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. 2009 May 20;20(2):378–390. doi: 10.1111/j.1750-3639.2009.00292.x

Neuropathogenesis of Naturally Occurring Encephalitis Caused by Listeria monocytogenes in Ruminants

Anna Oevermann 1,✉, Stefano Di Palma 2, Marcus G Doherr 1, Carlos Abril 3, Andreas Zurbriggen 1, Marc Vandevelde 4
PMCID: PMC8094665  PMID: 19476464

Abstract

Listeriosis is a serious food‐borne disease with increasing frequency in humans and ruminants. Despite the facts that in both hosts, listeriosis can occur as rhombencephalitis and ruminants are a reservoir of Listeria monocytogenes (LM) strains pathogenic for humans, little work has been done on the pathogenesis in ruminants. This study investigates the neuropathogenesis of listeric encephalitis in over 200 natural cases in cattle, sheep and goats by analyzing anatomical distribution, severity, bacterial load and temporal evolution of the lesions. Our results suggest that LM gains access to the brainstem of all three species via axonal migration not only along the trigeminal nerve, but also along other nerves. The ensuing encephalitis does not remain restricted to the brainstem. Rather, LM spreads further from the brainstem into rostral brain regions likely by intracerebral axonal migration. Significant differences in severity of the lesions and bacterial load were found between cattle and small ruminants, which may be caused by species‐specific properties of antibacterial immune responses. As histopathological lesions of human rhombencephalitis caused by LM strongly resemble those of ruminants, the disease likely has a similar pathogenesis in both hosts.

Keywords: Listeria monocytogenes, Encephalitis, Ruminants, Pathogenesis, Axonal spread, Intracerebral spread

INTRODUCTION

Listeria spp. are Gram‐positive, facultatively intracellular bacteria that are ubiquitously distributed in the environment and grow over a wide range of pHs and temperatures (68). Of the six currently known Listeria species, only two are considered potentially pathogenic: Listeria monocytogenes (LM) and Listeria ivanovii (68). The major pathogen is LM causing fatal disease in numerous animal species, but most frequently affecting domestic ruminants and men 21, 40. LM has been linked to sporadic episodes, as well as large outbreaks of human illness worldwide with increasing frequency in various European countries, and the awareness of its impact on public health is growing 15, 16, 27, 28. It is responsible for the highest hospitalization and mortality rates among known food‐borne pathogens (42), and is nowadays the third to fourth most common etiology of human bacterial meningitis in the Western hemisphere 23, 64, 65, 68. The central nervous system (CNS) form generally develops as a diffuse meningitis or meningoencephalitis, and in up to 24% of patients as rhombencephalitis, but the latter is probably under‐recognized 2, 4, 6. In contrast, the classical presentation of CNS disease in ruminants is rhombencephalitis with a similar phenotype of that in humans, while diffuse meningitis or meningoencephalitis has been very rarely reported (12). Prevalence estimates of listeric encephalitis in ruminants, based on neuropathological survey studies in Europe, range between 7.5 and 29.4%, and in Switzerland it is the most important CNS disease of small ruminants 30, 32, 41, 43, 49. Ruminants, particularly cattle, may be a possible link between environment and human disease representing a reservoir for LM strains causing epidemic and sporadic infections in humans 9, 11, 24, 45, 48, 50, 59, 70, 71. Transmission may occur indirectly through food products from infected animals or healthy carriers, as well as raw vegetables that are contaminated by LM‐containing manure 48, 53, 60.

Despite significant economical losses in livestock industry caused by listeriosis and the growing impact of this zoonosis in ruminants and humans 15, 28, 49, surprisingly few studies have been done on the pathology and pathogenesis of the encephalitic disease in its natural hosts. This is in contrast to the large number of studies on listeric encephalitis in mice and rats, which are not naturally susceptible to LM infection 1, 7, 17, 19, 33, 36, 38, 44, 56, 61, 62, 63, 69. Views on how the agent invades the brain of ruminants are in part controversial 5, 12, 14, 51, 54. Two studies originating from the 1970s and early 1980s on natural listeriosis in a small number of sheep described LM within axons of the trigeminal nerve and brainstem 12, 51, and concluded from these results that LM might reach the brain by intra‐axonal migration within the trigeminal nerve. Apart from an accurate description of the changes in the brainstem in these papers, no specific studies were done on the pathogenesis of the brain lesions. The aim of the present study was to gain more insight into the pathogenesis of listeric encephalitis in its natural hosts, and to identify interspecies differences by systematic neuropathological analysis of more than 200 brains of spontaneous cases in cattle, sheep and goats.

