Publications by authors named "Patricia Berthon"

31 Publications

Reevaluation of GLI1 Expression in Skin Tumors.

Am J Dermatopathol 2021 Feb 8. Epub 2021 Feb 8.

Department of Pathology, Université de Tours, Centre Hospitalier Universitaire de Tours, Tours, France "Biologie des Infections à Polyomavirus" Team, UMR INRA ISP 1282, Université de Tours, Tours, France CARADERM, French Network of Rare Cutaneous Cancer Department of Pathology, Timone University Hospital, Marseille, France Department of Pathology, Hôpital Haut-Lévêque, CHU de Bordeaux, Pessac, France.

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http://dx.doi.org/10.1097/DAD.0000000000001917DOI Listing
February 2021

Merkel Cell Polyomavirus T Antigens Induce Merkel Cell-Like Differentiation in GLI1-Expressing Epithelial Cells.

Cancers (Basel) 2020 Jul 21;12(7). Epub 2020 Jul 21.

Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Josef-Schneider-Straße 2, 97080 Würzburg, Germany.

Merkel cell carcinoma (MCC) is an aggressive skin cancer frequently caused by the Merkel cell polyomavirus (MCPyV). It is still under discussion, in which cells viral integration and MCC development occurs. Recently, we demonstrated that a virus-positive MCC derived from a trichoblastoma, an epithelial neoplasia bearing Merkel cell (MC) differentiation potential. Accordingly, we hypothesized that MC progenitors may represent an origin of MCPyV-positive MCC. To sustain this hypothesis, phenotypic comparison of trichoblastomas and physiologic human MC progenitors was conducted revealing GLI family zinc finger 1 (GLI1), Keratin 17 (KRT 17), and SRY-box transcription factor 9 (SOX9) expressions in both subsets. Furthermore, GLI1 expression in keratinocytes induced transcription of the MC marker SOX2 supporting a role of GLI1 in human MC differentiation. To assess a possible contribution of the MCPyV T antigens (TA) to the development of an MC-like phenotype, human keratinocytes were transduced with TA. While this led only to induction of KRT8, an early MC marker, combined GLI1 and TA expression gave rise to a more advanced MC phenotype with SOX2, KRT8, and KRT20 expression. Finally, we demonstrated MCPyV-large T antigens' capacity to inhibit the degradation of the MC master regulator Atonal bHLH transcription factor 1 (ATOH1). In conclusion, our report suggests that MCPyV TA contribute to the acquisition of an MC-like phenotype in epithelial cells.
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http://dx.doi.org/10.3390/cancers12071989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409360PMC
July 2020

Merkel cell carcinoma of lymph nodes without a skin primary tumor: A potential metastatic neoplasia associated with a brisk immune response.

J Am Acad Dermatol 2020 Dec 9;83(6):1789-1792. Epub 2020 Apr 9.

Department of Pathology, Université de Tours, Centre Hospitalier Universitaire de Tours, Chambray-les-tours, France; Dermatology Department, Université Francois Rabelais, Centre Hospitalier Universitaire de Tours, Chambray-les-tours, France.

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http://dx.doi.org/10.1016/j.jaad.2020.03.108DOI Listing
December 2020

Polyomavirus-Positive Merkel Cell Carcinoma Derived from a Trichoblastoma Suggests an Epithelial Origin of this Merkel Cell Carcinoma.

J Invest Dermatol 2020 05 22;140(5):976-985. Epub 2019 Nov 22.

Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany.

Merkel cell carcinoma (MCC), an aggressive neuroendocrine carcinoma of the skin, is to date the only human cancer known to be frequently caused by a polyomavirus. However, it is a matter of debate which cells are targeted by the Merkel cell polyomavirus (MCPyV) to give rise to the phenotypically multifaceted MCC cells. To assess the lineage of origin of MCPyV-positive MCC, genetic analysis of a very rare tumor combining benign trichoblastoma and MCPyV-positive MCC was conducted by massive parallel sequencing. Although MCPyV was found to be integrated only in the MCC part, six somatic mutations were shared by both tumor components. The mutational overlap between the trichoblastoma and MCPyV-positive MCC parts of the combined tumor implies that MCPyV integration occurred in an epithelial tumor cell before MCC development. Therefore, our report demonstrates that MCPyV-positive MCC can derive from the epithelial lineage.
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http://dx.doi.org/10.1016/j.jid.2019.09.026DOI Listing
May 2020

Prion strain-dependent tropism is maintained between spleen and granuloma and relies on lymphofollicular structures.

Sci Rep 2019 10 10;9(1):14656. Epub 2019 Oct 10.

VIM, INRA, Université Paris-Saclay, 78350, Jouy-en-Josas, France.

In peripherally acquired prion diseases, prions move through several tissues of the infected host, notably in the lymphoid tissue, long before the occurrence of neuroinvasion. Accumulation can even be restricted to the lymphoid tissue without neuroinvasion and clinical disease. Several experimental observations indicated that the presence of differentiated follicular dendritic cells (FDCs) in the lymphoid structures and the strain type are critical determinants of prion extraneural replication. In this context, the report that granulomatous structures apparently devoid of FDCs could support prion replication raised the question of the requirements for prion lymphotropism. The report also raised the possibility that nonlymphoid tissue-tropic prions could actually target these inflammatory structures. To investigate these issues, we examined the capacity of closely related prions, albeit with opposite lymphotropism (or FDC dependency), for establishment in experimentally-induced granuloma in ovine PrP transgenic mice. We found a positive correlation between the prion capacity to accumulate in the lymphoid tissue and granuloma, regardless of the prion detection method used. Surprisingly, we also revealed that the accumulation of prions in granulomas involved lymphoid-like structures associated with the granulomas and containing cells that stain positive for PrP, Mfge-8 but not CD45 that strongly suggest FDCs. These results suggest that the FDC requirement for prion replication in lymphoid/inflammatory tissues may be strain-dependent.
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http://dx.doi.org/10.1038/s41598-019-51084-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787085PMC
October 2019

Histogenesis of Merkel Cell Carcinoma: A Comprehensive Review.

