Neurotropic Lineage III Strains of Listeria monocytogenes Disseminate to the Brain without Reaching High Titer in the Blood

Abstract

Listeria monocytogenes is thought to colonize the brain using one of three mechanisms: direct invasion of the blood-brain barrier, transportation across the barrier by infected monocytes, and axonal migration to the brain stem. The first two pathways seem to occur following unrestricted bacterial growth in the blood and thus have been linked to immunocompromise. In contrast, cell-to-cell spread within nerves is thought to be mediated by a particular subset of neurotropic L. monocytogenes strains. In this study, we used a mouse model of foodborne transmission to evaluate the neurotropism of several L. monocytogenes isolates. Two strains preferentially colonized the brain stems of BALB/cByJ mice 5 days postinfection and were not detectable in blood at that time point. In contrast, infection with other strains resulted in robust systemic infection of the viscera but no dissemination to the brain. Both neurotropic strains (L2010-2198, a human rhombencephalitis isolate, and UKVDL9, a sheep brain isolate) typed as phylogenetic lineage III, the least characterized group of L. monocytogenes. Neither of these strains encodes InlF, an internalin-like protein that was recently shown to promote invasion of the blood-brain barrier. Acute neurologic deficits were observed in mice infected with the neurotropic strains, and milder symptoms persisted for up to 16 days in some animals. These results demonstrate that neurotropic L. monocytogenes strains are not restricted to any one particular lineage and suggest that the foodborne mouse model of listeriosis can be used to investigate the pathogenic mechanisms that allow L. monocytogenes to invade the brain stem. IMPORTANCE Progress in understanding the two naturally occurring central nervous system (CNS) manifestations of listeriosis (meningitis/meningoencephalitis and rhombencephalitis) has been limited by the lack of small animal models that can readily distinguish between these distinct infections. We report here that certain neurotropic strains of Listeria monocytogenes can spread to the brains of young otherwise healthy mice and cause neurological deficits without causing a fatal bacteremia. The novel strains described here fall within phylogenetic lineage III, a small collection of L. monocytogenes isolates that have not been well characterized to date. The animal model reported here mimics many features of human rhombencephalitis and will be useful for studying the mechanisms that allow L. monocytogenes to disseminate to the brain stem following natural foodborne transmission.

Listeria monocytogenes at the interface between ruminants and humans: A comparative pathology and pathogenesis review

“…Moreover, it remains unclear whether they are environmental reservoirs without the presence of shedding animals. 148,176,258 Fecal shedding from wild animals and bacterial persistence in invertebrates and protozoal carriers, as previously discussed, may promote bacterial introduction into the agricultural environment, 189,273,282,291 but a direct link between strains isolated from the pristine natural environment, farm environment, and ruminant host remains to be shown.…”

“…Very little is known about the pathogenesis of rhombencephalitis, partially due to the lack of adequate experimental animal models, although several rhombencephalitis models have been proposed over the years. 5,8,7,23,154,273 Nevertheless, pathological specimens provide strong evidence that the infection route differs from septicemic listeriosis and meningitis/ meningoencephalitis. Some authors have suggested a hematogenous origin for the infection, given the distribution of the inflammatory infiltrate and the association of early microglial foci with bacteria in the vicinity of parenchymal microvasculature.…”

Genome Sequences of Neurotropic Lineage III Listeria monocytogenes Isolates UKVDL9 and 2010L-2198

“…This suggests that some L. monocytogenes strains have virulence factors that promote brainstem infections. We recently reported two L. monocytogenes strains that caused brainstem infections in a mouse model of foodborne listeriosis; both were classified as lineage III by the Institut Pasteur multilocus sequence typing (MLST) database (2). Strain UKVDL9 (sequence type 1140 [ST1140] by MLST analysis), provided by the University of Kentucky Veterinary Diagnostic Laboratory, was isolated from the brain of a sheep with "circling disease."…”

inlF Enhances Listeria monocytogenes Early-Stage Infection by Inhibiting the Inflammatory Response

“…and Senay et al. verified that it did not play a role in the adhesion and invasion of non-phagocytic cells, and was not essential for infecting mice ( Dramsi et al., 1997 ; Senay et al., 2020 ). Kirchner and colleagues investigated the impact of the ROCK pathway on Lm serovar 1/2a 10403S infection of mammalian cells and found that inhibition of ROCK activity contributed to InlF-mediated invasion and virulence ( Kirchner and Higgins, 2008 ).…”

“…Senay et al. constructed an inlF -deficient 4b strain to assess its role in the infection of multiple cell types and found, that inlF was not required for hyper-invasiveness ( Senay et al., 2020 ). By contrast, our infection experiments in mice have demonstrated a role of inlF in the virulence and pathogenesis of a serovar 4b strain.…”