MATERIALS AND METHODS

Animals

Two hundred and twenty ruminants (59 goats, 89 sheep and 72 cattle) with natural listeric encephalitis were collected between 1996 and 2008 at the Vetsuisse Faculties of the Universities of Bern and Zürich, Switzerland. The animals originated from active Transmissible Spongiform Encephalopathies surveillance in Switzerland and from the archives of neuropathological diagnostic services. The animals had died spontaneously or had been killed because of neurological disease.

Brain tissues

Inclusion criteria were the presence of a brainstem encephalitis combined with demonstration of LM by bacterial culture and/or immunohistochemistry in brain tissue. The brains were fixed in 4% buffered neutral formaldehyde, and representative tissue blocks were embedded in paraffin. Tissue sections were cut at 5 µm for histopathologic and immunohistochemical examination. Sections for histopathologic examination were stained with hematoxylin and eosin (H&E). Immunohistochemistry was performed with a polyclonal rabbit antibody against listeriolysin O (1:200; Difco Laboratories, Detroit, MI, USA) on brainstem sections of all animals. Polyclonal rabbit antibodies against CD3 (1:600; DAKO, Glostrup, Denmark), CD20 (1:100; NeoMarkers, Fremont, CA, USA) and lysozyme (1:200; DAKO) were applied on brainstem sections of 60 animals. The anti‐CD20 antibody was used without pretreatment, whereas the other antibodies (CD3, listeriolysin O and lysozyme) required antigen retrieval by enzymatic digestion with trypsin 0.5%/chymotrypsin 0.5% at 37°C for 10 minutes. The sections were incubated with the primary antibodies either overnight at 4°C (CD3) or for 1 h (CD20, listeriolysin O) and 2 h (lysozyme) at room temperature. A labeled streptavidin–biotin complex method (LSAB™, DAKO) with AEC as chromogen was used as detection system. For bacterial culture, fresh brain tissue samples were sampled and placed on polymyxin acriflavine lithium chloride ceftazidime aesculin mannitol agar (Oxoid, Basel, Switzerland) at 37°C for 24 h. Bacterial colonies with morphological characteristics similar to Listeria spp. were isolated, and bacterial phenotypic identification was performed with the VITEK® 2 compact system (bioMérieux, Geneva, Switzerland).

Neuropathological examination

With few exceptions, examined cross sections from each case included the following regions: medulla oblongata, pontine area, cerebellum, midbrain, thalamus, hippocampus, basal nuclei and cerebral cortex. In some cases, sections of the upper cervical spinal cord were also available.

The following lesions were recorded: microabscesses, perivascular cuffing, neuronal necrosis, axonal degeneration, vasculitis, hemorrhages, necrosis, increased cellularity, multinucleated giant cells, ependymitis and meningitis.

Quantitative assessment

For each anatomical region, a semiquantitative assessment of the extent and size of microabscesses was performed: 0 = none; 1 = single small microabscesses; 2 = few small to large microabscesses; 3 = moderate number of microabscesses, possibly coalescing; 4 = high number of coalescing microabscesses involving a large area of parenchyma. Perivascular cuffs were graded as follows: 0 = none, 1 = single layer of perivascular inflammatory cells, 2 = two layers, 3 = three to four layers, 4 = more than four layers of inflammatory cells. The bacterial load was estimated on a scale from 0 to 4: 0 = no bacteria, 1 = single to few bacteria, 2 = moderate number of bacteria, 3 = high number of bacteria with occasional presence of colonies, 4 = myriad of densely packed bacteria with occasional presence of colonies. Numbers of CD3+, CD20+ and lysozyme+ cells were counted in 20 fields in the brainstem of 0.06 mm2 each and the sum of cells over the 20 fields further analyzed.

Cranial nerve involvement

Lesions affecting the cranial nerve nuclei and/or their intraparenchymal roots were recorded in each case. The available sections did not always cover all cranial nerve nuclei. Therefore, the frequency of involvement of the different cranial nerves in the whole population has to be interpreted with caution.

