Final Report Summary - BACNK (Recognition of bacteria by NK cells)
Natural Killer (NK) cells which are part of the innate immunity system are well known for their ability to kill viruses and tumors. The killing of NK cells is controlled by NK inhibitory and activating receptors. However we still do not completely understand how the activity of NK cells is controlled partially because because the ligand spectrum recognize by activating and inhibitory NK cell receptors is not fully known and the receptor repertoire of NK cells is not fully elucidated. In the framework of this grant we demonstrate that one of the NK activating receptors NKp46 (Ncr1 in mice) is involved in type II diabetes, in graft-versus-host, in allergic responses, in influenza and in the recognition of additional viruses. We also studied basic NK cell biology questions and identified new receptors that control NK killing of tumors and viruses. We have also generated various molecular biology tools and new mouse models to enable our investigations. These reagents are avalible to the scientific community.
We know very little about the interactions between NK cells and bacteria and fungi and the most fundamental questions in this field remain largely unknown. We do not know how many intracellular and extracellular bacteria are recognized by NK cells, whether NK cells recognize gram positive or gram negative bacteria, whether anaerobic, or aerobic bacteria are recognized, how bacteria are recognized and what are the functional consequences of such recognition. Similarly, questions exist regarding fungi. In short we do not understand the rules governing the interaction between specific NK cell receptors bacteria and fungi.
Using a systematic screen of bacteria that interact with NK cells and mutagenesis approach, we found that Uropathogenic Escherichia coli (UPEC) adheres to NK cells primarily via its type I fimbriae and employs its hemolysinA toxin to kill NK cells.
We also showed that Fusobacterium nucleatum inhibits the activity of immune cells by binding to human, but not by mouse TIGIT, an inhibitory receptor present on all human NK cells and on various T cells. In additon we discovered that Candida Glabrata is directly recognized and killed by NK cells via the interaction of NKp46 (Ncr1) in mice with the Candida Glabrata EPA proteins.
We know very little about the interactions between NK cells and bacteria and fungi and the most fundamental questions in this field remain largely unknown. We do not know how many intracellular and extracellular bacteria are recognized by NK cells, whether NK cells recognize gram positive or gram negative bacteria, whether anaerobic, or aerobic bacteria are recognized, how bacteria are recognized and what are the functional consequences of such recognition. Similarly, questions exist regarding fungi. In short we do not understand the rules governing the interaction between specific NK cell receptors bacteria and fungi.
Using a systematic screen of bacteria that interact with NK cells and mutagenesis approach, we found that Uropathogenic Escherichia coli (UPEC) adheres to NK cells primarily via its type I fimbriae and employs its hemolysinA toxin to kill NK cells.
We also showed that Fusobacterium nucleatum inhibits the activity of immune cells by binding to human, but not by mouse TIGIT, an inhibitory receptor present on all human NK cells and on various T cells. In additon we discovered that Candida Glabrata is directly recognized and killed by NK cells via the interaction of NKp46 (Ncr1) in mice with the Candida Glabrata EPA proteins.