Research

 

Overview

The Hancks Lab uses insights from the elaborate chess match between hosts and viruses to characterize immune defenses and discover cellular functions. We exploit genomics scars of host-pathogen conflict to identify novel battlegrounds, including host and viral factors, that shape infection outcomes.

We like the chess match analogy as it nicely demonstrates three principles:

  1. there are many pieces on the board with some more powerful than others - queens vs. pawns; where queens are master regulators.

  2. different pieces move in different ways - these are mechanisms

  3. one can learn from their opponent how to play their pieces including new "moves" of their piece – this is referring to lessons from viral mimics and viral-encoded antagonists of cellular functions

 

Viral genes that were stolen from infected cells are one of our favorite evolutionary "scars." These factors are derived from host genes and thus viral homologs referred to as virologs. Historically, virologs have led to key discoveries in immunity as well as cell biology - ranging from essential signaling pathways as in IL17 to oncogenes like SRC, MYC, and RAS. Furthermore, the oncogenic basis of mutated cellular SRC was worked out using comparative analysis with the virolog encoded by a chicken retrovirus. We use a variety of systems and methodology to address our research questions, such as mouse models, yeast, cell culture, and next-generation sequencing applications.

 

Ongoing research:

One of our major interests lies in mitochondria due to our identification of several virologs encoding doppelgängers of ultraconserved, accessory electron transport chain subunits lacking known functions. These virologs led to our discovery of the Mitochondrial Stress Response Circuit (MISTR) [Sorouri et al., PLOS Biology 2020], which consists of three related, but poorly characterized, micropeptides: MISTR1 (NDUFA4), MISTR AntiViral (MISTRAV/C15ORF48), and MISTR Hypoxia (NDUFA4L2). Our research has linked these factors to cell death outcomes. Subsequent research has implicated these factors in inflammatory signaling.


An interesting dimension to the MISTR circuit, which our data showed, is that one arm of the pathway appears to be regulated an exonic microRNA - miR-147b - embedded within the 3'UTR of one of the protein-coding components (MISTR AV), which targets its rapidly evolving paralog. Our studies, as well as the gene structure of MISTR AV/miR-147b, hints at a yet to be unearthed post-transcriptional switch regulating levels of the protein and its nested miRNA.

MISTR factors - MISTR1 and MISTRAV - display all three key hallmarks of pivotal immune defense factors; common to the broad-acting OAS1 and the executioner of necroptosis, MLKL (Palmer et al., Molecular Biology & Evolution 2021). Collectively, emerging data suggest unappreciated dimensions of electron transport chain complex composition and abundance in regulating immune responses (Sorouri, Chang, and Hancks, MBio 2022). This battleground is ancient given the virologs are encoded by viruses that infect diverse hosts - mammals, fish, and algae. Notably, cellular MISTR factors are ubiquitous in nature and even present in yeast; where they also remain largely uncharacterized. Overall, the MISTR circuit illustrates the power of using the chess match between hosts and viruses, especially virologs, to identify exciting untapped areas associated with textbook biology.

Additional projects are related to the characterization of other factors that display genomic scars of evolutionary conflict. For these other candidates, we are developing cell culture systems and animal models to study their function. Furthermore, we have projects examining early stages of the antiviral response and how viruses try to evade it. For these studies, we take advantage of several model and biomedically relevant viruses: the prototypical poxvirus vaccinia, herpes simplex virus-1 (HSV-1), and vesicular stomatitis virus (VSV).