Statistical analysis

The median age of affected animals with 95% confidence intervals was derived. Age and histological scores were compared between groups (species, lesion age, etc.) using parametric and nonparametric t‐tests (two‐sample t‐test, Wilcoxon test), and analysis of variance (ANOVA, Kruskal–Wallis ANOVA, both followed by the appropriate post hoc routines with correction for multiple comparisons), whenever appropriate. Score differences between brain regions were assessed using one‐sample t‐tests with the null hypothesis of zero (no difference in scores).

Frequencies of categorical variables were compared using cross tabulation, chi‐square and, in the case of 2 × 2 tables, Fisher's exact test statistics. All analyses were performed in the software package NCSS 2007 (http://www.ncss.com). The overall level of statistical significance was set to P < 0.05.

RESULTS

Age, sex and clinical signs of animals

The median age by species was 2.5 (95% confidence interval 2.0–3.5) years for goats, 4 (3.0–4.5) years for cattle and 4 (2.5–5.0) years for sheep. Observed differences were not statistically significant (Kruskal–Wallis ANOVA, P = 0.32). Eighty‐five percent of animals were female. Reported neurological signs included ataxia, tetraparesis, opisthotonus, tremor, compulsive movements, hyperexcitability, convulsions, stupor, vestibular signs and unilateral or bilateral cranial nerve palsies. Duration of clinical signs ranged between 1 and 10 days.

Neuropathological lesions

Microabscesses were a cardinal feature in all cases, and presented as variously sized compact aggregates of neutrophils mixed with varying amounts of macrophages. Such focal suppuration often assumed a linear configuration along fiber tracts (in 45.8, 75.3 and 66.7% of goats, sheep and cattle, respectively). The earliest lesions were composed of accumulations of neutrophils occasionally associated with concomitant aggregations of varying numbers of rod cell‐shaped microglia cells. Two types of microabscesses were distinguished, allowing to assess temporal progression of the encephalitis. In type 1, neutrophils were the most prevalent cell population (Figure 1A) representing the acute stage of a microabscess, whereas in type 2 macrophages prevailed over neutrophils reflecting a temporally more advanced stage of the lesion (Figure 1B). In the latter, occasionally multinucleated giant cells were present (Figure 1C). For descriptive purposes, cases exhibiting only type 1 microabscesses were staged as acute encephalitis, and cases with only type 2 microabscesses as chronic encephalitis. Animals, which had both types of microabscesses, were grouped together in the category of subacute encephalitis.

Figure 1.

Figure 1

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A. Neutrophilic microabscess in acute listeric encephalitis of a sheep. Neuronal necrosis and neuronophagia by neutrophils (arrowheads) in the hypoglossal nucleus. One intactly appearing neuron contains bacteria‐like structures (arrow). Hematoxylin and eosin (H&E), bar = 31 µm. B. Microabscess in a goat with predominantly macrophages and few neutrophils. H&E, bar = 25 µm. C. Small microabscess in chronic listeric encephalitis of a bovine containing macrophages and multinucleated giant cells. The surrounding neuropil shows increased cellularity and few degenerate axons. H&E, bar = 31 µm. D. Listeric encephalitis in a bovine. Neutrophilic microabscess (M) with adjacent necrosis (axonal spheroids are indicated by arrows). Although microabscesses are acute, distinct mononuclear perivascular cuffs are already present (arrowheads). H&E, bar = 100 µm. E. Third ventricle in a goat with subependymal neutrophilic microabscesses. The overlying ependyma is eroded. H&E, bar = 31 µm. F. Chronic listeric encephalitis in a sheep. Large perivascular cuff, composed of mainly lymphocytes, fewer histiocytes and plasma cells. The surrounding parenchyma contains increased numbers of cells including rod cell‐shaped microglia cells. H&E, bar = 60 µm.

Further histopathological changes included focal areas of necrosis (Figure 1D), which were usually continuous with or near microabscesses and contained swollen axons, necrotic neurons as well as accumulations of macrophages. Neuronal necrosis was characterized by increased eosinophilia and nuclear pyknosis, fading and rrhexis (Figure 1A). Its occurrence was predominantly associated with acute encephalitis (81.8%). Significantly lower frequencies were observed in cases of subacute (46.4%) and chronic (11.1%) encephalitis (chi‐square test, P < 0.0001). In more advanced stages, neuronophagia by neutrophils and macrophages was observed (Figure 1A). Occasionally, vasculitis affecting small veins was observed. Vascular changes consisted of increased eosinophilia and hyalinization of their wall with presence of nuclear fragments (fibrinoid vessel wall necrosis), endothelial cell necrosis and hypertrophy and perivascular microhemorrhages and proteinaceaous exudate. Their occurrence was associated with acute lesions and large areas of necrosis. Seven animals (three goats, one sheep, three cattle) had significant ependymitis with subependymal microabscesses affecting the entire ventricular system (Figure 1E).

