Neonatal bacterial infection alters fever to live and simulated infections in adulthood

Fever is a critical component of the host immune response to infection. An emerging literature demonstrates that experience with infectious organisms early in life, during the perinatal period, may permanently program immune responses later in life, including fever. We explored the influence of neonatal infection with Escherichia coli on fever responses to lipopolysaccharide (LPS) and E. coli in adulthood. Fever to a low dose of LPS in adulthood did not significantly differ as a consequence of early-life infection. Eight days after the LPS injection, the same group of rats received a high dose of live E. coli. This time, neonatally infected rats exhibited a markedly longer fever than controls. In a subsequent experiment, fever to a single high dose of E. coli without prior LPS in adulthood did not differ by group, suggesting that the previous difference was a lack of tolerance to the dual challenges in early-infected rats. Finally, both groups exhibited decreased tumor necrosis factor (TNF)-alpha and toll-like-receptor (TLR) 4 production to dual LPS challenges in isolated splenocytes, whereas only rats infected as neonates exhibited increased cyclooxygenase-2 within the hypothalamus in response to adult infection, suggesting that early infection-induced changes in fever regulation may involve a change in central mechanisms. Taken together, these data indicate that early-life infection is associated with marked changes in host temperature regulation in adulthood.