The gram-positive bacterium Listeria monocytogenes is the causative agent of listeriosis, a highly fatal opportunistic foodborne infection. Pregnant women, neonates, the elderly, and debilitated or immunocompromised patients in general are predominantly affected, although the disease can also develop in normal individuals. Clinical manifestations of invasive listeriosis are usually severe and include abortion, sepsis, and meningoencephalitis. Listeriosis can also manifest as a febrile gastroenteritis syndrome. In addition to humans, L. monocytogenes affects many vertebrate species, including birds. Listeria ivanovii, a second pathogenic species of the genus, is specific for ruminants. Our current view of the pathophysiology of listeriosis derives largely from studies with the mouse infection model. Pathogenic listeriae enter the host primarily through the intestine. The liver is thought to be their first target organ after intestinal translocation. In the liver, listeriae actively multiply until the infection is controlled by a cell-mediated immune response. This initial, subclinical step of listeriosis is thought to be common due to the frequent presence of pathogenic L. monocytogenes in food. In normal indivuals, the continual exposure to listerial antigens probably contributes to the maintenance of anti-Listeria memory T cells. However, in debilitated and immunocompromised patients, the unrestricted proliferation of listeriae in the liver may result in prolonged low-level bacteremia, leading to invasion of the preferred secondary target organs (the brain and the gravid uterus) and to overt clinical disease. L. monocytogenes and L. ivanovii are facultative intracellular parasites able to survive in macrophages and to invade a variety of normally nonphagocytic cells, such as epithelial cells, hepatocytes, and endothelial cells. In all these cell types, pathogenic listeriae go through an intracellular life cycle involving early escape from the phagocytic vacuole, rapid intracytoplasmic multiplication, bacterially induced actin-based motility, and direct spread to neighboring cells, in which they reinitiate the cycle. In this way, listeriae disseminate in host tissues sheltered from the humoral arm of the immune system. Over the last 15 years, a number of virulence factors involved in key steps of this intracellular life cycle have been identified. This review describes in detail the molecular determinants of Listeria virulence and their mechanism of action and summarizes the current knowledge on the pathophysiology of listeriosis and the cell biology and host cell responses to Listeria infection. This article provides an updated perspective of the development of our understanding of Listeria pathogenesis from the first molecular genetic analyses of virulence mechanisms reported in 1985 until the start of the genomic era of Listeria research.

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Listeria pathogenesis and molecular virulence determinants.

Listeria monocytogenes is a Gram positive, aerobic, facultative anaerobic and nonacid fast bacterium, which can cause the disease listeriosis in both human and animals. It is widely distributed thoroughout the environment and has been isolated from various plant and animal food products associated with listeriosis outbreaks.

Contaminated ready-to-eat food products such as gravad and cold-smoked salmon and rainbow trout have been associated with human listeriosis in Sweden. The aim of this study was to analyse the occurrence and level of L. monocytogenes in
gravad and cold-smoked salmon (Salmo salar) products packed under vacuum or modified atmosphere from retail outlets in Sweden. Isolated strains were characterized by serotyping and the diversity of the strains within and between
producers were determined with PFGE (Pulsed-field gel electrophoresis). The characterized fish isolates were compared with previously characterized human strains.
L. monocytogenes was isolated from 11 (three manufacturers) of 56 products analysed. This included gravad salmon products from three manufacturers and cold-smoked salmon from one manufacturer. The highest level of L. monocytogenes found was 1500 cfu/g from a cold-smoked salmon product but the level was low (<100 cfu/g) in most of the products. Serovar 1/2a was predominant,
followed by 4b. Three products of gravad salmon harboured more than one serovar. PFGE typing of the 56 salmon isolates detected five Asc I types: four types were identical to human clinical strains with Asc I and one was identical and one was closely related to human clinical strains with Apa I. Isolation of identical or closely related L. monocytogenes strains from human clinical cases of listeriosis and gravad and cold-smoked salmon suggested that these kinds of products are possible sources of listeriosis in Sweden. Therefore, these products should be considered risk products for human listeriosis.

Listeria monocytogenes, a food-borne pathogen

Circulating blood monocytes supply peripheral tissues with macrophage and dendritic cell (DC) precursors and, in the setting of infection, also contribute directly to immune defense against microbial pathogens. In humans and mice, monocytes are divided into two major subsets that either specifically traffic into inflamed tissues or, in the absence of overt inflammation, constitutively maintain tissue macrophage/DC populations. Inflammatory monocytes respond rapidly to microbial stimuli by secreting cytokines and antimicrobial factors, express the CCR2 chemokine receptor, and traffic to sites of microbial infection in response to monocyte chemoattractant protein (MCP)-1 (CCL2) secretion. In murine models, CCR2-mediated monocyte recruitment is essential for defense against Listeria monocytogenes, Mycobacterium tuberculosis, Toxoplasma gondii, and Cryptococcus neoformans infection, implicating inflammatory monocytes in defense against bacterial, protozoal, and fungal pathogens. Recent studies indicate that inflammatory monocyte recruitment to sites of infection is complex, involving CCR2-mediated emigration of monocytes from the bone marrow into the bloodstream, followed by trafficking into infected tissues. The in vivo mechanisms that promote chemokine secretion, monocyte differentiation and trafficking, and finally monocyte-mediated microbial killing remain active and important areas of investigation.