Perivascular cuffs with predominantly lymphocytes, macrophages and fewer plasma cells and neutrophils were mostly observed in areas with microabscesses (Figure 1D,F). Notably, distinct perivascular cuffs with mononuclear cells were not only present in animals with chronic and subacute encephalitis, but also in cases of acute encephalitis (Figure 1D). However, the size of perivascular cuffs was greatest in chronic encephalitis, followed by subacute encephalitis and less in acute encephalitis. All differences were significant (Kruskal–Wallis ANOVA, P < 0.0001). In line with the histopathological findings, high numbers of CD3+ and CD20+ lymphocytes were already present in acute encephalitis, predominantly located in perivascular cuffs (Figure 2A–C). The number of CD20+ lymphocytes increased significantly with chronicity (Kruskal–Wallis ANOVA, P = 0.03), whereas no significant differences in number of CD3+ lymphocytes (P = 0.39) and lysozyme‐positive macrophages (P = 0.3) were observed between acute, subacute and chronic encephalitis (Figure 2A,C,D). Diffuse increased cellularity of varying extent and intensity was a consistent finding in areas of inflammation and became more prominent in areas with chronicity (Kruskal–Wallis ANOVA, P < 0.004, Figure 1F). Meningitis with mainly lymphocytes, macrophages, varying numbers of neutrophils and few plasma cells was found in all animals and extended in most cases into the cortex.

Figure 2.

Figure 2

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A. Numbers of CD3+, CD20+ and lysozyme+ cells in acute, subacute and chronic encephalitis. Cells were counted in 20 fields of 0.06 mm2 each. Bars indicate the upper and lower 95% confidence limits around the median. Asterisks indicate significant differences in cell counts. B. Acute listeric encephalitis in a sheep. Perivascular cuff with numerous CD3+ lymphocytes. Polyclonal rabbit anti‐CD3 antibody, AEC, bar = 50 µm. C. Acute listeric encephalitis in a sheep. Perivascular cuff with numerous CD20+ lymphocytes. Polyclonal rabbit anti‐CD20 antibody, AEC, bar = 50 µm. D. Acute listeric encephalitis in a sheep. Perivascular cuff with moderate numbers of lysozyme+ macrophages. Polyclonal rabbit anti‐lysozyme antibody, AEC, bar = 50 µm.

Caudo‐rostral gradient of neutrophilic microabscesses

Most animals exhibited a subacute encephalitis with both types of microabscesses (Figure 3A). The relative proportion of microabscesses with neutrophilic preponderance (type 1) to microabscesses with mainly macrophages (type 2) clearly increased from the medulla toward the frontal brain areas in 56.5% of these cases. The increase is reflected in the overall caudo‐rostral gradient of neutrophilic microabscesses (Figure 3B). Concomitant reactive changes such as necrosis and increased cellularity were also gradually less advanced in rostral direction. These findings indicated a caudo‐rostral progression of the encephalitis. In the remaining 43.5% of animals with subacute encephalitis, both types of microabscesses occurred together within the same brain areas. Consistent with these observations, microabscesses with predominantly macrophages were never observed to occur rostrally when the brainstem contained only neutrophilic microabscesses.

Figure 3.

Figure 3

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A. Staging of lesions. In all three ruminant species, most animals had subacute encephalitis with both types of microabscesses (microabscesses with predominance of neutrophils and microabscesses with predominance of macrophages). In sheep and goats, acute encephalitis occurred more frequently than in cattle. Percentages above the columns describe the proportion of animals affected to the animals examined. B. Caudo‐rostral gradient of neutrophilic microabscesses. Median differences (Δ) between scores of neutrophilic microabscesses (NM) and those that contain mainly macrophages (MM) are shown for each brain region that was affected. Bars indicate the upper and lower 95% confidence limits around the median, and the straight line shows the linear regression trend. The relative proportion of neutrophilic microabscesses to microabscesses with mainly macrophages increases from the medulla toward the frontal brain. S = upper cervical spinal cord; B = brainstem; C = cerebellum; M = midbrain; T = thalamus; H = hippocampus; BN = basal nuclei; CC = cerebral cortex. C. Extension of lesions into rostral brain areas. B = brainstem; C = cerebellum; M = midbrain; T = thalamus; BN = basal nuclei; H = hippocampus; CC = cerebral cortex; S = upper cervical spinal cord; n = number of animals, which have lesions in a given area. D. Severity of lesions is shown as median differences in scores (on a semiquantitative scale from 0 to 4) between brainstem and the other brain regions of all animals (values in colored regions) and in a colored scale. The median score of the brainstem was used as reference value, and negative values describe a decrease in lesion severity. Median differences to the brainstem were highly significant for all rostral regions (P < 0.0001). B = brainstem; C = cerebellum; M = midbrain; T = thalamus; BN = basal nuclei; H = hippocampus; CC = cerebral cortex; S = spinal cord.

