Nucleic Acid Sensors

Bacteria are embroiled in a constant struggle with virulent bacteriophages. This battle for survival spans millions of years of evolution. Throughout this struggle, bacteria and phages have evolved remarkably diverse strategies to protect themselves. Using cutting edge structural biology and biochemical techniques, the Knott Lab seeks to uncover the molecular details of how novel bacterial immune systems specifically sense foreign nucleic acids to protect against infection.

RNA remodeling and editing

The recognition of foreign viral RNA requires bacteria to discriminate self from non-self.  Bacteria do this using a combination of specific structures, patterns of nucleotide modification, and/or protein factors. We are investigating families of bacterial innate immune systems that hone in on these molecular differences to identify viral transcripts and protect the host from infection. With a structural and biochemical understanding of how these novel systems function, we seek to apply them as biotech tools. 

Guided abortive infection

Upon detection of phage RNA, a bacterium often drives abortive infection - a cellular response that offers a community herd immunity to viral infection. CRISPR-Cas13 is a programmable RNA-guided nuclease that upon specific recognition of a viral RNA drives abortive infection by degrading the transcriptome. Using structural biology, we seek to understand the molecular details of this process with an eye to apply our findings to the effective implementation of Cas13 as a tool in CRISPR-based RNA detection and diagnostics.

Precision RNA targeting

Bacteria have evolved strategies to precisely interfere with phage replication through specific nuclease activity targeted to phage transcripts. These DNA or RNA guided nucleases are poorly understood as prokaryotic adaptive immune systems. We are leveraging structural biology to uncover how they are steered towards viral RNA targets for precise interference. With a better appreciation of their mechanisms, we are looking to apply them as tools for the study of specific RNA targets in bacterial, plant or human cells.