LATE GESTATION MATERNAL IMMUNE FUNCTION AND CONCURRENT ESCHERICHIA COLI INTRAMAMMARY INFECTION DYNAMICS

Abstract

Cows are susceptible to new Escherichia coli intramammary infections (IMI) in the non-lactating period of late gestation (known as the ‘dry period’). These IMI often persist up until parturition without inducing highly inflammatory responses and increase the risk of postpartum mastitis in the subsequent lactation. The bovine maternal immune system is hypothesized to be regulated during late gestation to prevent highly inflammatory, cell-mediated responses however the mechanisms in generating such tolerance have not been fully elucidated. In other mammalian species mononuclear phagocytes play a primary role in generating maternal immune tolerance, and although beneficial for the fetus, often negatively impacts immune responses to invading pathogens. The work presented here investigated changes in maternal immunity and its relationship to dry period E. coli IMI dynamics through the use of experimental and mathematical approaches. The objectives were to 1) characterize changes in blood monocyte composition and monocyte-derived dendritic cell (moDC) function over pregnancy to identify unique changes in late gestation, 2) investigate pregnancy-associated factors that regulate these cells, 3) investigate the relationship between maternal immune regulation and dry period E. coli IMI dynamics and risk of postpartum mastitis through mathematical models, and 4) investigate the effect of intramammary immunization with UV-killed E. coli on IMI dynamics and host response. Pregnancy was accompanied with a decrease in inflammatory monocytes and impaired moDC maturation following E. coli stimulation. Aspects of hindered moDC maturation could be induced by in vitro treatment of late gestation levels of progesterone and estradiol. Deviations in prepartum monocyte composition related to risk of postpartum disease. Mathematical model results indicated these shifts in cytokine production alone were not able to recapitulate IMI dynamics in the dry period, but rather it involved an interaction between maternal immune regulation and physiological and immunological changes to the mammary gland that accompany the dry period. Intramammary immunization at dry-off generated protective responses against E. coli challenge later in the dry period. Overall, shifts in maternal immunity both in the periphery and in the mammary gland during the dry period relate to persistent E. coli IMI and postpartum mastitis, and local immunity can be manipulated to generate protection against IMI in the dry period.