Caudo‐rostral gradient of brain lesions

In only 31 animals, lesions were restricted to the brainstem. In most animals (189), lesions extended from the brainstem into rostral brain regions (cerebellum, rostral brain areas) and/or upper cervical spinal cord (Figure 3C). Interestingly, in the vast majority of cases (181), the extension of lesions from the brainstem into other regions seemed to occur in a continuous pattern: lesions were only found in basal nuclei and cerebral hemispheres when midbrain and thalamus were affected as well. Only in one animal, this continuity could not be observed, and in seven animals, continuity could not be assessed because not all brain areas were available for neuropathological examination. When comparing the median lesion scores between the different brain regions, lesions were most severe in the brainstem and upper cervical spinal cord, and tapered off rostrally in all three ruminant species (Figure 3D). Median differences to the brainstem were highly significant for all regions (Wilcoxon signed rank test, all P < 0.0001).

Consistent pattern of white matter tract involvement in rostral brain regions

In most animals (64.5%), microabscesses could be observed along the course of fiber tracts (Figure 4). In the brainstem, microabscesses were present in both grey and white matter, whereas in midbrain and thalamus, they were located predominantly in the white matter. In the cerebellum, basal nuclei and cerebral hemispheres, microabscesses were only observed in the white matter. In midbrain, thalamus, basal nuclei and cerebral hemispheres, a consistent pattern of white matter tract involvement was observed. Lesions consistently involved the white matter ventral to the mesencephalic aqueduct, of the cerebral peduncles, internal capsule (Figure 4D) and corona radiata. Microabscesses were never seen in the hippocampus, except in the few cases with ependymitis, in which they were limited to the ependymal lining.

Figure 4.

Figure 4

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A. Listeric encephalitis in a sheep brainstem. The facial nucleus (F) contains numerous microabscesses. Microabscesses also follow the axonal course of the facial nerve root (arrows). Hematoxylin and eosin (H&E), bar = 360 µm. B. Listeric encephalitis in a sheep brainstem. The hypoglossal nucleus (H) is effaced by numerous microabscesses. Microabscesses also follow the course of the hypoglossal root (arrows). H&E, bar = 740 µm. C. Listeric encephalitis in a goat brainstem. The elongated microabscess follows the course of axons. Note the prominent gliosis in the surrounding tissue. H&E, bar = 100 µm. D. Listeric encephalitis in a sheep, basal nuclei. Neutrophilic microabscesses are restricted to white matter fascicles, whereas the grey matter is spared. CE = Capsula externa, CI = Capsula interna, P = Putamen. H&E, bar = 500 µm.

Multiple cranial nerve involvement

In 85% of animals (73.3% of goats, 91% of sheep and 84.7% of cattle), one or more cranial nerve nuclei were affected by microabscesses (Table 1; Figure 4A,B). In a large proportion of these cases (66.8%), their roots were involved as well (45.8% of goats, 81.5% of sheep and 44.4% of cattle; Figure 4A,B). The most commonly affected brainstem nuclei included the hypoglossal nerve nucleus (XII), facial nerve nucleus (VII) and trigeminal nerve nuclei (V) (Table 1). In a significant number of animals, lesions were also found in the nuclei of the III, VI, VIII and X, as well as nucleus ambiguous and the solitary tract nucleus.

Table 1.

Involvement of cranial nerve nuclei in goats, sheep and cattle with listeric encephalitis.

Cranial nerve nuclei affected Goats Sheep Cattle
Nucleus oculomotorius 2 17 4
Trigeminal nuclei 33 65 45
Nucleus abducens 0 11 7
Nucleus facialis 17 43 23
Nucleus vestibularis 3 3 2
Nucleus cochlearis 0 1 0
Nucleus ambiguus 0 0 3
Nucleus solitarius 2 5 0
Dorsal motor nucleus of the vagus 9 7 2
Nucleus hypoglossus 17 56 26
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Values indicate the numbers of animals in which a given cranial nerve nucleus was affected.

