The role of miR-132 in the immune response to pathogens

Infectious diseases are the second most common cause of death worldwide. Infections are particularly dangerous for people with weak immune systems, such as children, malnourished individuals, or individuals suffering from AIDS. Discovering the ways through which our body normally fights an infection and boosting these mechanisms in high-risk individuals is a valuable approach to treating, curing, or preventing diseases caused by infection. This is the main focus of our research plan. We are particularly interested in a class of genes that was recently discovered. These genes are called 'microRNAs' and unlike normal genes, do not generate proteins. Until ten years ago these parts of our genome were considered to be junk DNA, but we now know that they are as important as normal 'protein-coding' genes. In particular, we have discovered that miR-132 is a microRNA that normally prevents an exaggerated response to infection (an unnecessarily strong immune response would also lead to serious illness). We found that pathogens exploit this genetic Achilles' heel to escape from the immune system. These pathogens include viruses and parasites that significantly contribute to the global disease burden, especially in developing countries and among HIV-infected individuals. In particular, our studies suggest that miR-132 controls multiple arms of the immune response to the causative infectious agents of diseases such as Leishmaniasis. In addition, our studies indicate that inhibiting the activity of miR-132 boosts the anti-pathogen immune response. Therefore, we propose that blocking the action of miR-132 could limit infection with a broad range of pathogens and delay or prevent disease. To test this, we will investigate in detail how miR-132 works during infection and test the potential of anti-miR-132 drugs in experimental models of infection. In the proposed research programme, we aim to uncover crucial secrets of how our body fights infection and set the basis for the clinical use of agents that antagonize miR-132 for the treatment of infectious diseases.

An appropriate immune response requires coordination of a multitude of initiating, amplifying and resolving signals and processes. Understanding the mechanisms that ensure an optimal equilibrium between activating and regulatory immune processes is of utmost importance for the treatment of infectious diseases. In this project, we propose that microRNAs act as molecular integrators of the immune response through their ability to concurrently regulate expression of several genes in a tissue- and cellular state-specific manner. In particular, we will investigate the function of miR-132, a critical component of the regulatory arm of the innate immune response. We have recently found that genetic deletion of miR-132 provides protection against infection and infection-associated tissue remodeling. Our studies suggest that miR-132 negatively regulates inflammation by simultaneously limiting the interferon response and promoting angiogenesis. These findings will be used as a solid platform in the proposed project, which will investigate in-depth the effects of miR-132 on the inflammatory response to infection. Using unique gene knockout models and a tractable in vivo infection model, we will dissect the mechanisms employed by miR-132 at the cellular and molecular level, focusing on the role of miR-132 in macrophages and endothelial cells and its interactions with p300, a master transcriptional co-activator, and Rasa1, a fundamental signaling effector. In addition to gaining crucial insight into immunological mechanisms, the proposed studies will reveal how miR-132 interacts with its targets in a context-dependent manner to perform its function in different cell types. Therefore this project will result in significant conceptual advancements in the fields of immunology and microRNA biology, and also set the foundation towards the development of novel therapeutic approaches in infectious diseases.

A better understanding of the mechanisms underlying immunity can lead to improved treatment of infectious and autoimmune diseases. In this respect our proposal will provide significant clues regarding the role of microRNAs, and in particular miR-132, in inflammation. Our work will reveal microRNA-mediated mechanisms linking the vascular and inflammatory responses to infection. This will open up new routes for combinatorial therapies in infectious diseases, and identify therapeutic targets (such as miR-132) that act as hubs of multiple dysregulated, disease-associated processes during disease development. This is of notable value as miR-132 is a clinically targetable molecule. Basal expression of miR-132 outside the brain is low, but inducible upon pathological stress such as infection, autoimmune disease, and cancer. Our studies will focus on experimental models investigating the potential protective role of miR-132 inhibition against infection. Positive results in these models would have strong translational potential as the Locked Nucleic Acid (LNA) microRNA inhibitors used in our studies are clinically relevant (LNA inhibitors are currently used in the clinic as the first microRNA therapeutics) and do not cross the blood-brain barrier, which will prevent undesired effects in the brain where miR-132 basal expression is significant and functionally essential. During this project, we will study the function of miR-132 in an experimental model of infection. Therefore the primary future beneficiaries of our research could be individuals affected by complex infectious diseases, for which treatments are currently limited, such as Leishmaniasis. These conditions contribute significantly to the global disease burden. For example visceral Leishmaniasis is a major health problem in India and parts of South America (where leishmania infection is endemic), and a major cause of mortality and morbidity among immunosuppressed individuals, such as people infected with HIV, worldwide (including Europe and the UK). We expect that the proposed studies will be a major step towards the future use of anti-miR-132 agents for the treatment of these infectious diseases. Furthermore, our mechanistic findings will enhance our understanding of other conditions characterized by miR-132 induction such as chronic inflammatory conditions and cancer, which in the longer term could benefit individuals suffering with these diseases.