Front Oncol 2019 10;9:451. Epub 2019 Jun 10.

ISP "Biologie des infections à polyomavirus" team, UMR INRA 1282, University of Tours, Tours, France.

Merkel cell carcinoma (MCC) is a primary neuroendocrine carcinoma of the skin. This neoplasia features aggressive behavior, resulting in a 5-year overall survival rate of 40%. In 2008, Feng et al. identified Merkel cell polyomavirus (MCPyV) integration into the host genome as the main event leading to MCC oncogenesis. However, despite identification of this crucial viral oncogenic trigger, the nature of the cell in which MCC oncogenesis occurs is actually unknown. In fact, several hypotheses have been proposed. Despite the large similarity in phenotype features between MCC tumor cells and physiological Merkel cells (MCs), a specialized subpopulation of the epidermis acting as mechanoreceptor of the skin, several points argue against the hypothesis that MCC derives directly from MCs. Alternatively, MCPyV integration could occur in another cell type and induce acquisition of an MC-like phenotype. Accordingly, an epithelial as well as a fibroblastic or B-cell origin of MCC has been proposed mainly based on phenotype similarities shared by MCC and these potential ancestries. The aim of this present review is to provide a comprehensive review of the current knowledge of the histogenesis of MCC.
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http://dx.doi.org/10.3389/fonc.2019.00451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579919PMC
June 2019

Morphologic and immunophenotypical features distinguishing Merkel cell polyomavirus-positive and negative Merkel cell carcinoma.

Mod Pathol 2019 11 14;32(11):1605-1616. Epub 2019 Jun 14.

Department of Pathology, Université François Rabelais de Tours, CHU de Tours, avenue de la République, 37170, Chambray-les-tours, France.

In 2008, Feng et al. identified Merkel cell polyomavirus integration as the primary oncogenic event in ~80% of Merkel cell carcinoma cases. The remaining virus-negative Merkel cell carcinoma cases associated with a high mutational load are most likely caused by UV radiation. The current study aimed to compare the morphological and immunohistochemical features of 80 virus-positive and 21 virus-negative Merkel cell carcinoma cases. Microscopic evaluation revealed that elongated nuclei-similar to the spindle-shape variant of small cell lung cancer-were less frequent in Merkel cell polyomavirus-positive Merkel cell carcinoma compared to the virus-negative subset (p = 0.005). Moreover, virus-negative cases more frequently displayed a "large-cell neuroendocrine carcinoma" phenotype with larger cell size (p = 0.0026), abundant cytoplasm (p = 4×10) and prominent nucleoli (p = 0.002). Analysis of immunohistochemical data revealed frequent positivity for thyroid transcription factor 1 and cytokeratin 7, either absence or overexpression of p53, as well as frequent lack of neurofilament expression in virus-negative cases. By contrast, cytokeratin 8, 18 and 20 and a CD99 with a dot pattern as well as high EMA expression were identified as characteristic features of virus-positive Merkel cell carcinoma. In particular, the CD99 dot-like expression pattern was strongly associated with presence of the Merkel cell polyomavirus in Merkel cell carcinoma (sensitivity = 81%, specificity = 90%, positive likelihood ratio = 8.08). To conclude, virus-positive and -negative Merkel cell carcinoma are characterized by distinct morphological and immunohistochemical features, which implies a significant difference in tumor biology and behavior. Importantly, we identified the CD99 staining pattern as a marker indicating the virus status of this skin cancer.
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http://dx.doi.org/10.1038/s41379-019-0288-7DOI Listing
November 2019

VEGF-A Inhibition as a Potential Therapeutic Approach in Merkel Cell Carcinoma.

J Invest Dermatol 2019 03 22;139(3):736-739. Epub 2018 Oct 22.

Biologie des infections à polyomavirus team, INRA ISP 1282 Université de Tours, Tours, France.

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http://dx.doi.org/10.1016/j.jid.2018.08.029DOI Listing
March 2019

Diagnostic accuracy of a panel of immunohistochemical and molecular markers to distinguish Merkel cell carcinoma from other neuroendocrine carcinomas.

Mod Pathol 2019 04 22;32(4):499-510. Epub 2018 Oct 22.

Department of Pathology, Université de Tours, CHU de Tours, Avenue de la République, 37170, Chambray-les-tours, France.

Merkel cell carcinoma is a rare neuroendocrine carcinoma of the skin mostly induced by Merkel cell polyomavirus integration. Cytokeratin 20 (CK20) positivity is currently used to distinguish Merkel cell carcinomas from other neuroendocrine carcinomas. However, this distinction may be challenging in CK20-negative cases and in cases without a primary skin tumor. The objectives of this study were first to evaluate the diagnostic accuracy of previously described markers for the diagnosis of Merkel cell carcinoma and second to validate these markers in the setting of difficult-to-diagnose Merkel cell carcinoma variants. In a preliminary set (n = 30), we assessed optimal immunohistochemical patterns (CK20, thyroid transcription factor 1 [TTF-1], atonal homolog 1 [ATOH1], neurofilament [NF], special AT-rich sequence-binding protein 2 [SATB2], paired box protein 5, terminal desoxynucleotidyl transferase, CD99, mucin 1, and Merkel cell polyomavirus-large T antigen) and Merkel cell polyomavirus load thresholds (real-time PCR). The diagnostic accuracy of each marker was then assessed in a validation set of 103 Merkel cell carcinomas (9 CK20-negative cases and 15 cases without a primary skin tumor) and 70 extracutaneous neuroendocrine carcinoma cases. The most discriminant markers for a diagnosis of Merkel cell carcinoma were SATB2, NF expression, and Merkel cell polyomavirus DNA detection (positive likelihood ratios: 36.6, 44.4, and 28.2, respectively). Regarding Merkel cell carcinoma variants, cases without a primary skin tumor retained a similar immunohistochemical  profile and CK20-negative tumors displayed a different profile (decrease frequency of NF and SATB2 expression), but Merkel cell polyomavirus DNA remained detected (78% of cases by qPCR). Moreover, 8/9 (89%) CK20-negative Merkel cell carcinoma cases but only 3/61 (5%) CK20-negative extracutaneous neuroendocrine cases were positive for at least one of these markers. In conclusion, detection of SATB2 and NF expression and Merkel cell polyomavirus DNA helps distinguish between Merkel cell carcinoma classical and variant cases and extracutaneous neuroendocrine carcinomas.
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http://dx.doi.org/10.1038/s41379-018-0155-yDOI Listing
April 2019

Evaluation of mycobacteria-specific gamma interferon and antibody responses before and after a single intradermal skin test in cattle naturally exposed to M. avium subsp. paratuberculosis and experimentally infected with M. bovis.