Localization and bacterial load of LM

Listeria was readily identified on immunohistochemically stained sections in all animals. Bacterial load varied strongly between individual animals, but was significantly higher in acute encephalitis when compared to subacute and chronic encephalitis (Kruskal–Wallis ANOVA, P < 0.0001) (Figure 5A). Furthermore, bacterial load was significantly higher in animals with severe lesions (Kruskal–Wallis multiple comparison test with Bonferroni correction, P < 0.05). In acute lesions, the bacteria were frequently recognized in H&E stained sections. LM was observed most frequently and in highest numbers in microabscesses (Table 2). They were identified in nearly all animals within microabscesses. The bacteria were present within neutrophils and macrophages, but also in the extracellular space (Figure 5B). When bacterial load was heavy, LM were often present in colonies (Figure 5C). Furthermore, LM were frequently observed in linear chains within degenerating and intact axons and neurons, neuropil and white matter (Table 2; Figure 5D,E). The occurrence of LM in axons and neurons was significantly higher in acute encephalitis when compared to subacute and chronic encephalitis (chi‐square test, P < 0.0001). Some animals had single intracellular bacteria within phagocytes of perivascular cuffs in close association to microabscesses and in few animals, LM were present within ependymal cells and in the ventricular system. Only in one goat, few extracellular LM were observed within the lumen of a blood vessel.

Figure 5.

Figure 5

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A. Bacterial load of Listeria monocytogenes (LM) assessed semiquantitatively on a score of 0 to 4. Symbols indicate the median score of bacterial load in acute (), subacute (Inline graphic) and chronic (Inline graphic) encephalitis of goat, sheep, cattle and all species together (total). Differences between all median scores were significant in goats and sheep (Kruskal–Wallis analysis of variance, P < 0.0001). In cattle, median differences were significant between bacterial load of chronic encephalitis and acute encephalitis, and between chronic and subacute encephalitis. B. Listeric encephalitis in a bovine. Microabscess with LM in the cytoplasm of phagocytes and within the extracellular space. IHC for listeriolysin O, bar = 12 µm. C. Listeric encephalitis in a goat. Elongate microabscess with large central colonies of LM. The microabscess follows axonal tracts. Hematoxylin and eosin (H&E), bar = 100 µm. D. Listeric encephalitis in a sheep (of Figure 4B). Chains of intra‐axonal LM within an intact axon of the hypoglossal nerve root. Polyclonal rabbit anti‐listeriolysin O antibody, bar = 12 µm. Insert: IHC for listeriolysin O showing LM in a degenerated axon within an acute microabscess. E. Listeriosis in a goat brainstem. A neuron containing LM (arrows) is surrounded by numerous neutrophils. H&E, bar = 12 µm. Insert: IHC for listeriolysin O showing LM in a neuron within an acute microabscess.

Table 2.

Localization of Listeria monocytogenes (LM) in goats, sheep and cattle.

Localization of LM Goats n (%) Sheep n (%) Cattle n (%)
Microabscesses 59 (100) 89 (100) 69 (95.8)
Intraneuronal 8 (13.6) 30 (33.7) 3 (4.2)
Intra‐axonal 19 (32.2) 45 (50.6) 10 (13.9)
Intra‐ependymal 2 (3.4) 4 (4.5) 0 (0)
Intraventricular 1 (1.7) 2 (2.2) 1 (1.4)
Perivascular 4 (6.8) 12 (13.5) 10 (13.9)
Intravascular 1 (1.7) 0 (0) 0 (0)
Neuropil/white matter 27 (45.8) 52 (58.4) 18 (25)
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Values indicate the absolute number (n) and the ratio (%) of animals.

Species differences

Species differences could be observed in the extent and cellular composition of microabscesses and in bacterial load. Even though the semiquantitatively assessed severity of lesions varied in all three species between 1 and 4, overall median values were significantly lower in cattle than in sheep and goats (Kruskal–Wallis multiple comparison test with Bonferroni correction, P < 0.05, Figure 6A).

Figure 6.

Figure 6

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Box plots showing species differences in severity of lesions (A) and bacterial load of Listeria monocytogenes (B). Both severity and bacterial load were significantly lower in cattle than in small ruminants (Kruskal–Wallis multiple comparison test with Bonferroni correction, P < 0.05).

