Host and bacterial factors mediate adverse pregnancy outcomes during perinatal listeriosis

Active Project Grant Awarded Last action

Award ID
F32AI203393
Recipient
Awarding agency
Obligated
$77,779

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 0% complete
Place of performance
Madison, WI 53715, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Specialized pathogens that colonize gestational tissues during pregnancy are a major cause of morbidity and mortality. While these pathogens can induce devastating adverse pregnancy outcomes (APO) including spontaneous miscarriage, stillbirth, preterm birth (PTB), and invasive infant infections, little is known about the factors that permit successful gestational colonization or host pathways that mediate APO. Torch pathogens are the most recognized among these; however, non-torch pathogens can also cause severe congenital infections. The gram-positive bacterial pathogen listeria monocytogenes (LM) causes the foodborne illness listeriosis. Although infection is mild and self-limiting in healthy adults, infection risk increases up to 18X during pregnancy and infant fatality rates can reach ~60%. Here, we propose to use LM - a model bacterial pathogen - to dissect the host and bacterial factors that mediate gestational tissue colonization and onset of APO in a perinatal listeriosis mouse model. Recently, serotype 1/2A laboratory reference strains which are frequently used to probe LM pathogenesis were shown to be genetically distinct from major serotype 4B human clinical isolates. The 4B clinical isolate 2203 caused strikingly high rates of maternal infection and APO (85 and 100% versus 13% and 25% annual averages). In this proposal, we will test the hypothesis that 2203: 1) induces an early and robust gestational inflammatory response causing high rates of APO, and 2) possesses novel genetic factors that confer its successful gestational replication. In preliminary infections, 2203 causes significantly increased colonization of the gravid uterus, pups, and placentas compared to 10403S. 2203 also induces significantly elevated APO, recapitulating PTB and stillbirth as observed in the human outbreak. Uterine infection by 2203 - but not 10403S - significantly increased MCP-1 levels, while the placental cytokine responses are relatively quiescent in both infections. 2203-infected placentas also harbor high prostaglandin E2 (PGE2), a lipid eicosanoid strongly associated with spontaneous PTB. In aim 1, we will measure gestational immune cell dynamics and temporal chemokine, cytokine, and eicosanoid responses in our murine perinatal listeriosis model, allowing US to identify immune profiles associated with 10403S versus 2203 infection and to correlate specific pro-inflammatory factors with LM control or APO onset. We will also dissect the contribution of MCP-1 and PGE2 using transgenic mice and inhibitors. Preliminary in vitro work noted that L2 fibroblast infection by 2203 induces 2X larger plaques than 10403S. Thus, in aim 2 we will contrast the 10403S and 2203 intracellular lifecycles to identify stages where their phenotypes differ. To find novel genes that are important for 2203'S high efficiency cell-to-cell spread, we will also perform a forward genetic screen. Finally, we will test the hypothesis that 2203'S efficient cell-to-cell spread mediates high gestational tropism by testing a panel of 2203 small plaque mutants in our perinatal listeriosis model. Completion of these aims will define host and LM factors that mediate perinatal virulence, allowing future work to assess the conservation of these mechanisms for other perinatal pathogens.

Quick answers

Who received award F32AI203393?

F32AI203393 was awarded to University Of Wisconsin System by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on February 14, 2027.

How much is award F32AI203393 worth?

$77,779 has been obligated on F32AI203393.

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