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  Director : Michel Huerre (mhuerre@pasteur.fr)


  abstract

 

Histotechnology and Pathology is involved with its collaborators in the study of different experimental models of bacterial diseases that involves the respiratory system (Mycobacteria, Bordetella), digestive tract (Helicobacter, Shigella, Clostridium, Listeria), viral infections (Hepatitis B virus) and parasitic infections (Entamoeba, Leishmania, Aspergillus). Our Unit study the recruitment of inflammatory cells in tissues, especially dendritic leucocytes. We perform the phenotypic analysis of genetically modified mutant strain. The laboratory also carry out quantitative autoradiography on tissue sections or whole body sections using a beta-imager.



  report

cale

I Human pathology, expertises and collaborations.

In collaboration with Nice university and Ste Anne hospital, Toulon, we have performed an atlas on infectious diseases pathology, especially parasitic and fungal diseases. Elsevier. Collection " le pathologiste "

In collaboration with the International network of Pasteur institute we have initiated a multicentric study on emerging infections, focused on the role of histopathology.

II Experimental pathology

2-1-Pulmonary infectious diseases

We have studied the histopathology of lesions induced by different strains of Mycobacteria, Bordetella, and Neisseria, especially elementary lesions and local recruitment of dendritic cells. Virulence factors of Mycobacterium tuberculosis (Coll. S. Cole) and induced pulmonary lesions have been investigated. The rd1 gene is integrated to the genome of Mycobacterium tuberculosis (M.t) but not within the genome of Mycobacterium bovis BCG and Mycobacterium microti (Mm). The introduction of rd1 genes into the Mycobacterium BCG or Mm increases the virulence and induced similar lesions in a mouse and a guinea pig model to that induced by virulent strains of M.t. suggesting that rd1 genes plays a major role in the pathogenicity. Other programs are in progress in collaboration with the team of B. Gicquel and the reference center for Mycobacteria (G. Marchal and V. Vincent)

2-2 Digestive infectious diseases

2-2-1 Gastric diseases induce by Helicobacter pylori (Hp)(Coll. E. Touati & A. Labigne). We have studied the chronic gastritis induced by Hp and mutagen role on the gastric epithelium in the transgenic murine strain Big Blue l Lac I. Induction of mutagen effects and local production of NO correlated with the time course and severity of the gastritis and metaplasia, that are considered as precancerous lesions). We didn't observe dysplasia lesions neither carcinoma in this model.

Others programs are in progress especially the activation of NF-Kb , the role of the Nod protein and the study of geographic pathology induced by various strains of Hp from Cambodia and Oceania.

2-2-2 Pathology of the intestine: Listeria , Clostridium & Shigella

Listeria (Coll M. Lecuit & P. Cossart): Listeria infects the digestive tract and the group of P. Cossart demonstrated the role of E-cadherin. Virulent strains of Listeria monocytogenes express internalin, which is the ligand of E-cadherin. We have shown that transgenic mice expressing human E-cadherin become susceptible to infection induced by those virulents strains but not to non-virulents strains internaline negative which are not able to invade the intestinal barrier. Placental lesions in human pathology are being investigated.

Shigella (Coll P. Sansonetti et A. Phalipon) Different mutant strains of Shigella have been studied to investigate invasiveness and local inflammatory response. (see chapter 2-5)

2-3 Hepatic pathology

2-3-1 Hepatitis B virus and liver tumorigenesis (Coll. M.A. Buendia, P. Tiollais).

Transgenic mice expressing the c-Myc oncogene driven by Woodchuck Hepatitis Virus (WHV) regulatory sequences develop hepatocellular carcinoma with a high frequency. To investigate genetic lesions that cooperate with Myc in liver carcinogenesis, a genome-wide scan has been conducted for loss of heterozygosity (LOH) and mutational analysis of b-catenine in 37 hepatocellular adenomas and carcinomas from C57BL/6 x castaneus F1 transgenic mice. In 10 representative cases, comparative genomique hybridization analysis revealed recurrent gains at chromosomes 16 and 19, but losses or deletions involving mostly chromosomes 4 and 14 generally prevailed over gains. Thus, Myc activation in the liver might select for inactivation of tumor suppressor genes on regions of chromosomes 4 and 14 in a context of low genomic instability.

2-4-2 Entamoeba histolytica (Coll. N. Guillen, M.C. Rigothier)

The protozoan parasite Entamoeba histolytica is the causative agent of amoebiasis characterized by dysentery and liver abscess. The physiopathology of hepatic lesions can be reproduced in the hamster animal model by the administration of trophozoites through the portal vein route. Using immunohistochemistry combined with Beta-imager, we have studied the chronology of hepatic abcesses after inoculation of Entamoeba histolytica, in parallel with an histopathological analysis. This experimental model allow to study the pathogenesis and virulence of wild type and mutant strains of amoeba. ( see chapter 2-5)

2-4 Analyse phénotypique de lignées murines génétiquement modifiées (Coll. L. Gresh, M. Yaniv)

HNF1beta has an essential role in epithelial differentiation of the visceral endoderm. The inactivation of HNFbeta in the hepatocytes and bile ducts cells, using the Cre/Lox system leads to a severe jaundice, and dysmorphogenesis of gallbladder and biliary ducts. Mutant mice also lack interlobular arteries, which emphasizes the link between arterial and biliary formation.

2-5 Quantitative autoradiography (A. Cardona)

The unit has developped several applications of quantitative auoradiography using the Beta-Imager, combined with pathological studies. Especially we have studied the mucosal surfaces of the respiratory tract and the role of the secretory component of IgA, which is a crucial step in achieving efficient protection of the epithelial barrier (Coll A. Phalippon). This technique has been used in experimental amoebiasis to perform the quantification of the number inflammation foci during liver infection by Entamoeba histolytica (Coll N. Guillen).

This procedures have been used in the study of serotonin receptors of human monocytes and in the study of brain from TNF-a knock-out mice with and without LPS stimulation.

Photo 1: Amoebic liver abscess. Histology and immunohistochemistry.

Photo 2: Study of epithelial barreer and IgA secretory component in using the Beta-Imager.

Keywords: Pathology, histopathology, Infectious diseases, pathogenesis, beta-imager



  publications

puce Publications of the unit on Pasteur's references database


  personnel

  Office staff Researchers Scientific trainees Other personnel
  Alonso Françoise, falonso@pasteur.fr Fiette Laurence, pathologiste, Chargée de recherche, lfiette@pasteur.fr

Huerre Michel, pathologiste, Head of the Unit, mhuerre@pasteur.fr

Elies Laetitia, D.E.S.V. in Veterinary Pathology Ave Patrick, technician supérieur, pave@pasteur.fr

Cardona Ana, Research ingeneer, cardona@pasteur.fr

Chimy Marie Christine, technician, mcchimy@pasteur.fr

Khun Huot, technician, hkhun@pasteur.fr

Matondo Jeanne

Maurin Sabine, technician, smaurin@pasteur.fr

Tanguy Myriam, technician, mtanguy@pasteur.fr

Wuscher Nicole, technician, nwuscher@pasteur.fr


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