Virus-induced cell re-differentiation and a novel interorganelle protein transport pathway

• Main Authors: Shu-Fen Chiang, 姜淑芬
• Other Authors: Shiow-Her Chiou
• Format: Others
• Language: en_US
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/15407615374686967994

博士 === 國立中興大學 === 獸醫微生物學研究所 === 100 === Our studies included two subjects: (1) virus-induced cell re-differentiation; (2) a novel interorganelle protein transport pathway. Hematopoietic stem cells (HSCs), through mediation by various growth factors, cytokines and transcription factors, can differentiate into different lineages of blood cells. Although B cells and macrophages are both antigen-presenting cells, they were descended from two distinctively committed lineages. Their respective differentiation was restricted by specific transcription factors, and exhibited diverse patterns of gene expression. Recently, B cells were shown to be reprogrammed into macrophages by way of altering expression of transcription factors. In this study, we found that human peripheral B cells and B lymphoma cell lines could be transduced by recombinant baculovirus-expressed Severe Acute Respiratory Syndrome- Coronavirus (SARS-CoV) spike protein, and re-differentiated into macrophage-like cells. These macrophage-like cells enlarged with increased granules, and expressed marker molecular, CD11b and CD68. Moreover, we found that severe hypoxia also triggered B lymphoma cells re-differentiated. These phenomena were similar to the clinical features observed in SARS patients, such as atypical pneumonia-induced severe hypoxia, massive macrophage infiltrates in the lungs, and lymphopenia. Hence, we suggested that B cells were recruited into inflammatory lungs upon SARS-CoV infection. They were subsequently reprogrammed into macrophage-like cells by virus and hypoxia, and accumulated in the afflicted lungs. In the future, it is imperative to determine whether SARS-CoV may have the ability to trigger B cell re-differentiation. Function of mitochondria has been shown correlated with intracellular immunity. Certain viral proteins interact with mitochondrial proteins to affect cell survival. Most mitochondrial proteins are encoded by the nuclear genes. Traditionally, they were thought to be synthesized in the cytosol and imported into mitochondria through translocases. However, viral proteins may interfere with protein transport. Abnormal protein transport could hamper mitochondrial activities, and therefore influence cell function and viability. In this study, we found that mitochondrial protein apoptosis-inducing factor (AIF) was imported into mitochondria by a novel alternative transport pathway. We identified that AIF was synthesized in the endoplasmic reticulum (ER) and transported into mitochondria via mitochondria-associated membrane (MAM) and transport vesicle. This pathway may be similar to that for mitochondrial phospholipid transport, which requires three proteins: dynamin-related protein 1 (DRP1), mitofusin-2 (Mfn-2), and ATPase family AAA domain containing 3A (ATAD3A).