Andes virus infection of lymphatic endothelial cells causes giant cell and enhanced permeability responses that are rapamycin and vascular endothelial growth factor C sensitive.
Hantaviruses primarily infect endothelial cells (ECs) and nonlytically cause vascular changes that result in hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Acute pulmonary edema during HPS may be caused by capillary leakage and failure of lymphatic vessels to clear fluids. Uniquely regulated lymphatic ECs (LECs) control fluid clearance, although roles for lymphatics in hantavirus disease remain undetermined. Here we report that hantaviruses productively infect LECs and that LEC infection by HPS causing Andes virus (ANDV) and HFRS causing Hantaan virus (HTNV) are inhibited by α(v)β(3) integrin antibodies. Although α(v)β(3) integrins regulate permeabilizing responses directed by vascular endothelial growth factor receptor 2 (VEGFR2), we found that only ANDV-infected LECs were hyperpermeabilized by the addition of VEGF-A. However, VEGF-C activation of LEC-specific VEGFR3 receptors blocked ANDV- and VEGF-A-induced LEC permeability. In addition, ∼75% of ANDV-infected LECs became viable mononuclear giant cells, >4 times larger than normal, in response to VEGF-A. Giant cells are associated with constitutive mammalian target of rapamycin (mTOR) activation, and we found that both giant LECs and LEC permeability were sensitive to rapamycin, an mTOR inhibitor, and VEGF-C addition. These findings indicate that ANDV uniquely alters VEGFR2-mTOR signaling responses of LECs, resulting in giant cell and LEC permeability responses. This suggests that ANDV infection alters normal LEC and lymphatic vessel functions which may contribute to edematous fluid accumulation during HPS. Moreover, the ability of VEGF-C and rapamycin to normalize LEC responses suggests a potential therapeutic approach for reducing pulmonary edema and the severity of HPS following ANDV infection.
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA.
Irina N
IN
Gavrilovskaya
Elena E
EE
Gorbunova
Erich R
ER
Mackow
D000818:Animals; D002199:Capillary Permeability; D002460:Cell Line; D042783:Endothelial Cells / Q000166:cytology / Q000821:virology*; D015726:Giant Cells / Q000166:cytology / Q000821:virology*; D018063:Hantaan virus / Q000472:pathogenicity; D006476:Orthohantavirus / Q000472:pathogenicity*; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism; D020123:Sirolimus / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*
D007166:Immunosuppressive Agents; D042582:Vascular Endothelial Growth Factor C; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus