Lactoferrin Inhibits Cell Entry Of SARS-coronavirus And Plays A Protective Role In SARS-CoV Infection

The SARS coronavirus(SARS-CoV)was identified as the pathogen of the outbreak of SARS (severe acute respiratory syndrome) in the Guangdong province of China in November2002[1]. The Spike protein on the virion surface is responsible for both receptor binding and membrane fusion[1-4]. One potential SARS-CoV receptor has been identified by detailed research. That is angiotensin converting enzyme2(ACE2), the main cellular receptor[2-4]. The target cells that express abundant ACE2include pneumocytes and enterocytes in the respiratory system, mucosal cells of intestines, tubular epithelial cells of kidneys, epithelial cells of renal tubules, cerebral neurons and immune cells[5]. Whether there is a coreceptor or other molecules that are required for virus infection is uncertain.Lactoferrin was highly up-regulated in peripheral blood mononuclear cells (PBMCs) from SARS patients[7]. Lactoferrin exert a wide variety of biological functions, such as inhibition of infection of microbes including bacteria, viruses, protozoa, fungi, etc[8-11]. Our experiment results suggest that lactoferrin can inhibit the entry of SARS pseudovirus into293E-ACE2-Myc cell in a dose-dependent manner. Lactoferrin does not disrupt the interacton between Spike protein and ACE2receptor in vitro. But lactoferrin inhibits Spike protein and SARS pseudovirus binding to293E-ACE2-Myc cell. The target molecule that lactoferrin interact with is heparin sulfate proteoglycan on the cell membrane.Previous studies have proven that many viruses utilize HSPG as the first anchoring site on the target cells[45-47]. Through this weak and reversible interaction between virus and target cells, virus binds to the cells and scans the cell membrane for the specific receptors[48-50]. Our experiment results show that heparin can inhibit SARS pseudovirus infection of the293E-ACE2-Myc cell, which is consensus with the previous study which suggested that heparin inhibited SARS-CoV entry into Vero E6cell[43]. HSPG may facilitate SARS-CoV enter the host cells and play an important role in the SARS-CoV infection through the same mechanism.The physiological significance of up-regulation of lactoferrin in SARS patients is that lactoferrin can inhibit SARS-CoV entry into the host cells by binding to HSPG. So lactoferrin can prevent further spread of SARS-CoV and plays a protective role in SARS-CoV infection.