Nonhuman Primate Model for Listeria monocytogenes -Induced Stillbirths

Abstract

Listeria monocytogenes, isolated from outbreaks in either human or nonhuman primate populations, was administered orally at doses ranging from 10 6 to 10 10 CFU. Four of 10 treated animals delivered stillborn infants. L. monocytogenes was isolated from fetal tissue, and the pathology was consistent with L. monocytogenes infection as the cause of pregnancy loss. For all pregnancies resulting in stillbirths, L. monocytogenes was isolated from maternal feces, indicating that L. monocytogenes had survived and had probably colonized the gastrointestinal tract. Antibodies and antigen-specific lymphocyte proliferation against Listeria increased in animals that had stillbirths.Listeriosis resulting from exposure to food containing the bacterium L. monocytogenes causes serious disease, with case fatality rates between 20 and 40% (33). Listeriosis is especially serious in susceptible populations such as immunocompromised persons and pregnant women (11,14,16,20,24,26,29,32,35). For healthy nonpregnant adults, listeriosis has a relatively low incidence, presumably due to its low infectivity in immunocompetent individuals.Pregnancy-related listeriosis primarily affects the fetus or neonate. The maternal reaction to the presence of Listeria infection is generally an influenza-like episode with fever, backache, and perhaps diarrhea (7,11,13,24,29). The effect of fetal Listeria infection is dependent on the point in gestation time when infection occurs. First-trimester infection leads to spontaneous abortion, whereas second-and third-trimester infections lead to preterm birth followed by neonatal illness or fetal death with preterm delivery of a stillborn (7,11,13).The rhesus monkey (Macaca mulatta), with a reproductive cycle and placenta comparable to those of humans (31), is widely used as an experimental model for human reproduction and development. As with humans, exposure to L. monocytogenes in pregnant nonhuman primates may result in abortions, stillbirths, or neonatal deaths (4, 27; J. Paul-Murphy, J. E. Markovits, I. Wesley, and J. A. Roberts, Lab. Anim. Sci. 40:547 [abstr.], 1990). For humans and nonhuman primates, the pathogenesis and morphological findings associated with stillbirths due to L. monocytogenes are essentially the same (1,4,28,37).Despite several epidemiological studies confirming the relationship between L. monocytogenes and specific foods (soft cheeses, undercooked chicken, paté, etc.) (2, 30), an infectious dose has not been established for healthy or susceptible human populations due to the delay between exposure and the onset of symptoms. The severe ramifications of the disease in highrisk human populations such as pregnant women precludes the use of humans in volunteer feeding studies. Recently, a draft risk assessment of L. monocytogenes in ready-to-eat foods (36) reviewed human epidemiological and animal study data. The risk assessment concluded that mouse studies provide the only acceptable data for developing dose-response information at this time and acknowledged the difficulty with the use of...

Pathogenicity and Immunogenicity of a Vaccine Strain ofListeria monocytogenesThat Relies on a Suicide Plasmid To Supply an Essential Gene Product

“…immunization because we required a more precise delivery of bacteria than could be obtained orally, in order to compare the efficacies of L. monocytogenes dal dat and L. monocytogenes dal dat/pRRR. In the setting of natural infection, however, L. monocytogenes is an agent causing food-borne disease and is thought to spread to various tissues and the placenta from the gastrointestinal tract by hematogenous dissemination (3,51). Bypassing the gastrointestinal tract could lead to differences in dissemination.…”

“…Clinical syndromes include sepsis, central nervous system infections, endocarditis, gastroenteritis, and localized infections. Vertical transmission to the fetus often causes miscarriage or stillbirth in pregnant women (14,21,51). Since experimental infection is not a clinically ethical option, controlled trials have not allowed a drug of choice or duration of therapy to be established (40).…”

Live attenuated Listeria monocytogenes expressing HIV Gag: Immunogenicity in rhesus monkeys

“…Similar tests were performed for mucosal anti-IgG and IgA, except the secondary antibody to test for IgA was replaced with alkaline phosphatase-conjugated anti-monkey IgA (Rockland Immunochemicals Inc., Gilbertsville, PA). To test for anti-Lm antibodies, an ELISA using either whole bacteria (Lm strain 12443) [42] or recombinant listeriolysin-O (LLO) as antigen was employed; Immulon 2 microtiter plates were coated with LLO at 0.1 μg/well. E. coliproduced recombinant 6X his-tagged LLO was purified from culture medium using a Ni-NTA column (Qiagen, Inc., Valencia, CA) and tested for hemolytic activity as described [43].…”

CXCR3 blockade protects against Listeria monocytogenes infection–induced fetal wastage

“…For example, in 178 cases of prenatal L. monocytogenes infection, 20% of pregnancies terminated in abortion or stillbirth, and 68% of live offspring were infected (9). This predisposition for fetal wastage and disseminated L. monocytogenes infection during pregnancy is not limited to only humans but widely reiterated across mammalian species, including nonhuman primates (10), ruminants (11,12), and rodents (13)(14)(15). Interestingly, our recent studies using mice bearing allogeneic pregnancies designed to recapitulate the natural heterogeneity between maternal MHC haplotype antigens and fetal MHC haplotype antigens indicate that prenatal L. monocytogenes infection-induced fetal resorption may not require direct in utero bacterial invasion (16).…”