Dose-Response Model for Listeria monocytogenes -Induced Stillbirths in Nonhuman Primates

Abstract

A dose-response model using rhesus monkeys as a surrogate for pregnant women indicates that oral exposure to 10 7 CFU of Listeria monocytogenes results in about 50% stillbirths. Ten of 33 pregnant rhesus monkeys exposed orally to a single dose of 10 2 to 10 10 CFU of L. monocytogenes had stillbirths. A log-logistic model predicts a dose affecting 50% of animals at 10 7 CFU, comparable to an estimated 10 6 CFU based on an outbreak among pregnant women but much less than the extrapolated estimate (10 13 CFU) from the FDA-U.S. Department of Agriculture-CDC risk assessment using an exponential curve based on mouse data. Exposure and etiology of the disease are the same in humans and primates but not in mice. This information will aid in risk assessment, assist policy makers, and provide a model for mechanistic studies of L. monocytogenes-induced stillbirths.

Identification of Conserved and Species-Specific Functions of the Listeria monocytogenes PrsA2 Secretion Chaperone

“…In the United States, L. monocytogenes is a significant health threat, as it has been associated with numerous multistate foodborne outbreaks resulting in thousands of illnesses and hundreds of deaths (6,7). L. monocytogenes infections pose serious risks to immunocompromised populations, the elderly, pregnant women, and neonates, where fatality rates range from 20 to 50% (8)(9)(10)(11). As L. monocytogenes transitions between life in the environment to life within the cytosol of infected mammalian host cells, the bacterium requires increased expression of a number of secreted virulence factors that facilitate intracellular survival by promoting cell entry, bacterial escape from host vacuoles, replication within the cytosol, and spread to adjacent cells (12)(13)(14)(15)(16)(17).…”

Variation in Listeria monocytogenes Dose Responses in Relation to Subtypes Encoding a Full-Length or Truncated Internalin A

“…In parallel efforts, several studies have developed dose-response relationships using animals that express an isoform of E-cadherin that binds InlA, including rhesus monkeys (32,33) and guinea pigs (1,39,47). A log-logistic dose-response model fitted to data obtained from animal experiments with a clinical L. monocytogenes strain isolated from a rhesus monkey listeriosis outbreak resulted in an LD 50 (i.e., 50% lethal dose for stillbirth) of 8.45 ϫ 10 7 cells for pregnant monkeys (32) and 2.0 ϫ 10 7 cells for pregnant guinea pigs (47).…”

Dose Response of Listeria monocytogenes Invasion, Fetal Morbidity, and Fetal Mortality after Oral Challenge in Pregnant and Nonpregnant Mongolian Gerbils

“…While the numbers of positive samples for the intestine, liver, and spleen all showed a trend toward dose-dependent increases, only the liver showed a (25) significant difference between animals treated with 10 9 CFU and the other groups (see Table S2 in the supplemental material).…”

“…The FAO-WHO risk assessment for listeriosis during pregnancy estimates a 50% lethal dose (LD 50 ) of 1.9 ϫ 10 6 CFU for human fetuses (27). Previous studies using guinea pigs and nonhuman primates with fetal death as an endpoint have yielded LD 50 s of 2.00 ϫ 10 7 CFU and 8.45 ϫ 10 7 CFU, respectively (18,25). The 95% confidence intervals of these three dose-response curves overlap, but the inability of L. monocytogenes to interact with the guinea pig Met receptor during invasion has led some to believe that guinea pig susceptibility to the pathogen may not be equivalent mechanistically to that of humans (17).…”

“…Cells were prepared as previously described by Williams et al (18), with some minor modifications. L. monocytogenes strain 12443 (serotype 1/2a), an isolate known to cause stillbirths in primates (25) and guinea pigs (26), was grown at 37°C for 24 h in 10 ml tryptic soy broth (TSB) (Becton, Dickinson and Company [BD], Sparks, MD) and activated by two subcultures at 24-h intervals. Cells were harvested by centrifugation (3,600 ϫ g at 15°C for 10 min) and washed three times in 10 ml phosphate-buffered saline (PBS) (BD).…”