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News Article | February 21, 2017

MADISON, Wis. -- Listeria, a common food-borne bacterium, may pose a greater risk of miscarriage in the early stages of pregnancy than appreciated, according to researchers at the University of Wisconsin-Madison School of Veterinary Medicine studying how pathogens affect fetal development and change the outcome of pregnancy. "For many years, listeria has been associated with adverse outcomes in pregnancy, but particularly at the end of pregnancy," says Ted Golos, a UW-Madison reproductive physiologist and professor of comparative biosciences and obstetrics and gynecology. "What wasn't known with much clarity before this study is that it appears it's a severe risk factor in early pregnancy." Golos and his collaborators published their results Feb. 21, 2017 in the journal mBio. According to the Centers for Disease Control, listeria makes about 1,600 Americans sick each year -- a relatively small number, but a group heavy on newborn babies and older adults with undeveloped or weak immune systems. "The problem with this organism is not a huge number of cases. It's that when it is identified, it's associated with severe outcomes," says Charles Czuprynski, a UW-Madison professor of pathobiological sciences and director of the UW-Madison Food Research Institute. Pregnant women are warned to avoid many of the foods -- among them unpasteurized milk and soft cheese, raw sprouts, melon and deli meats not carefully handled -- that can harbor listeria, because the bacterium is known to cause miscarriage and stillbirth, and spur premature labor. Those severe outcomes have resulted in a zero-tolerance regulatory policy for listeria in ready-to-eat foods. But when it occurs, listeria infection in pregnancy may go unnoticed. The few recognizable symptoms are nearly indistinguishable from the discomfort most newly pregnant women feel. "It's striking that mom doesn't get particularly ill from listeria infection, but it has a profound impact on the fetus," says Golos, whose work is funded by the National Institutes of Health. "That's familiar now, because we've been talking about the same difference in Zika virus." Sophia Kathariou, a North Carolina State University professor of food science and microbiology, provided a strain of listeria that caused miscarriage, stillbirth and premature delivery in at least 11 pregnant women in 2000. Four pregnant rhesus macaques at the Wisconsin National Primate Research Center were fed doses of the listeria comparable to what one might encounter in contaminated food. Bryce Wolfe, a UW-Madison graduate student studying cellular and molecular pathology who is lead author of the study, monitored the speed and progression of listeria's spread. "What's particularly striking about the work Bryce did is the detailed information we now have about the organism," Czuprynski says. "The animal ingested it; she tracked it being shed in feces and showing up in the bloodstream. They did ultrasound analysis of the fetus, and could then show events in terms of where the organism was preceding fetal demise." None of the monkeys showed obvious signs of infection before their pregnancies came to abrupt ends. But in tissue samples taken after each monkey experienced intrauterine fetal death, Wolfe found listeria had invaded the placenta -- the connection between the mother-to-be and the fetus, which usually prevents transmission of bacteria -- as well as the endometrium, the lining of the uterus. "In that region, there's a rich population of specialized immune cells, and it is exquisitely regulated," says Wolfe. "When you introduce a pathogen into the midst of this, it's not very surprising that it's going to cause some sort of adverse outcome disrupting this balance." The researchers believe the inflammation caused by the maternal immune response to the fast-moving listeria also affects the placenta, keeping it from protecting the fetus. "It should be a barrier," Golos says. "But we're hypothesizing that the maternal immune system's attempt to clear the bacteria actually results in collateral damage to the placenta that then allows the bacteria to invade the fetus." The results suggest listeria (and perhaps other pathogens) may be the culprit in some miscarriages that usually go without diagnosed cause, but the bacteria's stealth and speed may still make it hard to control. "There are effective antibiotics available. It is treatable," Wolfe says. "The issue is that because it's asymptomatic, the fetus may be infected by the time anyone realizes the mother was infected." Golos and Wolfe plan to continue work with listeria to better define how the bacterium targets the reproductive tract, its incubation time and the problems it causes leading up to miscarriage. Their goal is to provide basic knowledge about the progression of infection and the maternal immune response to intracellular pathogens in pregnancy, which may help other researchers battling similar dangers such as Zika virus.

