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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 Jörg Fritz (Department of Microbiology/Immunology) focuses on understanding how innate immune recognition of microbes by pattern recognition molecules (PRM) such as Toll-like receptors (TLR) and Nod-like receptors (NLR) translates into immunological memory for successful protection of the host. A particular focus is given to mucosal pathogens of the respiratory and gastrointestinal system where he is trying to understand how the expression pattern and activity of innate resistance effectors adapts to changes in the tissue milieu due to the availability of nutritional metabolites, the composition of the mutualistic microflora, or infection with pathogens. In this context he is studying the priming and function of innate lymphoid cells (ILC) and B lineage cells for their role in mucosal immunity instructed to commensals, pathobionts and pathogens.

The laboratory of Philippe Gros (Department of Biochemistry, Human Genetics) uses a genetic approach in mouse models of infection with Mycobacterium tuberculosis (tuberculosis), Plasmodium chabaudi (blood stage malaria), Plasmodium berghei (cerebral malaria), and Candida albicans to identify host 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 (with other members of the group). Gene mutations discovered in mice as affecting susceptibility to infections are validated in clinical specimens from humans living 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 master myeloid and lymphoid transcriptional regulators IRF1, IRF8, and STAT1. We are also developing bioinformatic tools to analyze rare and common variants identified in cohorts of unique patients suffering from acute infections or chronic inflammatory conditions, for enrichment of variants in genes regulated by these pro-inflammatory transcription factors.

The laboratory of Samantha Gruenheid (Department of Microbiology/Immunology) 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 infections with EHEC/EPEC. The lab uses a genetic approach to identify the genes and proteins controlling inflammatory response at the intestinal mucosa, and 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 laboratory of Danielle Malo (Departments of Medicine, Human Genetics) 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. -induced anemia.

The laboratory of Ana Nijnik (Department of Physiology) investigates the process of blood and immune cell differentiation from hematopoietic stem cells. The current work explores the molecular mechanisms through which histone-deubiquitinase (H2A-DUB) protein MYSM1 controls bone marrow function and lymphocyte production by regulating gene expression and genetic stability in hematopoietic progenitors.  In the future the program will expand to analyze the functions of other poorly characterized H2A-DUBs, using novel transgenic mouse and stem cell models currently in production. Other research interests include the immunomodulatory properties of natural and synthetic host-defense peptides and potential activities of this class of compounds on the bone marrow.

TThe laboratory of Maya Saleh (Departments of Medicine, Biochemistry, Microbiology/ Immunology) investigates signal transduction pathways in inflammation, apoptosis and immunity. The lab focus is centered on pathways 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 macrophages and innate lymphocytes in the intestinal submucosa and their role in promoting homeostasis or tumorigenesis of the overlaying intestinal epithelium.

The laboratory of Silvia Vidal (Departments of Human Genetics, Microbiology/Immunology) 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.