The Histotechnology and Pathology unit of research and expertise includes a pathology unit and Pharmacology platform.

Research conducted in the Pathology laboratory over the period 2008-2009 has focused on the various patterns of inflammation in infectious diseases of the lung and digestive pathology.

Infectious diseases of the lung

Lung infections represent the first cause ofdeath due to infection. In our unit, we use human pathology and animal models to study the pathology and pathogenesis of lung infections caused by bacteria (Pseudomonas, Neisseria, Staphylococcus), fungi (Aspergillus) and viruses (Myxovirus). We have thus investigated pathological features induced by Pseudomonas aeruginosa& Burkholderia cenocepaciaand associated TLR pathways (in collaboration with M. Chignard, J.M. Sallenave, and Mustapha. Si Taha). We recently showed that inflammation induced by Pseudomonas cenocepacia is reduced in MyD88-/- deficient mice. Another study, carried out in collaboration with R. Ramphal and M. Chignard, focused on the effects of various strains of Pseudomonaswith and without the T2 and T3 toxin secretion sytem.

In a recent investigation of Neisserialung infection (with M. Kheir-Taha), we demonstrated that hyperexpression of the transferrin gene promotes dissemination of Neisseria meningitidis.

In collaboration with O. Dussurget and J.M. Cavaillon, Gregory Jouvion in our unit studied Staphylococcus pneumonia, focusing particularly on the involvement of Nod2. The study of Bacillus anthracis with and without capsula and toxins (in collaboration with P. Goossens and M. Mock) has shown a delicate balance between the specific effects of toxins and the extensive interaction between Bacillus anthracis and the endothelium. These patterns are observed in the systemic vascular system (liver, spleen). The pathological effects of Aspergillus fumigatus have been characterised in various models of immuno-depression induced by corticosteroids, vinblastin and cycloheximide (O. Granet).

We have also studied acute lung pneumonia induced by Myxovirus. For these studies, several human cases and a mouse model of H1N1 were analysed using immunohistochemistry. H1N1 virus was found in bronchial cells, macrophages and monocytes during the first days of infection and a vaccine candidate was successfully tested (N. Escriou and S. van der Werff).

Digestive pathology

Helicobacter pylori (Hp) induces ulcers, chronic gastritis and is a co-factor involved in stomach carcinoma. A multicentric study is underway within the Pasteur Institute international network (Antananarivo, Pnom Penh, Dakar, Noumea, Algiers, Athens). The genetic diversity of Hp ( Cag a and vac a) is correlated with its pathology and the patterns of inflammation. In parallel, we are studying the time course and patterns of inflammation in transgenic mice. Indeed, H. pylori infection has been shown to have a mutagenic effect in the Big Blue mouse model, due partly to oxidative DNA damage. We investigated the effects of deficiency in the DNA glycosylase OGG1 on the inflammatory and genotoxic host response to infection. Inactivation of OGG1 in mice reduced the severity of inflammatory lesions and abolished the H. pylori-inducedmutagenic effect in gastric epithelial cells levels.

Several models of inflammatory bowel diseases (IBD) have been investigated in the unit, including a new mouse model deficient for elafin.

The use of radioimagers in quantitative autoradiography (Beta-Imager and Micro-Imager: Ana Cardona)

Radioimagers provide an alternative to film autoradiography for in situquantitative studies of tissue sections. They can detect tritium and the usual beta-emitting isotopes in electrophoresis gels or membranes, tissue sections on glass slides and whole body sections. Their main applications are in: receptology (localisation and characterisation of isatin 5- hydroxyoxindole and acetyl choline receptors on brain sections), in situhybridisation (quantitative ISH of Dyrk1a in embryonic 152F7 brain), in vivopharmacokinetics and the biodistribution of molecules (oxindole and indole; peptidoglycan).

Ventura Grasiella M. de C., Balloy V., Huerre M., Plotkowski M.C.M., Chignard M., Si-Tahar M. Lack of MyD88 protects immunodeficient mice against fatal lung inflammation triggered by the opportunistic bacteria Burkholderia cenocepacia. J. Immunol.2009,183(1):670-676

- Glomski I., Dumetz F., Jouvion G., Huerre M.R., Mock M., Goossens P. Inhaled non capsulated Bacillus anthracisin A/J Mice: nasopharynx and alveolar space as dual portals of entry, delayed dissemination and specific organ targeting. Microbes and Infection.2008 oct 10 (123-13);1398-404

- Piris-Jimenez A., Corre J.P., Jouvion G., Candela , Khun H., Goossens Encapsulated Bacillus anthracis interacts closely with liver endothelium. Journal of Infectious Diseases, 2009, 200,(9),1381-1389

-Brock M., Jouvion G., Droin-Bergere S., Dussurget O., Nicola M.A., Ibrahim-Granet O. Bioluminescent Aspergillus fumigatus: a new tool for drug efficiency testing and in vivo monitoring of invasive aspergillosis. Applied and Environmental Microbiology. 2008,74 (22) 7023-7035

- Schappi M., Deffert C., Fiette L., Gavazzi G., Herrmann F., Belli D., Krause KH, Branched fungal beta-glucan causes hyperinflammation and necrosis enterocolitis in phagocyte NADPH-deficient mice. J. Pathol. 2008,214 (4):434-444

- Behgadi W, Porcherie A.S., Schneider B., Dubayle D., Peronet R., Huerre M.R., Watanabe T., Ohtsu H., Louis J., Mecheri S.Med. Sci. 2009, 4: 377-381

Grailhe R., Cardona A., Even N., SeifI, Changeux JP., Cloëz-Tayarani I. Regional changes in the cholinergic system in mice lacking monoamine oxidase A. Brain Research Bulletin2009,78: 283–289.

Lepagnol-Bestel AM, Zvara A., Maussion G, Quignon F., Ngimbous B., Ramoz N, Imbeaud S., Loe-Mie Y.,Benioud K., Agier N.,Salin P., Cardona A, Khun-Savatovski S., Kallunki P, Delabar JM., Puskas L.,Delacroix H., Aggerbeck L., Delezoide AL, Delattre O.,Gorwood P.,Moalic JM, Simonneau M. DYRK1A interacts with the REST/NRSF-SWI/SNF chromatin remodelling complex to deregulate gene clusters involved in the neuronal phenotypic traits of Down syndrome". Human Molecular Genetics 2009, 18(8): 1405-1414.