Dataset Information

Intratracheal Inoculation with Brucella melitensis in the Pregnant Guinea Pig Is an Improved Model for Reproductive Pathogenesis and Vaccine Studies.

ABSTRACT: Reproductive failure is the hallmark of brucellosis in animals. An uncommon but important complication in pregnant women who become acutely infected with Brucella melitensis is spontaneous pregnancy loss or vertical transmission to the fetus. Unfortunately, the mechanism behind reproductive failure is still obscure, partially due to the lack of a proper study model. Recently, it was demonstrated that intratracheal (IT) inoculation of nonpregnant guinea pigs would replicate features of clinical disease in humans. To determine if IT inoculation would induce reproductive disease, guinea pigs were infected at mid-gestation and monitored daily for fever and abortions. Fever developed between day 14 to 18 postinoculation, and by 3 weeks postinoculation, 75% of pregnant guinea pigs experienced stillbirths or spontaneous abortions mimicking natural disease. Next, to investigate the guinea pig as a model for evaluating vaccine efficacy during pregnancy, nonpregnant guinea pigs were vaccinated with S19, 16MΔvjbR + Quil-A, or 100 μl PBS + Quil-A (as control). Guinea pigs were bred and vaccinated guinea pigs were challenged at mid-gestation with B. melitensis IT inoculation and monitored for fever and abortions. Vaccination with both vaccines prevented fever and protected against abortion. Together, this study indicates that pregnant guinea pigs are an appropriate animal model to study reproductive disease and offer an improved model to evaluate the ability of vaccine candidates to protect against a serious manifestation of disease.

SUBMITTER: Hensel ME

PROVIDER: S-EPMC7504952 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Intratracheal Inoculation with Brucella melitensis in the Pregnant Guinea Pig Is an Improved Model for Reproductive Pathogenesis and Vaccine Studies.

Hensel Martha E ME Chaki Sankar P SP Stranahan Lauren L Gregory Anthony E AE van Schaik Erin J EJ Garcia-Gonzalez Daniel G DG Khalaf Omar O Samuel James E JE Arenas-Gamboa Angela M AM

Infection and immunity 20200918 10

Reproductive failure is the hallmark of brucellosis in animals. An uncommon but important complication in pregnant women who become acutely infected with <i>Brucella melitensis</i> is spontaneous pregnancy loss or vertical transmission to the fetus. Unfortunately, the mechanism behind reproductive failure is still obscure, partially due to the lack of a proper study model. Recently, it was demonstrated that intratracheal (IT) inoculation of nonpregnant guinea pigs would replicate features of cli ...[more]

PMID: 32690632

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Project description:Brucella species are considered a significant cause of reproductive pathology in male and female animals. Importantly, Brucella melitensis can induce reproductive disease in humans. Reproductive pathogenesis and evaluation of newly developed countermeasures against brucellosis studies have traditionally utilized female animal models. However, any potential, new intervention for use in humans would need to be evaluated in both sexes. Therefore, animal models for male reproductive brucellosis are desperately needed to understand disease progression. Accordingly, we evaluated guinea pigs and mice using B. melitensis 16 M in an intratracheal model of inoculation at different stages of infection (peracute, acute, and chronic) with an emphasis on determining the effect to the male reproductive organs. Aerosol inoculation resulted in colonization of the reproductive organs (testicle, epididymis, prostate) in both species. Infection peaked during the peracute (1-week post-infection [p.i.]) and acute (2-weeks p.i.) stages of infection in the mouse in spleen, epididymis, prostate, and testicle, but colonization was poorly associated with inflammation. In the guinea pig, peak infection was during the acute stage (4-weeks p.i.) and resulted in inflammation that disrupted spermatogenesis chronically. To determine if vaccine efficacy could be evaluated using these models, males were vaccinated using subcutaneous injection with vaccine candidate 16 MΔvjbR at 109 CFU/100 μl followed by intratracheal challenge with 16 M at 107. Interestingly, vaccination efficacy varied between species and reproductive organs demonstrating the value of evaluating vaccine candidates in multiple models and sexes. Vaccination resulted in a significant reduction in colonization in the mouse, but this could not be correlated with a decrease in inflammation. Due to the ability to evaluate for both colonization and inflammation, guinea pigs seemed the better model not only for assessing host-pathogen interactions but also for future vaccine development efforts.

Project description:Newborns exposed to prenatal opioids often experience intense postnatal withdrawal after cessation of the opioid, called neonatal opioid withdrawal syndrome (NOWS), with limited pre- and postnatal therapeutic options available. In a prior study in pregnant mice we demonstrated that the peripherally selective opioid antagonist, 6β-naltrexol (6BN), is a promising drug candidate for preventive prenatal treatment of NOWS, and a therapeutic mechanism was proposed based on preferential delivery of 6BN to fetal brain with relative exclusion from maternal brain. Here, we have developed methadone (MTD) treated pregnant guinea pigs as a physiologically more suitable model, enabling detection of robust spontaneous neonatal withdrawal. Prenatal MTD significantly aggravates two classic maternal separation stress behaviors in newborn guinea pigs: calling (vocalizing) and searching (locomotion) - natural attachment behaviors thought to be controlled by the endogenous opioid system. In addition, prenatal MTD significantly increases the levels of plasma cortisol in newborns, showing that cessation of MTD at birth engages the hypothalamic-pituitary-adrenal (HPA) axis. We find that co-administration of 6BN with MTD prevents these withdrawal symptoms in newborn pups with extreme potency (ID50 ∼0.02 mg/kg), at doses unlikely to induce maternal or fetal withdrawal or to interfere with opioid antinociception based on many prior studies in rodents and non-human primates. Furthermore, we demonstrate a similarly high potency of 6BN in preventing opioid withdrawal in adult guinea pigs (ID50 = 0.01 mg/kg). This high potency appears to run counter to our pharmacokinetic studies showing slow 6BN transit of both the placenta and maternal blood brain barrier in guinea pigs, and calls into question the preferential delivery mechanism. Rather, it suggests a novel receptor mechanism to account for the selectively high potency of 6BN to suppress opioid dependence at all developmental stages, even in adults, as compared to its well-established low potency as a classical opioid antagonist. In conclusion, 6BN is an attractive compound for development of a preventive therapy for NOWS.

Dataset Information

Intratracheal Inoculation with Brucella melitensis in the Pregnant Guinea Pig Is an Improved Model for Reproductive Pathogenesis and Vaccine Studies.

Publications

Intratracheal Inoculation with Brucella melitensis in the Pregnant Guinea Pig Is an Improved Model for Reproductive Pathogenesis and Vaccine Studies.

Similar Datasets

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