Listeriosis in the Pregnant Mouse

The purpose of the research proposed in this RO3 application is to better understand how pregnancy predisposes gravid animals to listeriosis. Amongst the factors that predispose a host to listeriosis, pregnancy stands out as the only condition that is neither abnormal nor rare amongst females. Comparatively little is known about factors that render the pregnant female more susceptible to disease.<P> We have recently devised a gravid mouse model in which listeriosis can be monitored in both the pregnant mouse and her unborn offspring following oral inoculation. In our studies, mice were inoculated unusually early in gestation (7.5 gestational days [of a total of about 19.5]), and at this stage an increased susceptibility was readily apparent. This and other results from our studies led us to a hypothesis: Increased disease severity in the gravid mouse will be concomitant with blastocyst implantation, which will provide an immunologically privileged site for unrestricted bacterial growth. <P>Since implantation occurs very early in pregnancy, experimental results favoring our hypothesis will be easily distinguished from results supporting a competing, and perhaps more prevailing, notion that systemic immunological changes late in pregnancy are responsible for increased disease severity. <P>In our proposed studies, we use an out-bred mouse strain (utilized extensively by embryologists) that becomes pregnant reliably and has large litters. We will employ a mouse-virulent Listeria monocytogenes strain and employ the natural (oral) inoculation route.<P> We have one specific aim: A systematic characterization of listeriosis in the gravid mouse. At various gestational times, mice will be orally inoculated with L. monocytogenes. Doses will be graded to obtain an LD50 determination (in one set of mice), and organ infectivity levels will be determined in another set in which a lower dose will be employed. Histological examination of embryos and fetuses will be carried out concurrently with the infectivity studies by routinely removing one uterine horn of a sacrificed mouse and examining the contents following fixation and staining. Immunological tests will determine how pregnancy affects the innate ability of the gravid animal to respond to infection. <P>Benefits from the work proposed in this grant application include some that are immediately transferable into changes in health policy. For example, experimental support for our hypothesis could influence the recommended clinical procedures associated with miscarriage (by encouraging a routine microbiological analysis of expelled embryos and dilatation and curettage material) and forestall many infections in women (by acquainting obstetricians with data suggesting an early risk).