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Biology subjects

Jaijyan, D. K.

Publications and source records attributed to Jaijyan, D. K..

2 recordsLinked to original sources

New intranasal and injectable gene therapy for healthy life extension

As the global elderly population grows, it is socioeconomically and medically critical to have diverse and effective means of mitigating the impact of aging on human health. Previous studies showed that adenovirus-associated virus (AAV) vector induced overexpression of certain proteins can suppress or reverse the effects of aging in animal models. Here, we sought to determine whether the high-capacity cytomegalovirus vector can be an effective and safe gene delivery method for two such-protective factors: telomerase reverse transcriptase (TERT) and follistatin (FST). We found that the mouse cytomegalovirus (MCMV) carrying exogenous TERT or FST (MCMVTERT or MCMVFST) extended median lifespan by 41.4% and 32.5%, respectively. This is the first report of CMV being used successfully as both an intranasal and injectable gene therapy system to extend longevity. Treatment significantly improved glucose tolerance, physical performance, and prevented loss of body mass and alopecia. Telomere shortening seen with aging was ameliorated by TERT, and mitochondrial structure deterioration was halted in both treatments. Intranasal and injectable preparations performed equally well in safely and efficiently delivering gene therapy to multiple organs, with long-lasting benefits and without carcinogenicity or unwanted side effects. Translating this research to humans could have significant benefits associated with increased health span.

cell biology↗

Structural basis for HCMV Pentamer recognition by antibodies and neuropilin 2

Human cytomegalovirus (HCMV) encodes for multiple surface glycoproteins and glycoprotein complexes1, 2. One of these complexes, the HCMV Pentamer (gH, gL, UL128, UL130 and UL131), mediates tropism to both epithelial and endothelial cells by interacting with the cell surface receptor neuropilin 2 (NRP2)3, 4. Despite the critical nature of this interaction, the molecular determinants that govern NRP2 recognition remain unclear. Here we describe the cryo-EM structure of NRP2 bound to the HCMV Pentamer. The high-affinity interaction between these proteins is calcium-dependent and differs from the canonical C-terminal arginine (CendR) binding that NRP2 typically utilizes5, 6. The interaction is primarily mediated by NRP2 domains a2 and b2, which interact with UL128 and UL131. We also determine the structures of four human-derived neutralizing antibodies in complex with the HCMV Pentamer to define susceptible epitopes. The two most potent antibodies recognize a novel epitope yet do not compete with NRP2 binding. Collectively, these findings provide a structural basis for HCMV tropism and antibody-mediated neutralization, and serve as a guide for the development of HCMV treatments and vaccines.

microbiology↗