Unit: Histopathology

Director: Michel-René Huerre

The Histotechnology and Pathology Unit is part of the Microbial Pathogenesis Department. We study the use of histology and related techniques, bacterial infections (mycobacteria, gram-positive and gram-negative bacteria and spirochetes), viral infections (coronavirus, HIV, Herpes virus 8, HTLV-I) and parasitic diseases (Entamoeba, Aspergillus) in humans and in animal models. We also study the mechanisms (Toll-like receptors) and transcription factors (hnF1) involved in inflammation. A Beta-imager is used for quantitative autoradiography on tissue or whole-body sections in several models of infectious diseases (experimental), to study the pharmacodistribution of neuroreceptors and to demonstrate the involvement of genes in development.

I-Infectious diseases in human and experimental pathology

1-1Bacteria

Mycobacteria (collaborations with the Mycobacteria Unit, B. Gicquel, the Bacterial Molecular Genetics Unit: S. Cole, P. Brodin; the Reference Centre for Mycobacteria: G. Marchal and the Immune Regulation Unit: C. Leclerc & L. Majlessi). Mycobacteria are a large, ubiquitous group of pathogens causing chronic inflammation. They generally have a bipolar histological spectrum – granulomatous with activated macrophages containing a few pathogens, or histiocytic, containing numerous bacteria – according to the pathogenicity of the bacteria and the immune status of the host. Several experimental models have been used to study the lesions induced by several types of characterised mutant strain (metabolic strains, rd1 BCG etc.) in which pathogenicity is correlated with the in situ production of ESAT-6 protein. The early host response has been studied in an elegant model showing that, after intradermic inoculation, polymorphonuclear cells play a much more important role than monocytes and dendritic cells.

Pseudomonas (collaboration with M. Chignard). We have shown in transgenic models that TLR2/4 is not involved in the pathogenesis of Pseudomonas-induced pneumonia.

Helicobacter (collaboration with the Mucosal Pathogenesis Unit, A. Labigne, E. Touati and H. de Reuse). We have investigated the chronic gastric lesions induced by Helicobacter pylori (Hp) mutant strains and mutagenic effects on the gastric epithelium in a transgenic mouse model (Big blue I lac z).

We have studied the persistence of Staphylococcus aureus in the nasal cavity in TLR2/4 transgenic mice and have demonstrated higher levels of colonisation in mice lacking TLR2, but not in mice lacking TLR4. We have also demonstrated, in a quail model, that Clostridium is the aetiological agent of necrotising colitis in children (collaboration with the Faculté de Pharmacie, M.J. Butel)

1-2 Viruses

Several models of coronavirus infection have been studied. (collaboration with P. Marianneau, H. Contamine, Lyons, N. Escriou & S. van der Werff, IP Paris). The bronchial epithelium was found to be a prime target during the first week of infection and the recruitment of inflammatory cells was shown to continue throughout the second week. These models can be used for the testing of vaccine candidates. In terms of human diseases, several series of Kaposi's sarcomas from Morocco, central Africa and South America have been studied. Herpes virus is endemic in these geographic areas and viral load and the nuclear integration of the provirus were found to be correlated with the density of spindle cells, which was in turn correlated with the level of immunosuppression (according to clinical profile; collaboration with A. Gessain, Viral Oncology, IP). The induction of the disease by HIV has been studied in two experiments: a) In collaboration with F. Barre-Sinoussi, the Retrovirus Unit; E. Menu has tested an original protocol involving the embedding of the placenta in a synthetic medium. Histological studies have demonstrated that architecture is preserved until day 10, and b) In collaboration with the team of Y. Rivière, SHIV challenge induces the loss of vaccine-induced CD4+ T cells.

Parasites and fungi

Entamoeba histolytica. (Liver amoebiasis. M.C. Rigothier and N. Guillen, Cellular Biology of Parasitism Unit). The kinetics of the inflammatory reaction and the role of mobility have been studied in the hamster model.

Aspergillosis (M. Chignard, V. Balloy, M. Si-Tahar; Pharmacology Unit and J.P. Latge, A. Beauvais, Aspergillosis Unit). Lung lesions have been characterised in various experimental models of invasive aspergillosis. Vinblastine treatment induced acute neutropenia and resulted in more severe aspergillosis, with numerous hyphae but no inflammatory reaction. Several mutant pathogenic and non-pathogenic strains have been studied and the role of TLR has been investigated: TLR 2 was found to be involved in experimental aspergillosis.

II- . Cancer in human Pathology and phenotypic analysis of genetically modified strains

2-1 Hepatoblastoma (M. Semeraro and M.A. Buendia, University of Bologna and M. Fabre, Kremlin Bicetre hospital. Hepatoblastoma is a rare tumor arising in children with an increased expression of alphafoetoprotein. ; Detection of genes involved in the development of embryonic hepatocyte and tumor progression is the main goal of this program.

2-2 HNF1 β (L. Fiette in collaboration with L. Gresh, E. Fisher, Genetics and Disease Unit) Hepatocyte nuclear factor 1beta (HNF1beta) is a homeoprotein predominantly produced in renal, pancreatic and hepatic epithelia. We have shown that mice with kidney-specific HNF1beta inactivation develop polycystic kidney disease.

2-3 SW1/SNF and SNF5. These factors are involved in hepatic development. Their inactivation induces hypoglycaemia, a defective glycogen storage and defects in hepatic differentiation.

III- Quantitative autoradiography (Ana Cardona). The unit has developed several applications for quantitative autoradiography, using the beta-imager combined with pathological studies to demonstrate the topography of labelled molecules within tissues, cells or whole-body sections. We have used these techniques to characterise several ligands of oxidative metabolites derived from 5-hydroxyoxindole and isatin (collaboration with M. Crumeyrolles INSERM U513, UFR Medécine, Université Paris XII, Val de Marne) These techniques have made it possible to study, in a rat model, the pharmacodistribution of sialorphin, the first natural inhibitor of NEP-encephalinase, to be characterised in mammals (collaboration with C. Rougeot. Pharmacology and Neuroendocrine Regulation Unit).

In collaboration with F. Blanchet and Oreste Acuto from the Molecular Immunity Unit, we have studied new mechanisms involved in CD28 signalling.

Photos : Demonstration of Coronavirus in epithelial cells of guinea pig? Day 2 after inoculation. Streptavidin peroxidase method X 200

Keywords: Infectious diseases, pathogenesis, transgenic methodology, Autoradiography


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