As people age, a greater number becomes susceptible to infections. Because the aged represent an ever-growing segment of the populations in the western world, morbidities due to infection are significant. We are interested in identifying alleles that underlie this age-acquired susceptibility. We developed a mouse model of human babesiosis due Babesia microti, an emerging infection particularly severe in the aged. We observed that young DBA/2 mice experience significant parasitemia but young C57BL/6, B10.D2 and BALB/c mice do not. In DBA/2 mice an early phase characterized by an intense and transient parasitemia is followed by a late phase of low grade, but persistent parasitemia. As age advances, both acute and chronic parasitemia become greater in DBA/2, but not in C57BL/6, B10.D2 or BALB/c mice. Using B10.D2 x DBA/2 (BXD) and BALB/c x DBA/2 (CXD) crosses as well as chromosome substitution mice, we have established that i) resistance is a complex trait in young and old mice, and ii) acute resistance in young mice maps to QTL that differ from those of old mice. We conclude that the greater susceptibility of old DBA/2 mice maps to age-restricted QTL. We now propose to identify resistance and susceptibility alleles and to uncover how they modulate the response to B. microti infection.
In Aim#1, we will identify the major genetic determinants of acute resistance in old mice of the BXD cross.
In Aim#2, we will identify the major genetic determinants of acute resistance in old mice of the CXD cross.
Both aims combine a positional cloning approach with bioinformatic analyses and gene expression studies.
In Aim#3, we will identify the cells that contribute to resistance and are affected by the polymorphisms underlying the major QTL. Strain differences in cell function will be studied and used to guide the genetic analysis. We are hopeful that the identification of age-sensitive polymorphisms that modulate immune resistance of old mice to babesiosis may inform the search of alleles that predispose aged individuals to infection.
As they age, many people become more susceptible to infection. The reasons are poorly understood. We are exploring the genes that render aged mice susceptible to infection. Because there is great similarity between the genes of mice and humans we believe our discoveries in mice will aid work to understand the genetic basis of age-related susceptibility to infection in humans. ? ? ?
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