The relative proportion of neutrophilic microabscesses (type 1) to those with mainly macrophages (type 2) also differed between species: bovines tended to have relatively more microabcesses with macrophages (type 2) than small ruminants, in which acute encephalitis was more frequent. The occurrence of multinucleated giant cells in microabscesses was significantly higher in cattle (48.6%, Figure 1C) than in sheep (3.4%) and goats (8.5%), respectively (chi‐square test, P < 0.0001). Perivascular cuffs with mononuclear cells were significantly more prominent in cattle than in small ruminants (Kruskal–Wallis ANOVA, P = 0.002). Neuronal necrosis occurred more frequently in small ruminants than in cattle.

The spread of lesions into the cerebellum, diencephalon and telencephalon was most pronounced in sheep, followed by goats and was less obvious in cattle, and involvement of basal nuclei and corona radiata occurred mainly in small ruminants.

Although there was a high variation in bacterial load between individuals in each species, the number of LM observed in lesions (Kruskal‐Wallis multiple comparison test with Bonferroni correction, P < 0.05, Figure 6B) and the occurrence of LM in axons and neurons (chi‐square test, P < 0.0001) were significantly lower in cattle than in small ruminants.

DISCUSSION

In the present study, a systematic neuropathological analysis of listeric encephalitis in three ruminant species was performed. The aim was to recognize lesion patterns within the brain that allowed us to draw conclusions about the pathogenesis of the disease in its natural hosts.

LM belongs to the most efficient neuroinvasive bacteria (64). In vitro and in vivo data suggest that the bacterium has the potential to invade the CNS by transport across the blood–brain or blood–choroid barriers within infected leukocytes 22, 36, 56 or direct invasion of endothelial cells by extracellular blood‐borne bacteria 21, 29. Alternatively, LM may enter the brain through a neural route by centripetal migration within axons 1, 5, 12, 19, 33, 51. A recent neuropathological study on autopsy material of nine human rhombencephalitis cases caused by LM suggests a similar neural route of invasion in humans (3). Our results support the hypothesis that LM spreads to the ruminant brain by axonal migration along cranial nerves in the vast majority of infected animals, and confirm frequent involvement of the fifth cranial nerve in all three ruminant species, which was proposed to be the main port of entry in sheep 12, 51. However, our findings show that, analogous to human listeric rhombencephalitis, other cranial nerves are frequently affected indicating that they might serve as a route of infection to a similar extent. As the median age of affected animals in our series was at the limit or beyond the age of completion of second dentition, it is questionable whether teeth eruption should be regarded as the main port of entry of LM as claimed 5, 47. Rather, our results suggest that there are multiple ports of entry anywhere in the oro‐pharyngeal cavity and probably also in the gut as indicated by the presence of lesions in the nucleus of the solitary tract in some cases. Frequent involvement of the oculomotor and facial nerves suggests that bacteria may gain access through the conjunctival tissues of the eye as well.

Our results show that the lesions in listeric encephalitis are not restricted to the medulla and pons in most animals, as may be suggested in the veterinary literature (67). Rather, lesions were consistently found rostrally to the mesencephalon including diencephalon and telencephalon with decreasing severity from the lower brainstem toward the cerebrum and cerebellum, and caudally in the spinal cord (Figure 3C,D). This gradient was also associated with an increasing relative proportion of neutrophilic microabscesses versus microabscesses with predominantly macrophages in rostral direction (Figure 3B). Surprisingly, these spreading lesions quite consistently involved selective areas of the white matter with suppuration along its fiber tracts. Taken together, we believe that LM, once gaining access to the CNS through the axons of the peripheral nervous system, can spread further along axonal connections between the brainstem and higher centers. Further in‐depth neuro‐anatomical studies are necessary to confirm this hypothesis. The possibility that LM invades the brain and spreads intracerebrally via the hematogenous route or the cerebrospinal fluid (CSF) seems unlikely. The regional distribution of microabscesses with consistent involvement of the brainstem, caudo‐rostral gradient of lesions and the common observation of microabscesses along fiber tracts would be an unusual topographical pattern for a hematogenous infection. In addition, our results included only a small group (3.2%) of animals with disseminated ependymitis, suggesting spread via the ventricular system as it occurs in humans and small rodents 31, 56, 62. However, all of these animals but one had concurrent rhombencephalitis, suggesting that the bacterium gained access to the brain via axonal migration as in the remaining animals and was then released into the CSF.

