Lab Website: https://medicine.uiowa.edu/microbiology/profile/balaji-manicassamy

Viral and host determinants of highly virulent influenza virus replication and pathogenesis

Our research program focuses on elucidating the contributions of both viral and host determinants to the enhanced disease associated with highly virulent influenza viruses such as H5N1, H7N7, H7N9 and 1918 H1N1 Spanish influenza, with the ultimate goal of developing novel therapeutic options against influenza viruses and other respiratory pathogens. Some of our ongoing research projects are:

(1) Assess the importance of viral cell tropism in the pathogenesis of highly virulent influenza viruses. We engineer influenza viruses incapable of replicating in specific cell types using miRNA-mediated restriction of viral replication, and assess pathogenesis in various animal models. Our studies show that restriction of H5N1 replication from endothelial cells via highly conserved endothelial specific miR-126 completely abrogated disease symptoms in mouse and ferret models (Tundup et al, PLoS Pathogens, 2017). We are currently utilizing a combination of miRNA restricted and fluorescent reporter viruses to investigate the contribution of cell tropism to the pathogenesis of virulent influenza viruses.

(2) Identify host factors important for influenza virus replication and cell intrinsic immunity. We have established a CRIPSR/Cas9 genome-wide screening strategy and discovered host pathways important for H5N1 entry as well as host factors critical for regulating cell intrinsic immunity, including capicua (CIC), a DNA binding transcriptional repressor. Loss of CIC resulted in the dysregulation of cell intrinsic immunity and restriction of replication for RNA viruses from diverse families, including influenza, Zika, EMCV and VSV (Han J et al., Cell Reports, 2018). We are currently performing RNASeq and ChIP-Seq analyses to identify cellular pathways that regulate CIC during viral infection to control the robustness of antiviral gene expression.

(3) Develop improved vaccines and novel small molecule inhibitors against influenza viruses. The currently existing vaccine strategies show limited efficacy against influenza viruses. We are improving influenza virus vaccine efficacy through modification of the viral genome. In collaboration with other groups, we are developing small molecules that inhibit influenza virus entry into host cells.

PubMed link

Department/Program Affiliations:
Microbiology and Immunology
Molecular Medicine