Vet Immunol Immunopathol 2018 Feb 12;196:35-47. Epub 2017 Dec 12.

Unit "Bacterial Zoonoses of livestock", Operational Direction Bacterial Diseases, Veterinary and Agrochemical Research Center (CODA-CERVA), Groeselenberg, Brussels, Belgium.

This study reports on the diagnostic potential of IFN-γ release assays and serology for Mycobacterium bovis in six naturally M. avium subsp. paratuberculosis (Map) exposed bulls of which four were intratracheally infected with a Belgian field strain of M. bovis. Heparinized blood, serum and fecal samples were collected at regular time intervals for mycobacteria-specific IFN-γ release assays, antibody analysis and for Map culture respectively. Single intradermal skin test (SIT) with bovine tuberculin (PPD-B) was performed on day 115 and animals were sacrificed on day 133 after M. bovis infection. Organs were collected and stored for histopathological examination, modified Ziehl-Neelsen staining and bacteriological analysis of M. bovis and Map by culture and RT-PCR. Prior to infection five animals showed positive IFN-γ responses to avian PPD (PPD-A) and four were positive in Map PCR (IS900) on faeces. Three M. bovis infected animals reacted as early as day 14 with sustained higher PPD-B than PPD-A specific IFN-γ responses, whereas the fourth animal (with the strongest PPD-A response prior to infection) showed sustained higher PPD-B specific IFN-γ levels only a day 56 after infection. Two of the infected animals had a sustained positive IFN-γ response to the ESAT-6/CFP-10/TB7.7 (QuantiFERON-TB Gold) peptide cocktail as early as day 14, among which the animal with the initial high PPD-A response. Later during infection, positive responses were found to ESAT-6 peptides in three infected bulls and to CFP-10 peptides in all four infected bulls. One of the control animals reacted intermittently to the ESAT-6/CFP10/TB7.7 cocktail. Prior to SIT, weak but positive MPB83/MBP70 specific antibody responses were detected in two of the infected bulls. All four M. bovis infected bulls reacted with a positive skin test and showed, as reported by others, increased mycobacteria specific IFN-γ production and increased positive responses in MPB83/MBP70 specific serology after SIT. At autopsy, M. bovis lesions were detected in all four experimentally infected bulls. Our results indicate that in Map exposed cattle, M. bovis diagnosis using IFN-γ assays needs a combination of PPD-B/A and ESAT-6/CFP10 for early and optimal sensitivity and that sensitivity of MPB83/MBP70 serodiagnosis is dramatically increased by prior skin testing. Map exposure did not interfere with the development of SIT in M. bovis infected animals, but resulted in a false positive M. bovis specific IFN-γ and antibody response after SIT in one of the two control animals (which remained negative in skin-test).
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http://dx.doi.org/10.1016/j.vetimm.2017.12.007DOI Listing
February 2018

Merkel cell carcinomas infiltrated with CD33 myeloid cells and CD8 T cells are associated with improved outcome.

J Am Acad Dermatol 2018 05 19;78(5):973-982.e8. Epub 2017 Dec 19.

Biologie des Infections à Polyomavirus Team, Unité Mixte de Recherche 1282 Infectiologie et Santé Publique INRA, Universite Francois Rabelais, Tours, France; Department of Dermatology, CHU de Tours, Université Francois Rabelais, France. Electronic address:

Background: Merkel cell carcinoma (MCC) is a rare tumor of the skin that has an aggressive behavior. Immunity is the main regulator of MCC development, and many interactions between lymphocytes and tumor cells have been proven. However, the impact of tumor-infiltrating myeloid cells needs better characterization.

Objective: To characterize tumor-infiltrating myeloid cells in MCC and their association with other immune effectors and patient outcome.

Methods: MCC cases were reviewed from an ongoing prospective cohort study. In all, 103 triplicate tumor samples were included in a tissue microarray. Macrophages, neutrophils, and myeloid-derived suppressor cells were characterized by the following markers: CD68, CD33, CD163, CD15, CD33, and human leukocyte antigen-DR. Associations of these cell populations with programmed cell death ligand 1 expression, CD8 infiltrates, and vascular density were assessed. Impact on survival was analyzed by log-rank tests and a Cox multivariate model.

Results: The median density of macrophages was 216 cells/mm. CD68 and CD33 macrophage densities were associated with CD8 T-cell infiltrates and programmed cell death ligand 1 expression. In addition, MCC harboring CD8 T cell infiltrates and brisk CD33 myeloid cell infiltrates were significantly and independently associated with improved outcomes (recurrence-free and overall survival).

Limitations: Sampling bias and the retrospective design were potential study limitations.

Conclusion: Infiltration of CD33 myeloid cells and CD8 T lymphocytes defines a subset of MCC associated with improved outcome.
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http://dx.doi.org/10.1016/j.jaad.2017.12.029DOI Listing
May 2018

The Pig: A Relevant Model for Evaluating the Neutrophil Serine Protease Activities during Acute Pseudomonas aeruginosa Lung Infection.

PLoS One 2016 16;11(12):e0168577. Epub 2016 Dec 16.

INSERM, Centre d'Etude des Pathologies Respiratoires, UMR 1100, Tours cedex, France.