Based on the results of the present study and recent literature, we propose the following pathogenesis of listeric encephalitis in ruminants. LM is able to invade various cranial nerves or nerve endings within the gastrointestinal tract either through an interaction with a yet unidentified membrane receptor on the axonal surface or indirectly via cell‐to‐cell spread from infected macrophages 19, 20, 34. Bacteria spread in axons to the neuronal bodies within the brainstem and midbrain as suggested by their linear arrangement within axons of cranial nerves. The equal affection of motor and sensory nerves indicates that LM is able to migrate antero‐ and retrogradely within axons, possibly by employing its actin tail 18, 19, 35. Transganglionic migration within sensory nerves and further intracerebral spread between functionally connected neuronal cell populations likely occur via cell‐to‐cell spread. This would be in line with the importance of phosphatidylcholine‐specific phospholipase C in the pathogenesis of experimental murine LM meningoencephalitis, an LM virulence factor that promotes cell‐to‐cell spread (63). The staging of microabscesses indicates that an influx of neutrophils associated with a concomitant focal accumulation of rod cells (microglia) are the first reactive changes in LM‐infected structures. Both could be provoked either by the release of LM into the extracellular compartment resulting from bacterially induced axonal and neuronal damage, or by secretion of chemotactic factors by LM and infected neurons into the tissue 8, 25, 26, 52, 57, 63, 66. The latter may be supported by the presence of LM, even in high numbers, within morphologically intact neuronal structures. Invading neutrophils are crucial to disrupt bacterial proliferation, but likely contribute to neuronal necrosis by secretion of reactive oxygen intermediates 13, 39, 46. Concomitant with the acute suppurative tissue damage, a cell‐mediated immune response is mounted as indicated by the presence of perivascular cuffs with CD3+ and CD20+ lymphocytes in each animal independently of the stage of encephalitis. This suggests either that these animals had been already exposed to the agent previously, which is supported by the frequent detection of anti‐listeria antibodies in clinically normal cattle (10), or that because of the relatively long incubation time of listeric encephalitis, the cell‐mediated immune response is established before initial lesions occur in the brain (5). Influx of lymphocytes is associated with reduction of bacterial load as could be seen with immunohistochemical staining for LM.

Although the fundamental pathology of lesions appears to be remarkably similar in all three affected species, there are neuropathological differences which may be attributed to species‐specific features of the host immune response. The allover lesion score, the bacterial load and the rostral spread of the lesions were significantly less in bovines as compared to small ruminants. Bovines had a significantly higher proportion of subacute microabscesses often containing multinucleated giant cells. These were only rarely observed in small ruminants, suggesting a more efficient activation of macrophages in cattle in line with former observations 37, 55, 58. Taken together, the results indicate that the immune response of cattle is more efficient in restricting the bacterial infection, and might explain the longer survival of and the lower mortality of cattle compared to small ruminants (40). More in‐depth immunopathological studies are in progress.

In conclusion, the results from the present study extend our current understanding of listeric rhombencephalitis caused by LM in ruminants. LM gains access to the brainstem of all three ruminant species via migration through axons of various cranial nerves using any mucosal area in the oropharynx, gut and external mucosae as port of entry. We also showed that the infection, once in the brain, spreads further from the brainstem into other brain regions probably by intracerebral axonal migration. Finally, the initial lesion consists of acute suppuration with necrosis of neurons and axons in infected areas, and is identical in all three species. However, the lower bacterial load in cattle and further evolution of the lesion may be determined by species‐specific properties of the immune response. As the similarity of lesions in rhombencephalitis in humans and ruminants suggests a similar pathogenesis, the spontaneous listeric encephalitis in ruminants can be considered to be a relevant animal model for this disease in humans. The more so, as the natural disease in ruminants and humans is probably caused by the same LM strains. Ongoing studies are focusing on the characterization of neurovirulence factors in LM strains isolated from the natural cases presented in this report.

ACKNOWLEDGMENTS

This work was financed by the Swiss Federal Veterinary Office. We thank Ursula Forster and Isabelle Bornand for excellent technical assistance, and Torsten Seuberlich for help in editing the manuscript. Furthermore, we thank Monika Hilbe and Felix Ehrensperger, who provided us with brain materials from listeric encephalitis cases from the Vetsuisse Faculty Zurich.

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