a location on chromosome 15 where susceptibility genes seem to reside. Over the years, they have narrowed the region of interest from about 300 genes to about 15 genes. Among them are genes in a family known as Ly6. Genes in this family are known to encode proteins that are found on cell surfaces and are involved in immune system response.
“The Ly6 genes are expressed in the cells that MAV-1 targets, so they’re good candidates for susceptibility genes,” says Spindler, who’s now trying to pinpoint and determine the function of the exact gene or genes involved.
While Spindler’s adenovirus work continues, she recently has begun looking at host susceptibility in another virus, Punta Toro, which causes severe infections in mice and is a model for Rift Valley fever virus in humans.
If host genes for susceptibility to MAV-1 and Punta Toro virus can be identified, a logical next step would be to see if human counterparts of those genes make people more susceptible to human adenovirus and Rift Valley fever, respectively. Whether or not that turns out to be the case, the work will have value, Spindler says.
“Whenever researchers identify microbial-host interactions and host genes involved in susceptibility, we learn something new about the immune system and host response that may lead to improved disease therapies.”