The main features of lung infection and inflammation are a massive recruitment of neutrophils and the subsequent release of neutrophil serine proteases (NSPs). Anti-infectious and/or anti-inflammatory treatments must be tested on a suitable animal model. Mice models do not replicate several aspects of human lung disease. This is particularly true for cystic fibrosis (CF), which has led the scientific community to a search for new animal models. We have shown that mice are not appropriate for characterizing drugs targeting neutrophil-dependent inflammation and that pig neutrophils and their NSPs are similar to their human homologues. We induced acute neutrophilic inflammatory responses in pig lungs using Pseudomonas aeruginosa, an opportunistic respiratory pathogen. Blood samples, nasal swabs and bronchoalveolar lavage fluids (BALFs) were collected at 0, 3, 6 and 24 h post-insfection (p.i.) and biochemical parameters, serum and BAL cytokines, bacterial cultures and neutrophil activity were evaluated. The release of proinflammatory mediators, biochemical and hematological blood parameters, cell recruitment and bronchial reactivity, peaked at 6h p.i.. We also used synthetic substrates specific for human neutrophil proteases to show that the activity of pig NSPs in BALFs increased. These proteases were also detected at the surface of lung neutrophils using anti-human NSP antibodies. Pseudomonas aeruginosa-induced lung infection in pigs results in a neutrophilic response similar to that described for cystic fibrosis and ventilator-associated pneumonia in humans. Altogether, this indicates that the pig is an appropriate model for testing anti-infectious and/or anti-inflammatory drugs to combat adverse proteolytic effects of neutrophil in human lung diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168577PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161375PMC
July 2017

Mycoplasma hyopneumoniae does not affect the interferon-related anti-viral response but predisposes the pig to a higher level of inflammation following swine influenza virus infection.

J Gen Virol 2016 10 5;97(10):2501-2515. Epub 2016 Aug 5.

ANSES, Laboratoire de Ploufragan-Plouzané, Unité Virologie Immunologie Porcines, Ploufragan, France.

In pigs, influenza A viruses and Mycoplasma hyopneumoniae (Mhp) are major contributors to the porcine respiratory disease complex. Pre-infection with Mhp was previously shown experimentally to exacerbate the clinical outcomes of H1N1 infection during the first week after virus inoculation. In order to better understand the interactions between these pathogens, we aimed to assess very early responses (at 5, 24 and 48 h) after H1N1 infection in pigs pre-infected or not with Mhp. Clinical signs and macroscopic lung lesions were similar in both infected groups at early times post-H1N1 infection; and Mhp pre-infection affected neither the influenza virus replication nor the IFN-induced antiviral responses in the lung. However, it predisposed the animals to a higher inflammatory response to H1N1 infection, as revealed by the massive infiltration of neutrophils and macrophages into the lungs and the increased production of pro-inflammatory cytokines (IL-6, IL-1β and TNF-α). Thus, it seems it is this marked inflammatory state that would play a role in exacerbating the clinical signs subsequent to H1N1 infection.
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http://dx.doi.org/10.1099/jgv.0.000573DOI Listing
October 2016

Oral Uptake of Chlamydia psittaci by Ducklings Results in Systemic Dissemination.

PLoS One 2016 11;11(5):e0154860. Epub 2016 May 11.

ANSES, Animal Health Laboratory, Bacterial Zoonoses Unit, Maisons-Alfort, France.

Enteric infections caused by Chlamydia (C.) psittaci are frequent in ducks, but mostly remain subclinical under field conditions. To emulate natural infection, we investigated the pathogenic potential of a C. psittaci field strain in orally inoculated 4-day-old ducklings. Three different challenge doses were tested and seven contact animals were also mock-inoculated with buffer in each group. Over the course of ten days, the birds were monitored for clinical symptoms and chlamydial dissemination before final examination of tissues using histopathology and immunohistochemistry. While the challenge strain disseminated systemically to all internal organs, mild signs of diarrhea were confined to ducklings inoculated with the highest dose (4.3 x 108 IFU/mL, Group 1). No other clinical symptoms or histopathological lesions were seen. The chlamydial load in internal organs as measured by PCR depended on the challenge dose and was unevenly distributed, i.e. high loads in spleen, liver, and distal small and large intestinal tract (ileum, cecum and rectum) vs. ten times lower values in lungs and proximal small intestinal tract (duodenum and jejunum). Notably, the C. psittaci infection of contact birds became evident on day 10 post-infection, with bacterial loads comparable to those of experimentally-infected animals, thus suggesting rapid bird-to-bird transmission of the challenge strain.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0154860PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864072PMC
July 2017

IL-17A Is an Important Effector of the Immune Response of the Mammary Gland to Escherichia coli Infection.

J Immunol 2016 Jan 18;196(2):803-12. Epub 2015 Dec 18.

UMR1282 Infectiologie et Santé Publique, Institut National de la Recherche Agronomique, F-37380 Nouzilly, France; and UMR1282 Infectiologie et Santé Publique, Université François-Rabelais de Tours, F-37000 Tours, France

The cytokine IL-17A has been shown to play critical roles in host defense against bacterial and fungal infections at different epithelial sites, but its role in the defense of the mammary gland (MG) has seldom been investigated, although infections of the MG constitute the main pathology afflicting dairy cows. In this study, we showed that IL-17A contributes to the defense of the MG against Escherichia coli infection by using a mouse mastitis model. After inoculation of the MG with a mastitis-causing E. coli strain, the bacterial load increased rapidly, triggering an intense influx of leukocytes into mammary tissue and increased concentrations of IL-6, IL-22, TNF-α, and IL-10. Neutrophils were the first cells that migrated intensely to the mammary tissue, in line with an early production of CXCL2. Depletion of neutrophils induced an increased mammary bacterial load. There was a significant increase of IL-17-containing CD4(+) αβ T lymphocyte numbers in infected glands. Depletion of IL-17A correlated with an increased bacterial colonization and IL-10 production. Intramammary infusion of IL-17A at the onset of infection was associated with markedly decreased bacterial numbers, decreased IL-10 production, and increased neutrophil recruitment. Depletion of CD25(+) regulatory T cells correlated with a decreased production of IL-10 and a reduced bacterial load. These results indicate that IL-17A is an important effector of MG immunity to E. coli and suggest that an early increased local production of IL-17A would improve the outcome of infection. These findings point to a new lead to the development of vaccines against mastitis.
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http://dx.doi.org/10.4049/jimmunol.1500705DOI Listing
January 2016

Computed Tomography (CT) Scanning Facilitates Early Identification of Neonatal Cystic Fibrosis Piglets.