News Article | February 21, 2017

Washington, DC - February 21, 2017 -Researchers in Wisconsin have discovered how Listeria monocytogenes, a common foodborne pathogen, travels through the mother's body to fatally attack the placenta and fetus during early pregnancy in a macaque monkey. The study, published this week in mBio®, an open-access journal of the American Society for Microbiology, clarifies why Listeria infection is devastating for many infected pregnant women and their fetuses. The work raises questions about our current understanding of the risk for listeriosis in early pregnancy, and reveals clues that may lead to better screening and interventions during pregnancy. "There was a profound reproductive tract colonization and rapid fetal demise with a first trimester exposure to Listeria," says Ted Golos, professor of reproductive sciences at the School of Veterinary Medicine at the University of Wisconsin--Madison and senior author on the study. "At any time during pregnancy, we wish that we could carefully monitor what's happening in the mom and the fetus following exposure to an infectious agent." (image: scanning electron micrograph of Listeria monocytogenes, Wikimedia Commons) Of course, that is nearly impossible to do in human patients, so Golos and his colleagues at the Wisconsin National Primate Research Center have developed a nonhuman primate model of pregnancy using the cynomolgus macaque--a monkey whose pregnancy, placental and fetal development closely matches that of humans. Listeriosis has been thought to pose the greatest danger to a woman in her third trimester, when it can lead to preterm labor, fetal infection or fetal death. It is the reason pregnant women are cautioned against eating deli meats and milk or soft cheeses that are unpasteurized. "What makes Listeria particularly dangerous is that it can multiply at refrigeration temperatures," says Chuck Czuprynski, director of the Food Research Institute at UW-Madison and project collaborator. Most healthy people can easily clear the bacteria from their systems. Until now, not much was known about Listeria's impact on early pregnancy. The new research raises the possibility that some first trimester miscarriages might be due to an undetected Listeria infection, which often causes no or mild symptoms, like low fever or nausea, in pregnant women. "Obstetricians will tell you that a number of early pregnancy miscarriages are thought to be due to chromosomal problems," says Golos. "But how many may be due to other causes like infections?" His team exposed four pregnant macaques to a moderate dose of Listeria bacteria by tube-feeding them a dollop of tainted whipped cream on days 36-46 of gestation--corresponding to about week 6 or 7 of a human pregnancy. They expected to see some adverse pregnancy outcomes, but they were surprised by how rapidly infection spread to the fetus: by days 7-13 after exposure, all four fetuses had died in the womb. Graduate student Bryce Wolfe tracked the infections in the mothers through blood and fecal sampling and in the fetuses via ultrasound. All of the mothers showed signs of bacterial infection in their bloodstream, but displayed few to no symptoms. When Wolfe examined maternal and fetal tissues for signs of infection, she found that the mothers' immune systems apparently cleared the infections, with very few bacteria showing up in their spleens, livers, and gastrointestinal (GI) lymph nodes. In contrast, Wolfe found high loads of bacteria present in the fetal tissues, amniotic fluid, umbilical cord, placenta, and the decidua, the specialized lining of the pregnant uterus. "We didn't expect to see the bacteria colonize the fetus so quickly, so consistently," says Wolfe, a PhD candidate at UW-Madison and the lead author on the study. "The decidua and the placenta, which make up the maternal-fetal interface, were loaded with bacteria." It appears that the monkey's immune system can protect mom, but not the fetus and that the bacteria target the vulnerable reproductive tissues. In the macaques, Wolfe saw cellular damage to the placenta and the fetal membranes that is often seen in Listeria infections during human pregnancy. Golos hypothesizes that damage to the decidua and placenta could be disrupting the placental barrier meant to keep pathogens out of the womb. Czuprynski says the study raises significant questions about whether Listeria and perhaps other pathogens cause mild infections in mothers that negatively impact pregnancy. The study is the first to track the progress of a pathogen from the GI tract through a pregnant primate's body to the fetus, he notes. "We have reason to believe it mirrors what happens in women." Next, the team will investigate what is happening with the immune cells that survey and protect the maternal-fetal interface. Improving our understanding of what those cells are doing during an infection might lead to better ways to detect and treat the infection to protect the fetus. Again, this takes advantage of the animal model, says Golos. "You can follow the time course of the infection, understand the initiating events, and hopefully devise ways to prevent the damage that leads to a bad pregnancy outcome." The American Society for Microbiology is the largest single life science society, composed of over 48,000 scientists and health professionals. ASM's mission is to promote and advance the microbial sciences. ASM advances the microbial sciences through conferences, publications, certifications and educational opportunities. It enhances laboratory capacity around the globe through training and resources. It provides a network for scientists in academia, industry and clinical settings. Additionally, ASM promotes a deeper understanding of the microbial sciences to diverse audiences.

