TAM Receptors Are Not Required for Zika Virus Infection in Mice

• Published in: Cell reports (Cambridge) 2017-04, Vol.19 (3), p.558-568
• Main Authors: Hastings, Andrew K., Yockey, Laura J., Jagger, Brett W., Hwang, Jesse, Uraki, Ryuta, Gaitsch, Hallie F., Parnell, Lindsay A., Cao, Bin, Mysorekar, Indira U., Rothlin, Carla V., Fikrig, Erol, Diamond, Michael S., Iwasaki, Akiko
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; c-Mer Tyrosine Kinase; CNS; congenital infection; Female; Fetus - virology; flavivirus; Injections, Intraperitoneal; Mice; neurotropic virus; Placenta - virology; Pregnancy; Proto-Oncogene Proteins - metabolism; Receptor Protein-Tyrosine Kinases - metabolism; Tropism; Vagina - virology; viral entry; Virus Replication; Zika Virus - physiology; Zika Virus Infection - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.03.058

Tyro3, Axl, and Mertk (TAM) receptors are candidate entry receptors for infection with the Zika virus (ZIKV), an emerging flavivirus of global public health concern. To investigate the requirement of TAM receptors for ZIKV infection, we used several routes of viral inoculation and compared viral replication in wild-type versus Axl−/−, Mertk−/−, Axl−/−Mertk−/−, and Axl−/−Tyro3−/− mice in various organs. Pregnant and non-pregnant mice treated with interferon-α-receptor (IFNAR)-blocking (MAR1-5A3) antibody and infected subcutaneously with ZIKV showed no reliance on TAMs for infection. In the absence of IFNAR-blocking antibody, adult female mice challenged intravaginally with ZIKV showed no difference in mucosal viral titers. Similarly, in young mice that were infected with ZIKV intracranially or intraperitoneally, ZIKV replication occurred in the absence of TAM receptors, and no differences in cell tropism were observed. These findings indicate that, in mice, TAM receptors are not required for ZIKV entry and infection. [Display omitted] •TAM receptors are not essential for ZIKV infection in mice•TAM receptors are not required for mother-to-fetus transmission in IFNAR-blocked mice•ZIKV tropism in the placenta and brain does not depend on TAM receptors•Murine Axl is capable of facilitating ZIKV infection in human cells in vitro TAM receptors have been implicated as entry receptors for the Zika virus. In this study, Hastings et al. used genetic knockout mouse models to demonstrate that they are not necessary for the infection of mice via multiple routes of viral challenge. These results suggest the existence of redundant entry receptors for ZIKV in mice.