We are using this model to evaluate vaccines and therapeutics and as reported herein, have used the model to establish a baseline of ZIKV pathogenesis. a mouse exposed to ZIKV IP that succumbed on day 7 PI; scale bar Lodoxamide Tromethamine represents 50 m. (B) Representative ISH staining demonstrating no ZIKV RNA is detected in the kidney of an uninfected control mouse; scale bar represents 100 m. (C) IFA confirmed the presence of ZIKV in the smooth muscle (SMA) of a blood vessel in the kidney of a mouse exposed to ZIKV IP that succumbed on day 7 PI. (D) IFA did not detect ZIKV in the kidney from uninfected control mice; scale bar represents 20 m. (E) Isotype control antibody staining in the kidney of a mouse exposed to ZIKV IP that succumbed on day 7 PI; scale bar represents 20 m. The findings in the kidney are from one independent experiment where a total of 11 ZIKV-infected mice (3 uninfected controls) were analyzed. All sections were analyzed by an unblinded, Lodoxamide Tromethamine board-certified veterinary pathologist.(TIF) pntd.0005296.s002.tif (1.6M) GUID:?9A10109A-8939-430F-AA02-6185A73F766D S2 Fig: Histologic and ISH Findings in the Skeletal Muscle of ZIKV-Infected Wild-type Mice Treated with an IFNAR1-Blocking MAb or Uninfected Control Mice. (A) Hematoxylin and eosin staining showed myocyte degeneration, inflammation, and nuclear rowing (indicated by the arrows) in Lodoxamide Tromethamine the vertebral column skeletal muscle of a mouse exposed to ZIKV IP that was euthanized on day 12 PI; scale bar represents 100 m. (B) Hematoxylin and eosin staining showed multifocal myocyte degeneration and inflammation (indicated by asterisks) in the skeletal muscle of the head of a mouse exposed to ZIKV IP that succumbed on day 11 PI; scale bar represents 50 m. (C) ISH staining demonstrating that ZIKV RNA is detected in the skeletal muscle cells of a mouse exposed to ZIKV IP that was euthanized on day 3 PI; scale bar represents 200 m. (D) Representative ISH staining demonstrating no ZIKV RNA is detected in the skeletal muscle of an uninfected control mouse; scale bar represents 200 m. (E) Representative hematoxylin and eosin staining in the skeletal muscle of an uninfected control mouse; scale bar represents 100 m. The findings in the skeletal muscle are from two independent experiments where a total of 16 ZIKV-infected mice (3 uninfected controls) were analyzed. All sections were analyzed by an unblinded, board-certified veterinary pathologist.(TIF) pntd.0005296.s003.tif (2.0M) GUID:?FF7940E0-10CA-4FCE-833A-1DF1060DD884 Data Availability StatementAll relevant data are within the paper and its Supporting Information files. Abstract Animal models are needed to better understand the pathogenic mechanisms of Zika virus (ZIKV) and to evaluate candidate medical countermeasures. Adult mice infected with ZIKV develop a transient viremia, but do not demonstrate signs Lodoxamide Tromethamine of morbidity or mortality. Mice deficient in type I or a combination of type I and type II interferon (IFN) responses are highly susceptible to ZIKV infection; however, the absence of a competent immune system limits their usefulness for studying medical countermeasures. Here we employ a murine model for ZIKV using wild-type C57BL/6 mice treated with an antibody to disrupt type I IFN signaling to study ZIKV pathogenesis. We observed 40% mortality in antibody treated mice exposed to ZIKV subcutaneously whereas mice exposed by intraperitoneal inoculation were highly susceptible incurring 100% mortality. Mice infected by both exposure routes experienced weight loss, high viremia, and severe neuropathologic changes. The most significant histopathological findings occurred in the central nervous system where lesions represent an acute to subacute encephalitis/encephalomyelitis that is characterized by neuronal death, astrogliosis, microgliosis, scattered necrotic cellular debris, and inflammatory cell infiltrates. This model of ZIKV pathogenesis will be valuable for Tmem10 evaluating medical countermeasures and the pathogenic mechanisms of ZIKV because it allows immune responses to be elicited in immunologically competent mice with IFN I blockade only induced at the time of infection. Author Summary Research addressing the severe clinical complications associated with ZIKV infection, including GBS and congenital ZIKV syndrome, are urgently needed. Key to this effort is development of well-characterized animal models that recapitulate human disease. Adult wild-type mice infected with ZIKV can develop viremia in some instances, but they do not emulate the Lodoxamide Tromethamine disease associated with the severe congenital and adult neuropathology. Several groups have recently described type I or type II IFN-deficient murine models that are permissive for viral replication in several organs including the brain. The major limitation of these models is they utilize immunodeficient knockout mice lacking key components of the innate antiviral response. We describe the use of a lethal murine model for ZIKV where the innate response of immunocompetent mice is suppressed only at the time of infection. We show that the mice develop severe neurological disease similar to that previously demonstrated in mice deficient in the type I or II IFN response. Using this model, we provide a detailed description of the ZIKV-associated pathologic.