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Monocyte-Mediated Defense Against Microbial Pathogens

https://www.cell.com/cell/pdf/S0092-8674(00)81070-3.pdf

E-Cadherin Is the Receptor for Internalin, a Surface Protein Required for Entry of L. monocytogenes into Epithelial Cells

http://cdmalaboratorio.com.br/link/cfd3e86518d586ae1c32d4e53a65464d13d42d3c.pdf

Directions for the diagnosis, clinical staging, treatment and prevention of canine leishmaniosis

Identification of Leishmania donovani amastigotes in canine tissues by immunoperoxidase staining.

Forty-three dogs affected by canine leishmaniasis (CL) with skin lesions have been studied clinically and histopathologically. Identification of leishmaniads in tissues was achieved using indirect immunoperoxidase staining. According to both macroscopic and microscopic lesions, four different dermatological patterns have been observed. Twenty-six dogs showed alopecia and desquamation as the main skin lesions. Histologically a diffuse non-suppurative dermatitis, with numerous leishmaniads inside macrophages was present. Ten animals showed skin ulcerations on limbs, especially over articulations. Histologically, the number of leishmaniads was very reduced. Five animals presented a generalised nodular disease. Each nodule corresponded with a focal accumulation of macrophages, multinucleated giant cells and lymphocytes, with a high number of parasites. Finally, two dogs presented generalised skin pustules. The possible pathogenesis and the differential diagnosis of each form is discussed.

Skin lesions in canine leishmaniasis

A microbiological, histopathological and immunohistological study of the intragastric inoculation of Listeria monocytogenes in mice

