Abstract
Bacterial infections of the central nervous system (CNS) remain a major cause of mortality in the neonatal population. Commonly used parenteral infection models, however, do not reflect the early course of the disease leaving this critical step of the pathogenesis largely unexplored. Here, we analyzed nasal exposure of 1-day-old newborn mice to Listeria monocytogenes (Lm). We found that nasal, but not intragastric administration, led to early CNS infection in neonate mice. In particular, upon bacterial invasion of the olfactory epithelium, Lm subsequently spread along the sensory neurons entering the brain tissue at the cribriform plate and causing a significant influx of monocytes and neutrophils. CNS infection required listeriolysin for penetration of the olfactory epithelium and ActA, a mediator of intracellular mobility, for translocation into the brain tissue. Taken together, we propose an alternative port of entry and route of infection for neonatal neurolisteriosis and present a novel infection model to mimic the clinical features of late-onset disease in human neonates.
Highlights
Bacterial infections of the central nervous system (CNS) remain a major cause of mortality in the neonatal population
We here evaluated the situation of the human neonate during parturition exposed to the maternal vaginal and enteric microbiota and at risk to acquire Listeria monocytogenes (Lm)-mediated LOD
Bacterial CNS infections are associated with high mortality and significant long-term sequelae and remain a major health problem worldwide
Summary
Bacterial infections of the central nervous system (CNS) remain a major cause of mortality in the neonatal population. LOD develops several days after birth and is thought to be transmitted during parturition through contact with the maternal vaginal or intestinal microbiota It usually manifests as meningitis or meningoencephalitis with high cell counts in the cerebrospinal fluid[3,7,8]. Employing a novel nasal Lm infection model in neonate mice, we demonstrate (i) colonization of the neonatal nasopharyngeal mucosa independent of the bacterial adhesions InlA and InlB, (ii) bacterial invasion of the olfactory epithelium and disruption of epithelial integrity dependent on the bacterial virulence factor listeriolysin (LLO), (iii) bacterial association with nerve cell structures, ascending infection and penetration of the cribriform plate in a Lm ActA dependent manner, and (iv) initial infection of the frontal brain segments with significant cytokine induction and immune cell recruitment and subsequent bacterial spread to other brain segments in the course of the infection. The occurrence of CNS infections in the absence of bacteremia in the majority of LOD cases suggests that a similar route of infection may apply to the infection in human neonates
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