Dubois S.L.,University of Wisconsin - Madison | Acosta-Martinez M.,State University of New York at Stony Brook | DeJoseph M.R.,Rosalind Franklin University of Medicine and Science | Wolfe A.,Johns Hopkins University | And 5 more authors.
Endocrinology | Year: 2015

Hypothalamic kisspeptin (Kiss1) neurons express estrogen receptor α (ERα) and exert control over GnRH/LH secretion in female rodents. It has been proposed that estradiol (E2) activation of ERα in kisspeptin neurons in the arcuate nucleus (ARC) suppresses GnRH/LH secretion (negative feedback), whereas E2 activation of ERα in kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) mediates the release of preovulatory GnRH/LH surges (positive feedback). To test these hypotheses, we generated mice bearing kisspeptin cell-specific deletion of ERα (KERαKO) and treated them with E2 regimens that evoke either negative or positive feedback actions on GnRH/LH secretion. Using negative feedback regimens, as expected, E2 effectively suppressed LH levels in ovariectomized (OVX) wild-type (WT) mice to the levels seen in ovary-intact mice. Surprisingly, however, despite the fact that E2 regulation of Kiss1 mRNA expression was abrogated in both the ARC and AVPV of KERαKO mice, E2 also effectively decreased LH levels in OVX KERαKO mice to the levels seen in ovary-intact mice. Conversely, using a positive feedback regimen, E2 stimulated LH surges in WT mice, but had no effect in KERαKO mice. These experiments clearly demonstrate that ERα in kisspeptin neurons is required for the positive, but not negative feedback actions of E2 on GnRH/LH secretion in adult female mice. It remains to be determined whether the failure of KERαKO mice to exhibit GnRH/LH surges reflects the role of ERα in the development of kisspeptin neurons, in the active signaling processes leading to the release of GnRH/LH surges, or both. Copyright © 2015 by the Endocrine Society

Seltzer L.J.,University of Wisconsin - Madison | Ziegler T.E.,Wisconsin National Primate Research Center | Pollak S.D.,University of Wisconsin - Madison
Proceedings of the Royal Society B: Biological Sciences | Year: 2010

Vocalizations are important components of social behaviour in many vertebrate species, including our own. Less well-understood are the hormonal mechanisms involved in response to vocal cues, and how these systems may influence the course of behavioural evolution. The neurohormone oxytocin (OT) partly governs a number of biological and social processes critical to fitness, such as attachment between mothers and their young, and suppression of the stress response after contact with trusted conspecfics. Rodent studies suggest that OT's release is contingent upon direct tactile contact with such individuals, but we hypothesized that vocalizations might be capable of producing the same effect. To test our hypothesis, we chose human mother-daughter dyads and applied a social stressor to the children, following which we randomly assigned participants into complete contact, speech-only or no-contact conditions. Children receiving a full complement of comfort including physical, vocal and non-verbal contact showed the highest levels of OTand the swiftest return to baseline of a biological marker of stress (salivary cortisol), but a strikingly similar hormonal profile emerged in children comforted solely by their mother's voice. Our results suggest that vocalizations may be as important as touch to the neuroendocrine regulation of social bonding in our species. © 2010 The Royal Society.

Ziegler T.E.,Wisconsin National Primate Research Center | Sosa M.E.,Wisconsin National Primate Research Center
Hormones and Behavior | Year: 2016

Parental experience and hormones play a large role in the common marmoset (Callithrix jacchus) father's care of their offspring. We tested the effect of exogenous estradiol or testosterone on the responsiveness of common marmosets to respond to infant distress vocalizations and whether males who haven't become fathers yet (paired males) would have increased responsiveness to infant distress calls with either steroid or whether parental experience is the most important component for the onset of paternal care. Sixteen male marmosets (8 fathers, 8 paired males) received a vehicle, low dose or high dose of estradiol and additional 16 males were tested with testosterone at three doses for their response either to a vocal control or a recording of an infant distress call for 10. min. Without steroid stimulation fathers were significantly more likely to respond to the infant distress stimulus than paired males. Low dose estradiol stimulation resulted in a significant increase in fathers' behavioral response towards the infant distress stimulus but not in paired males. Fathers also showed a significant increase in infant responsiveness from the vehicle dose to the estradiol low dose treatment, but not to the estradiol high dose treatment. Testosterone treatment did not show significant differences between infant responsiveness at either dose and between fathers and paired males. We suggest that neither steroid is involved in the onset of paternal care behaviors in the marmoset but that estradiol may be involved in facilitating paternal motivation in experienced fathers. © 2015 Published by Elsevier Inc.