PLoS One 2015 23;10(11):e0143459. Epub 2015 Nov 23.

INRA, UMR1282 ISP, Nouzilly, France.

Background: Cystic Fibrosis (CF) is the most prevalent autosomal recessive disease in the Caucasian population. A cystic fibrosis transmembrane conductance regulator knockout (CFTR-/-) pig that displays most of the features of the human CF disease has been recently developed. However, CFTR-/- pigs presents a 100% prevalence of meconium ileus that leads to death in the first hours after birth, requiring a rapid diagnosis and surgical intervention to relieve intestinal obstruction. Identification of CFTR-/- piglets is usually performed by PCR genotyping, a procedure that lasts between 4 to 6 h. Here, we aimed to develop a procedure for rapid identification of CFTR-/- piglets that will allow placing them under intensive care soon after birth and immediately proceeding with the surgical correction.

Methods And Principal Findings: Male and female CFTR+/- pigs were crossed and the progeny was examined by computed tomography (CT) scan to detect the presence of meconium ileus and facilitate a rapid post-natal surgical intervention. Genotype was confirmed by PCR. CT scan presented a 94.4% sensitivity to diagnose CFTR-/- piglets. Diagnosis by CT scan reduced the birth-to-surgery time from a minimum of 10 h down to a minimum of 2.5 h and increased the survival of CFTR-/- piglets to a maximum of 13 days post-surgery as opposed to just 66 h after later surgery.

Conclusion: CT scan imaging of meconium ileus is an accurate method for rapid identification of CFTR-/- piglets. Early CT detection of meconium ileus may help to extend the lifespan of CFTR-/- piglets and, thus, improve experimental research on CF, still an incurable disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0143459PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4658176PMC
June 2016

Transgenic Rabbits Expressing Ovine PrP Are Susceptible to Scrapie.

PLoS Pathog 2015 Aug 6;11(8):e1005077. Epub 2015 Aug 6.

INRA-CNRS-ENVA, UMR1198, Biologie du Développement et Reproduction, BDR, Jouy-en-Josas, France.

Transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative diseases affecting a wide range of mammalian species. They are caused by prions, a proteinaceous pathogen essentially composed of PrPSc, an abnormal isoform of the host encoded cellular prion protein PrPC. Constrained steric interactions between PrPSc and PrPC are thought to provide prions with species specificity, and to control cross-species transmission into other host populations, including humans. Transgenetic expression of foreign PrP genes has been successfully and widely used to overcome the recognized resistance of mouse to foreign TSE sources. Rabbit is one of the species that exhibit a pronounced resistance to TSEs. Most attempts to infect experimentally rabbit have failed, except after inoculation with cell-free generated rabbit prions. To gain insights on the molecular determinants of the relative resistance of rabbits to prions, we generated transgenic rabbits expressing the susceptible V136R154Q171 allele of the ovine PRNP gene on a rabbit wild type PRNP New Zealand background and assessed their experimental susceptibility to scrapie prions. All transgenic animals developed a typical TSE 6-8 months after intracerebral inoculation, whereas wild type rabbits remained healthy more than 700 days after inoculation. Despite the endogenous presence of rabbit PrPC, only ovine PrPSc was detectable in the brains of diseased animals. Collectively these data indicate that the low susceptibility of rabbits to prion infection is not enciphered within their non-PrP genetic background.
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http://dx.doi.org/10.1371/journal.ppat.1005077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527776PMC
August 2015

In , a BspA family protein is required for chemotaxis toward tumour necrosis factor.

Microb Cell 2015 Jul 6;2(7):235-246. Epub 2015 Jul 6.

Institut Pasteur, Unité Biologie Cellulaire du Parasitisme, F-75015 Paris, France. ; INSERM U786, F-75015 Paris, France.

Background: cell migration is essential for the development of human amoebiasis (an infectious disease characterized by tissue invasion and destruction). The tissue inflammation associated with tumour necrosis factor (TNF) secretion by host cells is a well-documented feature of amoebiasis. Tumour necrosis factor is a chemoattractant for , and the parasite may have a TNF receptor at its cell surface.

Methods: confocal microscopy, RNA Sequencing, bioinformatics, RNA antisense techniques and histological analysis of human colon explants were used to characterize the interplay between TNF and .

Results: an antibody against human TNF receptor 1 (TNFR1) stained the trophozoite surface and (on immunoblots) binds to a 150-kDa protein. Proteome screening with the TNFR1 sequence revealed a BspA family protein in that carries a TNFR signature domain and six leucine-rich repeats (named here as "cell surface protein", CSP, in view of its cellular location). Cell surface protein shares structural homologies with Toll-Like receptors, colocalizes with TNF and is internalized in TNF-containing vesicles. Reduction of cellular CSP levels abolished chemotaxis toward TNF and blocked parasite invasion of human colon.

Conclusions: there is a clear link between TNF chemotaxis, CSP and pathogenesis.
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http://dx.doi.org/10.15698/mic2015.07.214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349171PMC
July 2015

T helper 17-associated cytokines are produced during antigen-specific inflammation in the mammary gland.

PLoS One 2013 16;8(5):e63471. Epub 2013 May 16.

Infectiology and Public Health Research Unit, Institut National de la Recherche Agronomique, Nouzilly, France.

