Research & Discoveries
Current Areas of Study
Our lab focuses on the entry mechanisms of enveloped viruses. Our previous work includes the identification of the HIV-1 coreceptor CCR5 (Choe et al., 1996, Cell) and NW arenavirus receptor (Radoshitsky et al., 1997, Nature). We co-identified the cellular receptor for SARS-CoV, ACE2 (Li et al., 2003, Nature), which also turned out to be the receptor for SARS-CoV-2. We also identified TFR1 as the receptor for New World hemorrhagic fever arenaviruses (Radoshitzky et al., 2007, Nature). In addition to receptor identification, we studied host factors that contribute to virus replication and pathogenesis. These include identification of tyrosine sulfation as a common element to all HIV coreceptors and being essential for coreceptor function (Farzan et al., 1999, Cell), as well as the importance of cathepsins for SARS-CoV infection (Huang et al., 2006, J Biol Chem). Our current projects described below are built on such experience.
Viral Vectors for Gene Therapy
Adeno-associated virus (AAV) is one of the most commonly used gene-therapy vectors. However, there still remain several challenges: high cost, toxicity at high doses, and anti-transgene antibody production boosted by the AAV capsid packaged DNA. Most of these challenges could be eased with the development of more efficient vectors. We hypothesized that by targeting receptors expressed at high levels in a target cell, we could enhance AAV transduction in a cell-type-specific manner. As a proof of principal, we recently enhanced in vivo muscle transduction efficiency of AAV9 nearly 20-fold by targeting insulin receptor, using an insulin-mimetic peptide inserted into the AAV9 capsid (Jackson et al., 2020, Mol Ther Methods Clin Dev). Using similar strategies, we are currently developing T-cell and B-cell targeting AAV vectors.
Although the mutation rate of SARS-CoV-2 is lower than that of other smaller RNA viruses, recent analyses of SARS-CoV-2 sequences identified several genomic regions of increased genetic variation. One of these variations encodes a mutation, D614G, in the spike protein (S). As the SARS-CoV-2 isolates carrying this mutation now predominates globally, it was suggested that the mutation increased virus transmissibility. Our study shows that pseudovirus infectivity is increased by the D614G mutation and that reduced S1 shedding and increased S-protein density on the virion correlate with this increased infectivity (Zhang, Jackson, Mou et al., 2020, Nat Commun). We are currently focusing on identifying viral and cellular factors that contribute to SARS-CoV-2 infection.
PS Receptors and Flavivurses
Phosphatidylserine (PS) receptors mediate clearance of apoptotic cells by recognizing the PS exposed on those cells. They also mediate the entry of enveloped viruses by binding PS in the virion membrane, a mechanism described as “apoptotic mimicry”. Among many PS receptors, T-cell Immunoglobulin Mucin (TIM)- and TYRO3, AXL, and MERTK (TAM)-family members are best characterized for their ability to mediate the apoptotic-cell clearance and virus entry. We showed many enveloped viruses including filoviruses and flaviviruses efficiently utilized TIM1 (Jemielity et al., 2013, PLoS Pathog; Richard et al, 2015, PNAS). We also showed, however, closely-related flaviviruses differentially use AXL; Zika virus (ZIKV), but not other flaviviruses, uses AXL to productively infect fetal endothelial cells, suggesting a role of AXL in microcephaly caused by ZIKV (Richard et al., 2017, PNAS). We are currently investigating the mechanisms underlying differential use of AXL by ZIKV vs other flaviviruses.