Cani ne leishmani asis is a seve re, often fata l, systemic disease of the dog caused by the pro tozoan parasite Leishmania infantum. T he disease is endemic in Med iterranean countries and is occas ionally seen in North Euro pe and in the United States in dogs that have been in ende mic areas. Thi s parasite is transmi tted by sand flies of the subfamily Phlebotominae. In the dog, leishmani ds mu ltipl y inside macroph ages and ot her cells of the mononuclear-ph agocyte-system, causing chro nic inflamma tory processes. ' .2 Classic canine leishman iasis app ears clinically as a chronic wast ing disease, with anemia, cutaneo us lesion s, and generalized lymphadenopathy. Some dogs also show epis taxis, arthritis, keratocon j unctivi tis , or uveitis. l' In the later stages of the disease, a fata l, chro nic renal failure , du e to an immune-mediated glomeru lonephritis, appears in most of the affected animals.v\" In this paper , we present two cases of canine leishm ani asis in which the prima ry clin ical sign was chro nic diarrhea, a change not usua lly associated with leishman iasis. Two unrelated dogs, a I-year-old, male mo ngrel (dog No. I) and a 10-m onth-old , male Ge rma n Shepherd Dog (No. 2), were brought to the Veterinary Teac hing Hospital with chronic large bowe l diarrhea. T he result s of prelim inary labora tory tests, including parasitological examinatio n of the feces, were normal. T he dogs did not respon d to antibiotics or to metron idazol. Fina lly, the anima ls were referred for endoscopic exa mi natio n and biopsy. Both anima ls had been routinely vaccinated and had been healthy previously. Th ey had not received an y treatment with imm unos upp resive effects . T he results of the physical exami nation were norma l except for the presence of mucus and blood in the feces. Hemogram s and blood che mis tries were nor mal except for plasma proteins, which in both anima ls were clearly eleva ted: 8.2 g/d l in dog No. I and 7.9 g/dl in dog No. 2. No para sites could be found, eve n afte r multipl e fecal examinatio ns. Rad iographs of the abdomen did not reveal any ab no rmali ties . After war m-water enemas , the large bowe l was exa mined using fiberoptic equipment. T he colonic mu cosa appeared diffusely hyperemi c, with a few focal eros ions. Four forcep bio psies were obtained from eac h anima l. Histologically, the mos t evident cha nge was a severe inflammatory infiltrate mainly in the intestina l mucosa but also in the mu scularis mucosae and the submucosa (Fig. I). Most of the inflammatory cells were macrophages, altho ugh some plasm a cells, lymphocytes and polynuclear neut roph ils could be seen scattered between the macrophages . In some areas, erosions cha racte rized by the adherence of cellular deb ris to the surface were seen. Basoph ilic bod ies were seen in sma ll vac uoles in the cyto plasm of num erous macrophages and also in the intercellular spaces (Fig. 2). Leishm aniasis, which is ende mic in the cou ntry , was suspected , and a specific ind irect imm unoperoxidase stai ning on para ffi n-emb edded sectio ns was performed} T his techn ique confirmed that the basophi lic bodies were amas tigotes of Leishmania, and colitis d ue to Leishmania infec tion was diagnosed. In bot h dogs, several bone marrow examinations were made from bone marrow samples taken from the iliac crest. Marrow films were prepared in the same way as blood film s, and sta ined by the May Grtinwa ld-Giemsa meth od . Exam ina tion of the samp les revealed some parasites inside macrophages , confirming the previous diagnosis of leishmaniasis. T he owners of the two anima ls were told of the ser iousness of the d isease and that leishmaniasis is a zoo nos is. T he owners of dog No . I opted to have it euthanatize d while the owners of dog No.2 chose treatmen t. Three series of 5 injec tio ns (a total of 15) of Glucantime R (Rhone-Merieux, Lyon , France, 100 rug/kg/day, intra muscularly) were given , sepa rated by 10-day rest period s. With the last series Glucantime was give n concurre ntly at the rate of 1.5 g/day , perorally. Th e incidence of diarrhea began to dec rease slowly, and after 2 month s had ceased altogether. Thirty days after the beginning oftreatment, the dog showed a bilateral uveitis. A year after the end of treatment , the genera l hea lth of the anima l was good, defecat ion was normal, and endoscopic exa mina tio n showed norm al intestinal mu cosa. Th e uveiti s continued, but with less intensi ty. Ana lyses of blood and urine were nor ma l (total protein: 6.8 g/dl), Acco rd ing to the literatu re, chron ic large bowe l diarrhea is very uncommon as the prim ary clinical sign of canine leishmanisais. In an extensive report of 95 cases published recently, chronic diarrhea was never the primary clinica l sign.\" Diarrhea has been reported in dogs affected by leishman iasis, but in these cases the affected animals showed other systemic signs, inclu ding anorexia, emaciation, anemia , lymphad enopath y, and skin lesion s.:\" Inflam matory lesion s in the gastro intestinal tract assoc iated with the presence ofamas tigotes ins ide macroph ages have been report ed in dogs infected experiment ally with Leishmania amastigotes.v -' In one of the reports, the lesions and clinical signs were simi lar to those described in this paper .' Our cases show that one of the clinical signs of canine leishmaniasis can be the presence of diarrhea du e to colitis . Th e presence of Leishma nia in the bone marrow of both dogs confirmed that in our cases the infection was syste mic. T he reason for the predominant localization of the parasites in the intestina l mucosa is unknow n. Th e clinical signs of this colitis are those of large bowel diarrh ea: increased frequency of defecat ion and low-volum e stool with tenesm us an d dyschezia . Mucus or blood or bot h are commonly seen in the feces. An inc rease in the plasma pro teins is qu ite commo n in canine leishmaniasis and was also present in our dogs . Uve itis has been descr ibed as an allergic reactio n in dogs with leishmaniasis during treatment with Glucantime R, simi lar to post-Kala-Azar leishmaniasis in human beings .\" As a result of our findings, leishmaniasis should be con -

https://journals.sagepub.com/doi/pdf/10.1177/030098589102800414

Chronic Colitis Due to Leishmania Infection in Two Dogs

In a study of central nervous system involvement in experimental listeriosis 27 Swiss CD1 mice were inoculated subcutaneously withListeria monocytogenes. Systemic infection developed, as shown by the isolation ofListeria monocytogenes and histopathological lesions in the spleen and liver. In the central nervous system a mixed inflammatory infiltration in the ventricular system, especially in the choroid plexus, and leptomeningitis were the most relevant lesions. Inflammatory lesions were associated with the presence ofListeria monocytogenes, as demonstrated by a positive anti-Listeria monocytogenes immunoperoxidase reaction within phagocytic cells. It is suggested that choroiditis and meningitis developed as a consequence of hematogenous dissemination ofListeria monocytogenes within mononuclear phagocytes and penetration of these cells into the ventricular system through the choroid plexus.

J. A. Ramos

Papers

Identification of Leishmania donovani amastigotes in canine tissues by immunoperoxidase staining.

Skin lesions in canine leishmaniasis

A microbiological, histopathological and immunohistological study of the intragastric inoculation of Listeria monocytogenes in mice

Chronic Colitis Due to Leishmania Infection in Two Dogs

Choroiditis and meningitis in experimental murine infection with Listeria monocytogenes.