Disease tolerance by the heat shock response

• Applicant: Professor Dr. Sebastian Weis
• Subject Area: Gastroenterology ; Immunology
• Term: from 2012 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 233479293

Living organisms use different evolutionary conserved defense strategies to survive infections. The best recognized of these is resistance to infection, which relies on the capacity of the infected host to mount an appropriate innate (i.e. inflammatory) and/or adaptive immune response reducing its pathogen load. Disease tolerance is a less well-recognized defense strategy that limits the extent of tissue damage associated with infection, without targeting directly the pathogen. Presumably, disease tolerance is controlled by a number of transcriptional master regulators that provide cellular adaptation to different forms of stress. We hypothesized that the heat shock factor 1 (HSF 1), a master regulator of the heat shock response, confers tissue damage control and limits the pathologic outcome of infectious diseases without targeting directly pathogens, thus conferring disease tolerance. This application to the DFG is aimed at pursuing a 2 year fellowship at the laboratory of Professor Miguel P. Soares at the Instituto Gulbenkian de Ciência, Oeiras, Portugal, testing this hypothesis in mice subjected to viral, bacterial or protozoan infections. The hypotheses to be tested are novel and therefore the data obtained should provide important information to our current understanding of host microbial interactions, contributing to the development of new therapeutic approaches for the treatment of infectious diseases. The hypotheses and specific aims of this proposal are:Hypothesis 1: That the heat shock response confers disease tolerance to systemic infections.Specific Aim 1: Assess whether ubiquitous deletion of the Hsf1 allele impairs disease tolerance to influenza virus, polymicrobial and/or Plasmodium infections as compared to control mice.Hypothesis 2: That the heat shock response acts in a tissue specific manner to confer disease tolerance to systemic infections.Specific Aim 2: Assess whether deletion of the Hsf1 allele in myeloid or endothelial cells, impairs disease tolerance to influenza virus, polymicrobial and Plasmodium infections.Hypothesis 3: That the heat shock response confers disease tolerance to systemic infections via regulation of gene expression in macrophages and/or endothelial cells.Specific Aim 3: Identify and characterize the mechanism via which HSF1 regulates the expression of genes associated with macrophage and/or endothelial cell activation.Hypothesis 4: That pharmacologic activation of HSF1 can be used therapeutically to confer host protection against systemic infections.Specific Aim 4: Assess whether pharmacologic induction of HSF1 acts therapeutically against influenza, severe sepsis and severe forms of malaria in mice.

• DFG Programme: Research Fellowships
• International Connection: Portugal
• Host: Miguel Che Soares, Ph.D.