Infectious mastitis cuts down milk production profitability and is a major animal welfare problem. Bacteria-induced inflammation in the mammary gland (MG) is driven by innate immunity, but adaptive immunity can modulate the innate response. Several studies have shown that it is possible to elicit inflammation in the MG by sensitization to an antigen subsequently infused into the lumen of the gland. The objective of our study was to characterize the inflammation triggered in the MG of cows sensitized to ovalbumin, by identifying the cytokines and chemokines likely to play a part in the reaction. Among immunized cows, responders mobilized locally high numbers of leukocytes. An overexpression of the genes encoding IL-17a, IL-17F, IL-21, IL-22 and INF-γ was found in milk cell RNA extracts in the early phase of the inflammatory response. At the protein level, IL-17A was detected in milk as soon as the first sampling time (8 h post-challenge), and both IL-17A and IFN-γ concentrations peaked at 12 to 24 h post-challenge. In mammary tissue from challenged quarters, overexpression of the genes encoding IL-17A, IL-17F, IL-21, IL-22, IL-26 and IFN-γ was observed. Neutrophil-attracting chemokines (CXCL3 and CXCL8) were found in milk, and overexpressed transcripts of chemokines attracting lymphocytes and other mononuclear leukocytes (CXCL10, CCL2, CCL5, CCL20) were detected in mammary tissue. Expression of IL-17A, as revealed by immunohistochemistry, was located in epithelial cells, in leukocytes in the connective tissue and in association with the epithelium, and in migrated alveolar leukocytes of challenged quarters. Altogether, these results show that antigen-specific inflammation in the MG was characterized by the production of IL-17 and IFN-γ. The orientation of the inflammatory response induced by the antigen-specific response has the potential to strongly impact the outcome of bacterial infections of the MG.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0063471PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3656053PMC
December 2013

Neuroimmune connections in ovine pharyngeal tonsil: potential site for prion neuroinvasion.

Cell Tissue Res 2012 Apr 17;348(1):167-76. Epub 2012 Mar 17.

Department of Morphology and Pathology, Faculty of Veterinary Medicine, University of Liege, Liege, Belgium.

Recent studies have established the involvement of nasal-associated lymphoid tissues, mainly the pharyngeal tonsil, in prion pathogenesis. However, the mechanisms of the associated neuroinvasion are still debated. To determine potential sites for prion neuroinvasion inside the ovine pharyngeal tonsil, the topography of heavy (200 kDa) and light (70 kDa) neurofilaments and of glial fibrillar acidic protein has been semi-quantitatively analysed inside the various compartments of the tonsil. The results show that the most innervated areas are the interfollicular area and the connective tissue located beneath the respiratory epithelium. The existence of rare synapses between follicular dendritic cells and nerve fibres inside the germinal centre indicates that this mechanism of neuroinvasion is possible but, since germinal centres of lymphoid follicles are poorly innervated, other routes of neuroinvasion are likely. The host PRNP genotype does not influence the pattern of innervation in these various tonsil compartments, unlike ageing during which an increase of nerve endings occurs in a zone of high trafficking cells beneath the respiratory epithelium. A minimal age-related increase of innervation inside the lymphoid follicles has also been observed. An increase in nerve fibre density around the lymphoid follicles, in an area rich in mobile cells such as macrophages and dendritic cells capable of capturing and conveying pathogen prion protein (PrPd), might ensure more efficient infectivity, not in the early phase but in the advanced phase of lymphoinvasion after the amplification of PrPd; alternatively, this area might even act as a direct site of entry during neuroinvasion.
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http://dx.doi.org/10.1007/s00441-012-1376-xDOI Listing
April 2012

Depletion of CD25⁺ cells during acute toxoplasmosis does not significantly increase mortality in Swiss OF1 mice.

Mem Inst Oswaldo Cruz 2012 Mar;107(2):155-62

Université François Rabelais de Tours, UMR1282 Infectiologie et Santé Publique, F-37000 Tours, France.

The interleukin (IL)-2R alpha chain (CD25) is expressed on regulatory T cells (Treg), which constitute more than 85% of the CD25+ T cell population in a naïve mouse. CD25 is also expressed on effector T cells in mice suffering from an acute infection by the obligate intracellular protozoan parasite, Toxoplasma gondii. Lethal toxoplasmosis is accompanied by a significant loss of Treg in mice naturally susceptible to toxoplasmosis. The present study was done to explore the role of Treg cells using an anti-CD25 antibody-mediated depletion in mice naturally resistant to toxoplasmosis. Although a significant decrease in the percentage of Treg cells was observed following anti-CD25 monoclonal antibody injections, the depletion of CD25+ cells during acute toxoplasmosis did not significantly increase the mortality of Swiss OF1 mice and no significant difference was observed in the brain parasitic load between the mice in the depleted-infected and isotype-infected groups. We found no significant difference between the titres of total IgG in the sera of the mice from the two groups in the chronic phase. However, CD25+ cells depletion was followed by significantly higher levels of IL-12 in the serum of depleted mice than in that of mice injected with the isotype control antibody.
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http://dx.doi.org/10.1590/s0074-02762012000200002DOI Listing
March 2012

Porcine colon explants in the study of innate immune response to Entamoeba histolytica.

Vet Immunol Immunopathol 2012 Feb 12;145(3-4):611-7. Epub 2012 Jan 12.

Institut Pasteur, Unité Biologie Cellulaire du Parasitisme, Paris, France.

Human amebiasis is caused by the protozoan Entamoeba histolytica. This protozoan is responsible for muco-hemorrhagic diarrhoea and liver abscess in affected populations. E. histolytica can be asymptomatic commensally confined to the intestinal lumen or can result in invasion of the colonic mucosa leading to ulceration and/or liver abscesses. Recently, human colonic explants have been identified as valuable in the study of host-parasite interactions. Here we investigated the potential of porcine colonic explants as an alternative to human tissues which are far less available. Porcine colonic explants were cultured with two strains of E. histolytica, one virulent (HM1:IMSS) and one avirulent (Rahman). Results from histopathological and real-time PCR analysis showed that porcine explants cultured with virulent ameba trophozoites react similarly to their human counterparts with an invasion of the tissue by the trophozoites and the triggering of typical innate immune response against the parasite. On the contrary, explants cultured with avirulent ameba trophozoites were preserved. The study open the way to the use of porcine colonic explants in the study of the complex interactions between the parasite and the host.
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http://dx.doi.org/10.1016/j.vetimm.2012.01.002DOI Listing
February 2012

Towards the establishment of a porcine model to study human amebiasis.

