Why Are People More Susceptible to Infection As They Age?
Infection in the elderly is both a significant and growing problem. Infection causes 40% of all mortality in those aged 65 years and older. In the future, the problem of infection in the aged will have even greater impact as by the year 2020 the number of people over the age of 65 will reach 65 million, representing 25% of the US population.
As people age some become more susceptible to infection. This observation suggests that genetic variation is a determinant of this loss of resistance. Which are the genes that are contribute to this variation? Which immune mechanisms are affected? Our approach to these questions is to study a disease in which there is a dramatic increase in susceptibility in aged humans: The infection by the protozoan parasite Babesia microti, an organism that can cause a fatal anemia in older individuals.
Figure 1. The left panel illustrates the increased susceptibility of older individuals to infection with Babesia. The middle panel highlights an area in which infection is common. The right panel shows the tick vector (top) and infected red blood cells (bottom).
We have found that the outcome of Babesia infection in mice is strongly influenced by the strain of mice. The experiment shown below examines the level of parasitemia following infection of different strains of mice, inoculated with the parasite at different ages. DBA/2 mice develop higher levels of infection compared to mice of other stains even when they are young. The initial infection resolves in the BALB/c and C57 mouse strains as is indicated by the lower levels of parasitemia at later time points post infection. In contrast to the pattern observed in young mice, older DBA/2 animals fail to resolve the infection and substantial levels of parasitemia persist for long periods of time.
Figure 2. Different levels of parasitemia are characteristic of different strains of inbred mice.
Other experiments, using nude mice, which have a mutation that results in a lack of T cells, cannot clear the parasites from their blood. As shown, this contrasts with the pattern of parasitemia found in normal mice.
Figure 3. Levels of parasitemia were monitored in normal and nude mice. Infection resolves in the normal mice but persists in the nude mice.
Our goal is to identify the genes responsible for controlling the outcome of infection. Other experiments examine the critical elements of the immune system needed to control infection. Our hypothesis is that the two experimental approaches will converge, allowing us to identify the genes responsible for age-related immune resistance.
Genetic mapping of resistance indicates that multiple loci are involved. In the figure below mouse chromosomes (1-19) are spread across the X axis. The likelihood of a resistance gene (Quantitative Trait Locus or QTL) at any point on the map is shown on the Y axis.). Data from young mice are shown above and data from old mice below. Interestingly, the two maps suggest that different loci contribute to resistance in old and young mice.
Figure 4. Mapping of genes associated with resistence to Babesia. See the text for a full explanation of these data