Weinfurter J.T.,Wisconsin National Primate Research Center | Weinfurter J.T.,University of Wisconsin - Madison | Brunner K.,Wisconsin National Primate Research Center | Capuano III S.V.,Wisconsin National Primate Research Center | And 7 more authors.
PLoS Pathogens | Year: 2011

In mouse models of influenza, T cells can confer broad protection against multiple viral subtypes when antibodies raised against a single subtype fail to do so. However, the role of T cells in protecting humans against influenza remains unclear. Here we employ a translational nonhuman primate model to show that cross-reactive T cell responses play an important role in early clearance of infection with 2009 pandemic H1N1 influenza virus (H1N1pdm). To "prime" cellular immunity, we first infected 5 rhesus macaques with a seasonal human H1N1 isolate. These animals made detectable cellular and antibody responses against the seasonal H1N1 isolate but had no neutralizing antibodies against H1N1pdm. Four months later, we challenged the 5 "primed" animals and 7 naive controls with H1N1pdm. In naive animals, CD8+ T cells with an activated phenotype (Ki-67+ CD38+) appeared in blood and lung 5-7 days post inoculation (p.i.) with H1N1pdm and reached peak magnitude 7-10 days p.i. In contrast, activated T cells were recruited to the lung as early as 2 days p.i. in "primed" animals, and reached peak frequencies in blood and lung 4-7 days p.i. Interferon (IFN)-γ Elispot and intracellular cytokine staining assays showed that the virus-specific response peaked earlier and reached a higher magnitude in "primed" animals than in naive animals. This response involved both CD4+ and CD8+ T cells. Strikingly, "primed" animals cleared H1N1pdm infection significantly earlier from the upper and lower respiratory tract than the naive animals did, and before the appearance of H1N1pdm-specific neutralizing antibodies. Together, our results suggest that cross-reactive T cell responses can mediate early clearance of an antigenically novel influenza virus in primates. Vaccines capable of inducing such cross-reactive T cells may help protect humans against severe disease caused by newly emerging pandemic influenza viruses. © 2011 Weinfurter et al.

Seltzer L.J.,University of Wisconsin - Madison | Prososki A.R.,University of Wisconsin - Madison | Ziegler T.E.,Wisconsin National Primate Research Center | Pollak S.D.,University of Wisconsin - Madison
Evolution and Human Behavior | Year: 2012

Human speech evidently conveys an adaptive advantage, given its apparently rapid dissemination through the ancient world and global use today. As such, speech must be capable of altering human biology in a positive way, possibly through those neuroendocrine mechanisms responsible for strengthening the social bonds between individuals. Indeed, speech between trusted individuals is capable of reducing levels of salivary cortisol, often considered a biomarker of stress, and increasing levels of urinary oxytocin, a hormone involved in the formation and maintenance of positive relationships. It is not clear, however, whether it is the uniquely human grammar, syntax, content and/or choice of words that causes these physiological changes, or whether the prosodic elements of speech, which are present in the vocal cues of many other species, are responsible. In order to tease apart these elements of human communication, we examined the hormonal responses of female children who instant messaged their mothers after undergoing a stressor. We discovered that unlike children interacting with their mothers in person or over the phone, girls who instant messaged did not release oxytocin; instead, these participants showed levels of salivary cortisol as high as control subjects who did not interact with their parents at all. We conclude that the comforting sound of a familiar voice is responsible for the hormonal differences observed and, hence, that similar differences may be seen in other species using vocal cues to communicate. © 2012.