PLoS One 2011 21;6(12):e28795. Epub 2011 Dec 21.

Institut Pasteur, Unité Biologie Cellulaire du Parasitisme, Paris, France.

Background: Entamoeba histolytica is an important parasite of the human intestine. Its life cycle is monoxenous with two stages: (i) the trophozoite, growing in the intestine and (ii) the cyst corresponding to the dissemination stage. The trophozoite in the intestine can live as a commensal leading to asymptomatic infection or as a tissue invasive form producing mucosal ulcers and liver abscesses. There is no animal model mimicking the whole disease cycle. Most of the biological information on E. histolytica has been obtained from trophozoite adapted to axenic culture. The reproduction of intestinal amebiasis in an animal model is difficult while for liver amebiasis there are well-described rodent models. During this study, we worked on the assessment of pigs as a new potential model to study amebiasis.

Methodology/principal Findings: We first co-cultured trophozoites of E. histolytica with porcine colonic fragments and observed a disruption of the mucosal architecture. Then, we showed that outbred pigs can be used to reproduce some lesions associated with human amebiasis. A detailed analysis was performed using a washed closed-jejunal loops model. In loops inoculated with virulent amebas a severe acute ulcerative jejunitis was observed with large hemorrhagic lesions 14 days post-inoculation associated with the presence of the trophozoites in the depth of the mucosa in two out four animals. Furthermore, typical large sized hepatic abscesses were observed in the liver of one animal 7 days post-injection in the portal vein and the liver parenchyma.

Conclusions: The pig model could help with simultaneously studying intestinal and extraintestinal lesion development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0028795PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3244410PMC
April 2012

The chemokine CXCL3 is responsible for the constitutive chemotactic activity of bovine milk for neutrophils.

Mol Immunol 2008 Sep 26;45(15):4020-7. Epub 2008 Jul 26.

INRA, UR1282, Infectiologie Animale et Santé Publique, Centre de recherche de Tours, Nouzilly 37380, France.

Bovine milk is known to exert a potent chemotactic activity on neutrophils, but the responsible agent has not been identified. The objective of the study was to characterize the main biochemical component responsible for this chemotactic activity. A neutrophil shape change assay was used to locate active milk fractions separated by chromatography. A single protein was isolated and identified by amino acid sequencing and mass spectrometry as CXCL3. Recombinant bovine chemokines and specific antibodies were used to show that normal milk contains active concentrations of CXCL1 (1-5ng/ml) and CXCL3 (100-500ng/ml), whereas CXCL2 and CXCL8/IL-8 were not detected. Depletion experiments with antibodies showed that CXCL3 was the main chemotaxin for neutrophils in normal (non-mastitic) milk. The chemokine CXCL3 was located by immunohistochemistry in mammary epithelial cells, and abundant mRNA was found in uninflamed mammary tissue, suggesting constitutive secretion by the lactating mammary epithelium. These results indicate that CXCL3/GRO-gamma is the major chemotactic factor for neutrophils in bovine milk in the absence of inflammation, and that it is secreted constitutively in milk by mammary epithelial cells. This finding prompts the question of the biological significance of permanent high concentrations of a CXC chemokine in milk.
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http://dx.doi.org/10.1016/j.molimm.2008.06.010DOI Listing
September 2008

Bovine spongiform encephalopathy agent in spleen from an ARR/ARR orally exposed sheep.

J Gen Virol 2006 Apr;87(Pt 4):1043-1046

INRA, Pathologie Infectieuse et Immunologie, INRA Nouzilly, 37380 Nouzilly, France.

Oral contamination with bovine spongiform encephalopathy (BSE) agent in susceptible PRNP genotype sheep results in widespread distribution of prion in the host. Because ARR homozygous sheep are considered to be resistant to transmissible spongiform encephalopathies, they have been selected to eradicate scrapie from sheep flocks and to protect the human food chain from small ruminant BSE risk. However, results presented here show that several months after an oral challenge with BSE agent, healthy ARR/ARR sheep can accumulate significant amounts of PrP(Sc) in the spleen.
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http://dx.doi.org/10.1099/vir.0.81318-0DOI Listing
April 2006

Immunolocalisation of an ABC transporter, P-glycoprotein, in the eggshells and cuticles of free-living and parasitic stages of Haemonchus contortus.

Parasitol Res 2005 Jun 26;96(3):142-8. Epub 2005 Apr 26.

MultiResistances and Antiparasitic Drugs, INRA-Tours: UR086-BioAgressors, Health and Environment, 37380, Nouzilly, France.

Recent data have suggested that P-glycoprotein (Pgp), working as membrane efflux "pumps", plays a major role in the transport of anthelmintic drugs in parasitic nematodes of ruminants. Flow cytometry analyses has shown that active Pgp is probably present in the external layers of Haemonchus contortus eggshells, following staining with the mouse monoclonal anti-human MDR1 antibody UIC2, which binds to Pgp in its active conformation. We evaluated the presence and distribution of this protein in the envelopes (eggshells and cuticles) of H. contortus and compared the various stages (eggs, L1-L2 larvae, L3 larvae, adult male and female worms). Electrophoresis revealed a 170-kDa band, corresponding to the molecular weight of Pgp in all stages. Indirect immunofluorescence staining with UIC2 showed Pgp to be located in the external layer of eggshells or cuticles. Transmission electron microscopy was used to localise Pgp more accurately in the three layers of the eggshells and cuticles. The conformation and biological functions of this protein, which we did not expect to find in such structures, remain to be determined.
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http://dx.doi.org/10.1007/s00436-005-1345-3DOI Listing
June 2005

Genetic parameters for resistance to the Salmonella abortusovis vaccinal strain Rv6 in sheep.

