Ding Lab Research


Fig. 1Our current research program focuses on understanding how rotavirus (RV), an important enteric viral pathogen, interacts with the host innate immune system in the small intestine. RV is a major cause of gastroenteritis and diarrhea in young children, the immunocompromised and healthy adults, accounting for an annual death of approximately 215,000 people worldwide. Using a highly innovative human intestinal organoid model that comprise of primary human intestinal epithelial cells (IECs) and a recently developed RV reverse genetics system, I have examined in several aspects how RV successfully disarms the interferon (IFN) signaling pathway. I found that RV-encoded non-structural protein 1 (NSP1) hijacks the host cullin-3 E3 ligase complex to target β-TrCP for co-destruction at the proteasome, thereby inhibiting the NF-κB signaling (Fig. 1), challenging the current paradigm that NSP1 itself is a viral E3 ligase. I also made the unexpected discovery that VP3, the RV methyl- and guanylyl-transferase, induces the degradation of MAVS, pivotal to IFN activation in response to RNA viruses (Fig. 1). Taken together, these findings uncover novel and unique strategies employed by RV to dampen host innate immunity at the mucosal barrier. In addition, through fruitful collaborations with seasoned investigators who have provided considerable support in proteomics, genome-scale screens, and mouse genetics, we recently published a series of papers and just began to unveil the role and identities of host factors that regulate RV replication.


Moving forward, we will continue to utilize genetic and proteomic screening approaches and mouse models to dissect how RVs interact with (activate, evade, or suppress) the host innate immune system in the small intestine. Our long-term goal is to expand the ongoing RV research program to study other enteric microbes, both pathogens and commensals, and examine their interaction in vivo and in primary human intestinal organoids. Understanding the complex interplay between enteric viruses, bacteria, parasites, host metabolites and the intestinal immunity will expedite the development of new antiviral interventions (e.g. small molecule inhibitors, antibody therapeutics, and microbiome manipulation), and offer new therapeutic and prophylactic avenues to reduce the morbidity and mortality associated with the human enteric virus infections.

 

Current research areas of the lab include:
1) Identification and characterization of host factors that support or inhibit RV replication
2) Antiviral innate immune signaling pathways in the small intestinal epithelium
3) Innate immune evasion strategies employed by RV to successfully replicate in vivo
4) Molecular mechanisms of RV pathogenesis in vivo
5) RV host cell and tissue tropism and host range restriction