Seltzer L.J.,University of Wisconsin - Madison | Ziegler T.,Wisconsin National Primate Research Center | Connolly M.J.,University of Wisconsin - Madison | Prososki A.R.,University of Wisconsin - Madison | Pollak S.D.,University of Wisconsin - Madison
Child Development | Year: 2014

Child maltreatment often has a negative impact on the development of social behavior and health. The biobehavioral mechanisms through which these adverse outcomes emerge, however, are not clear. To better understand the ways in which early life adversity affects subsequent social behavior, changes in the neuropeptide oxytocin (OT) in children (n = 73) aged 8.1-11.5 years following a laboratory stressor were examined. Girls with histories of physical abuse have higher levels of urinary OT and lower levels of salivary cortisol following the stressor when compared to controls. Abused and control boys, however, do not differ in their hormonal responses. These data suggest that early adversity may disrupt the development of the stress regulation system in girls by middle childhood. Child Development © 2014 The Society for Research in Child Development, Inc.

Crockford C.,University of St. Andrews | Crockford C.,Max Planck Institute for Evolutionary Anthropology | Wittig R.M.,University of St. Andrews | Wittig R.M.,Max Planck Institute for Evolutionary Anthropology | And 6 more authors.
Proceedings of the Royal Society B: Biological Sciences | Year: 2013

Animals that maintain cooperative relationships show gains in longevity and offspring survival. However, little is known about the cognitive or hor-monal mechanisms involved in cooperation. Indeed, there is little support for a main hypothesis that non-human animals have the cognitive capacities required for bookkeeping of cooperative exchanges. We tested an alternative hypothesis that cooperative relationships are facilitated by an endocrino-logical mechanism involving oxytocin, a hormone required for bonding in parental and sexual relationships across mammals. We measured urinary oxytocin after single bouts of grooming in wild chimpanzees. Oxytocin levels were higher after grooming with bond partners compared with non-bond partners or after no grooming, regardless of genetic relatedness or sexual interest. We ruled out other possible confounds, such as grooming duration, grooming direction or sampling regime issues, indicating that changes in oxytocin levels were mediated by social bond strength. Oxytocin, which is thought to act directly on neural reward and social memory systems, is likely to play a key role in keeping track of social interactions with multiple individuals over time. The evolutionary linkage of an ances-tral hormonal system with complex social cognition may be the primary mechanism through which long-term cooperative relationships develop between both kin and non-kin in mammals. © 2013 The Author(s) Published by the Royal Society. All rights reserved.

Radovick S.,Johns Hopkins University | Levine J.E.,Wisconsin National Primate Research Center | Wolfe A.,Johns Hopkins University
Frontiers in Endocrinology | Year: 2012

Reproductive function is regulated by the secretion of luteinizing hormone (LH) and follicle-stimulating hormone from the pituitary and the steroid hormones from the gonads. The dynamic changes in the levels of the reproductive hormones regulate secondary sex char-acteristics, gametogenesis, cellular function, and behavior. Hypothalamic GnRH neurons, with cell bodies located in the basal hypothalamus, represent the final common path-way for neuronally derived signals to the pituitary. As such, they serve as integrators of a dizzying array of signals including sensory inputs mediating information about cir-cadian, seasonal, behavioral, pheromonal, and emotional cues. Additionally, information about peripheral physiological function may also be included in the integrative signal to the GnRH neuron. These signals may communicate information about metabolic status, disease, or infection. Gonadal steroid hormones arguably exert the most important effects on GnRH neuronal function. In both males and females, the gonadal steroid hormones exert negative feedback regulation on axis activity at both the level of the pituitary and the hypothalamus. These negative feedback loops regulate homeostasis of steroid hormone levels. In females, a cyclic reversal of estrogen feedback produces a positive feedback loop at both the hypothalamic and pituitary levels. Central positive feedback results in a dra-matic increase in GnRH secretion (Moenter et al., 1992; Xia et al., 1992; Clarke, 1993; Sisk et al., 2001).This is coupled with an increase in pituitary sensitivity to GnRH (Savoy-Moore et al., 1980;Turzillo et al., 1995), which produces the massive surge in secretion of LH that triggers ovulation. While feedback regulation of the axis in males is in part mediated by estrogen receptors (ER), there is not a clear consensus as to the relative role of ER versus AR signaling in males (Lindzey et al., 1998; Wersinger et al., 1999). Therefore, this review will focus on estrogenic signaling in the female. © 2012 Radovick, Levine and Wolfe.

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