Genet Sel Evol 2003 Mar-Apr;35(2):199-217

Station d'amélioration génétique des animaux, Institut national de la recherche agronomique, BP 27, 31326 Castanet-Tolosan Cedex, France.

An experimental population (1216 lambs from 30 sires) of the Inra401 sheep was created in an Inra flock to allow QTL detection for susceptibility to Salmonella infection, wool and carcass traits. The Inra401 is a sheep composite line developed from two breeds: Berrichon du Cher and Romanov. At 113 days of age on average, the lambs were inoculated intravenously with 10(8) Salmonella abortusovis Rv6 (vaccinal strain). They were slaughtered 10 days after the inoculation. Several traits were measured at inoculation and/or slaughtering to estimate the genetic resistance of the lambs to Salmonella infection: specific IgM and IgG1 antibody titres, body weight loss, spleen and pre-scapular node weights and counts of viable Salmonella persisting in these organs. This paper presents a quantitative analysis of the genetic variability of the traits related to salmonellosis susceptibility. The heritabilities of the traits varied between 0.10 and 0.64 (significantly different from zero). Thus, in sheep as well as in other species, the determinism of resistance to Salmonella infection is under genetic control. Moreover, the correlations between the traits are in agreement with the known immune mechanisms. The genetic variability observed should help QTL detection.
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http://dx.doi.org/10.1186/1297-9686-35-2-199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2732695PMC
October 2003

Astrocytes accumulate 4-hydroxynonenal adducts in murine scrapie and human Creutzfeldt-Jakob disease.

Neurobiol Dis 2002 Dec;11(3):386-93

UMR INRA-ENVT, Physiopathologie Infectieuse et Parasitaire des Ruminants, Ecole Nationale Vétérinaire de Toulouse, 31076, Toulouse, France.

Scrapie-infected mice are considered a model for study in prion diseases, which are characterized by the progressive accumulation in the brain of an abnormal isoform (PrPsc) of the normal cellular prion protein (PrPc). Increasing data suggest that the neurodegenerative process in prion diseases may result, at least partially, from a defect in antioxidant function, but so far in vivo oxidative stress remains poorly documented. We report here that 4-hydroxynonenal, a lipid peroxidation by-product, forms protein adducts in brains of scrapie-infected mice and of Creutzfeldt-Jakob disease affected patients. In scrapie mice, studies on the progression of PrPsc accumulation, glial activation, ubiquitin deposition, and 4-HNE adduct formation allowed us to conclude the late occurrence of oxidative damage in the course of the disease. Massive 4-HNE accumulation was identified in astrocytes, but not in neurons or microglial cells. These findings suggest an important oxidative stress (and subsequent lipid peroxidation) in astrocytes, with possible consequences on their neuronal trophic function.
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http://dx.doi.org/10.1006/nbdi.2002.0558DOI Listing
December 2002

Phenotyping of protein-prion (PrPsc)-accumulating cells in lymphoid and neural tissues of naturally scrapie-affected sheep by double-labeling immunohistochemistry.

J Histochem Cytochem 2002 Oct;50(10):1357-70

UMR INRA-ENVT, Physiopathologie Infectieuse et Parasitaire des Ruminants, Ecole Nationale Vétérinaire, Toulouse, France.

Transmissible spongiform encephalopathies are fatal neurodegenerative diseases characterized by amyloid deposition of protein-prion (PrPsc), the pathogenic isoform of the host cellular protein PrPc, in the immune and central nervous systems. In the absence of definitive data on the nature of the infectious agent, PrPsc immunohistochemistry (IHC) constitutes one of the main methodologies for pathogenesis studies of these diseases. In situ PrPsc immunolabeling requires formalin fixation and paraffin embedding of tissues, followed by post-embedding antigen retrieval steps such as formic acid and hydrated autoclaving treatments. These procedures result in poor cellular antigen preservation, precluding the phenotyping of cells involved in scrapie pathogenesis. Until now, PrPsc-positive cell phenotyping relied mainly on morphological criteria. To identify these cells under the PrPsc IHC conditions, a new, rapid, and highly sensitive PrPsc double-labeling technique was developed, using a panel of screened antibodies that allow specific labeling of most of the cell subsets and structures using paraffin-embedded lymphoid and neural tissues from sheep, leading to an accurate identification of ovine PrPsc-accumulating cells. This technique constitutes a useful tool for IHC investigation of scrapie pathogenesis and may be applicable to the study of other ovine infectious diseases.
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http://dx.doi.org/10.1177/002215540205001009DOI Listing
October 2002

PrP(Sc) accumulation in placentas of ewes exposed to natural scrapie: influence of foetal PrP genotype and effect on ewe-to-lamb transmission.

J Gen Virol 2002 Oct;83(Pt 10):2607-2616

UMR 959 INRA-ENVT, Physiopathologie Infectieuse et Parasitaire des Ruminants, Ecole Nationale Vétérinaire, 23 Chemin des Capelles, 31076 Toulouse Cedex 3, France1.

Placentas from scrapie-affected ewes are known to be infectious. Nevertheless, placenta infectivity in such ewes is not systematic. Maternal transmission to lambs is highly suspected but contamination of the foetus in utero has not been demonstrated. Using ewes from a naturally scrapie-infected flock, it was demonstrated that abnormal prion protein (PrP(Sc)) accumulation in the placenta (i) is controlled by polymorphisms at codons 136, 154 and 171 of the foetal PrP gene and (ii) is restricted mainly to placentome foetal trophoblastic cells. In order to go deeper into the role of the placenta in scrapie transmission, the pattern of PrP(Sc) dissemination was established in susceptible lambs (genotype VRQ/VRQ) sampled from 140 days post-insemination to the age of 4 months from either VRQ/VRQ ewes with PrP(Sc)-positive placentas or ARR/VRQ ewes with PrP(Sc)-negative placentas. In both VRQ/VRQ lamb groups, PrP(Sc) spatial and temporal accumulation patterns were similar, suggesting post-natal rather than in utero contamination.
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http://dx.doi.org/10.1099/0022-1317-83-10-2607DOI Listing
October 2002