Dr. C. Cheng Kao, Principal Investigator

Reseach in the Kao Lab

The Kao Lab's research is in two broad areas: viral processes, with emphasis on RNA virus replication, and innate immune receptors that detect viruses. For each of these two areas, we have two developed systems. In addition, the Kao lab is interested in building techniques to facilitate research and drug development.

Innate Immunity

Multiple, at least partially overlapping, pathways are used to detect RNAs and DNAs during viral infection. During RNA virus infection, double-stranded RNAs (dsRNA) generated during replication and uncapped transcripts can serve as pathogen associated molecular patterns recognized by innate receptors. Agonist binding by these receptors can result in changes in signal transduction that can lead to establishment of antiviral response as well as mediate an adaptive immunity. Improper regulation of signaling by these receptors could result in inflammation-associated responses. It is therefore important to be able to modulate the responses by the innate immune receptors. We study two sensors of RNA virus infections, RIG-I and Toll-like receptor 3. The two receptors work at different locations in the cells to activate cellular stress responses and also the production of the cytokines that will change gene expression to better prevent the spread of viral infection.

i. Toll-Like receptor 3

The Toll-like receptor 3 (TLR3) detects viral double-stranded (ds) RNAs and initiates innate immune responses. While important in limiting viral infection, prolonged TLR3 signaling can lead to inflammation and tissue injury. TLR3 signaling must therefore be tightly regulated. Our project seeks to understand the regulation of TLR3 signaling using cell-based and biochemical approaches. More specifically, we study how TLR3 traffics in cells between the plasma membrane and endosomes as well as the factors that act activate and suppress signaling by TLR3.

ii. RIG-I Receptor

The Retinoic acid inducible gene I (RIG-I) encodes a receptor that recognize RNAs in the cell's cytoplasm. The RIG-I protein contains two N-terminal caspase recruitment domains (CARD), a central DExD/H RNA helicase domain and a C-terminal 190 amino acids that forms a regulatory domain. The regulatory domain interacts with the helicase domain and the CARD signaling domain in the absence of ligand. Upon agonist binding, RIG-I undergoes a conformational change to expose the N-terminal signaling CARD domain and may also cause multimerization of RIG-I. The exposed CARDs can then interact with and activates its adaptor protein IPS-1 (also known as MAVS, VISA and Cardif), a mitochondrial membrane protein, to activate signal transduction through the transcription factors IRF3 and NF-kB and increase cytokine production.

RNA Virus Infection and Replication

i. Brome Mosaic Virus

Viral capsid proteins have many essential roles during a virus infection, including the regulation of translation, defense against cellular innate immune detection, and to regulate RNA replication. We study how the capsid protein of the simple icosahedral virus, brome mosaic virus, interacts with the viral RNA to regulate gene expression, to reconfigure the shape of the RNA during encapsidation, and mediates entry into cells.

ii.Hepatitis C Virus

Hepatitis C virus (HCV) infects approximately 2% of the world's population and is the primary cause of liver transplants in the United States. Based on lessons learned from diseases such as AIDS, HCV RNA replication is a promising target for antiviral development. However, the replication of all viruses with plus-strandRNA genomes is poorly understood, especially at the biochemical level. The overall goal of our research is to understand the mechanism of RNA virus replication. More specifically, we seek to study how RNA synthesis is regulated at different stages of synthesis, the mechanistic basis for drug resistant mutations in the polymerase and how the polymerase interacts with membranes and other hepatitis C virus-encoded proteins.

iii.Norovirus

Noroviruses (genus Norovirus, family Caliciviridae) are responsible for more than 90% of all epidemic non-bacterial gastroenteritis outbreaks in the United States and they are now recognized as the second leading cause of deaths due to gastroenteritis. Human noroviruses (HuNoVs) are one of the most poorly characterized groups of plus-strand RNA viruses, because of their inability to grow in cultured cells and/or lack of a robust small animal model and hence has been difficult to study and manipulate for the development of anti-noroviral therapeutics. The discovery that the murine norovirus (MNV) replicates in cell culture and mice has made MNV an attractive model for the studies of NoV molecular biology. The overall goal of our research is to understand the mechanism of norovirus virus replication. More specifically, we seek to study how norovirus RNA synthesis is regulated at different stages of synthesis, the mechanistic basis for polymerase drug resistance and polymerase interactions with norovirus structural and non-structural proteins as well as host proteins.

Research Overview Collage
Dr. Cheng Kao- PI

Recent Publications

Ni P, Cheng Kao C. Non-encapsidation activities of the capsid proteins of positive-strand RNA viruses. Virology.2013.Nov;446(1-2):123-32. doi: 10.1016/j.virol.2013.07.023. Epub 2013 Aug 27. PMID:24074574

Park IW, Ndjomou J, Wen Y, Liu Z, Ridgway ND, Kao CC, He JJ.Inhibition of HCV Replication by Oxysterol-Binding Protein-Related Protein 4 (ORP4) through Interaction with HCV NS5B and Alteration of Lipid Droplet Formation. PLoS One. 2013 Sep 17;8(9):e75648. PMID:24069433

Ni P, Vaughan RC, Tragesser B, Hoover H, Kao CC. The Plant Host Can Affect the Encapsidation of Brome Mosaic Virus (BMV) RNA: BMV Virions Are Surprisingly Heterogeneous. J Mol Biol. 2013 Sep 13. PMID: 2403642

Leen EN, Kwok KY, Birtley JR, Simpson PJ, Subba-Reddy CV, Chaudhry Y, Sosnovtsev SV, Green KY, Prater SN, Tong M, Young JC, Chung LM, Marchant J, Roberts LO, Kao CC, Matthews S, Goodfellow IG, Curry S.Structures of the compact helical core domains of feline calicivirus and murine norovirus VPg proteins. J Virol. 2013 May;87(10):5318-30. Epub 2013 Mar 13. PMID:23487472

Singh D, Qi R, Jordan JL, San Mateo L, Kao CC. The human antimicrobial peptide LL-37, but not the mouse ortholog, mCRAMP, can stimulate signaling by poly(I:C) through a FPRL1-dependent pathway. J Biol Chem. 2013 Mar 22;288(12):8258-68. Epub 2013 Feb 5. PMID:23386607