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Research Themes

Members of the Complex Traits Program at the Bellini Life Sciences Building currently focus their research activity on several aspects of host: pathogen interactions, including early sensing of pathogens, inflammatory response, as well as innate and acquired immunity against bacterial, viral and parasitic infections. The current effort targets not only the host genes, proteins and response pathways involved, but also the microbial pathogenicity determinants that trigger such responses. The effect of these cellular and biochemical responses on the regulation of other important events, such as cell division, cell death and neoplastic transformation is also being investigated by members of the Group. Please see separate web pages for individual investigators of the Group.


The laboratory of Samantha Gruenheid studies the pathogenesis and host response to infection with enterohemorrhagic and enteropathogenic Escherichia coli (EHEC/EPEC), a group of water and food-borne Gram-negative bacteria responsible for acute cases of diarrheal disease with potentially fatal complications. The lab studies inbred mouse strains that are either resistant or susceptible to infection with the mouse pathogen Citrobacter rodentium, a model of human the EHEC/EPEC. The lab uses a genetic approach to identify the genes and proteins controlling inflammatory response at the intestinal mucosa, and over susceptibility to lethal infection. On the pathogen side, the laboratory studies a group of EHEC and EPEC proteins that are injected into host intestinal epithelial cells by the bacterial by Type III secretion system to interfere with host functions leading to disease. The ability of one of these bacterial proteins (NleA) to interfere with the normal function of the cell Golgi’s apparatus is being investigated.


The laboratory of Maya Saleh investigates signal transduction pathways in inflammation, apoptosis and immunity. The lab focus is centered onpathways driven by pattern recognition receptors (PRRs), their activation by microbes (both commensals and pathogens) and endogenous danger signals, and the signaling events linking these PRRs to effectors of inflammation. The recently identified family of Nod-like receptors (NLRs), which assemble “inflammasomes” and activate the inflammatory caspases, is a major focus of study. The lab explores PRR biology in the context of infectious disease (sepsis, infectious colitis, malaria), immune-mediated inflammatory diseases (IBD) and tumorigenesis. The group is also interested in investigating the crosstalk between the commensal microflora, the activation of resident myeloid cells in the intestinal submucosa and their role in promoting tumorigenesis of the overlaying intestinal epithelium.

 

The laboratory of Silvia Vidal investigates the molecular interactions between several human pathogenic viruses and the host innate response to virus infection using mouse genetic models. Specifically, they address the role of activating natural killer cell receptors in both recognition of the infected cell and regulation of natural killer cell activity during cytomegalovirus infection. Other topics of the lab are the role of type I-IFN dependent and independent mechanisms that control coxsackievirus-mediated myocarditis, and the genetic basis of the dysregulated inflammatory response leading to influenza pneumonia. A second goal, as part of a collaborative group, is to establish mouse chemical mutagenesis and large-scale phenotyping to identify defective host resistance in all major classes of microbial pathogens as a means to provide a comprehensive understanding of the key physiologic pathways of protective immunity.


The laboratory of Danielle Malo works on the identification and characterization of genes involved in the host immune response to pathogenic Salmonella using mouse models of the disease and forward functional genetics. Salmonella infections in humans cause diseases (typhoid fever, salmonellosis and invasive non-typhoidal salmonellosis) that are an increasingly important public health issue both in developed and developing countries.The lab is using different models of infection (typhoid-like, chronic carriage and typhlocolitis) and genetic approaches (positional cloning of Mendelian and complex phenotypes and chemical mutagenesis) to study the complex mechanisms underlying the host response to Salmonella infection. Different pathophysiological and immunological aspects of Salmonella infections are being studied including recognition of Salmonella by phagocytic cells, bacterial killing mechanisms, cell recruitment at the site of infection and the pathogenesis of Salmonella-induced anemia.

 

The laboratory of Philippe Gros uses a genetic approach in mouse models of infection with Mycobacterium tuberculosis (tuberculosis), Plasmodium chabaudi (blood stage malaria), Plasmodium berghei (cerebral malaria), Legionella pneumophila, Candida albicans, and Chlamydia pneumoniae to identify hos t genes and proteins that affect onset, progression and outcome of these infections. The mouse genetic discovery platforms include inbred mouse strains, AcB/BcA recombinant congenic strains and ENU chemical mutagenesis (wi th other members of the group). Gene mutations discovered in mice as affecting susceptibility to infections are validated in clinical specimens from humans leaving in endemic areas of diseases and/or in rare patients suffering of specific non-syndromic immunodeficiencies. Genes and proteins being studied include the phagosomal iron transporter Slc11a1 (Nramp1), the bacterial flagellin intracellular sensor of macrophages Birc1e (Naip5), and the innate immune response transcriptional regulator IRF8.