Crimean-Congo Hemorrhagic Fever in Humanized Mice Reveals Glial Cells as Primary Targets of Neurological Infection

Abstract

Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne viral hemorrhagic disease seen exclusively in humans. Central nervous system (CNS) infection and neurological involvement have also been reported in CCHF. In the current study, we inoculated NSG-SGM3 mice engrafted with human hematopoietic CD34+ stem cells with low-passage CCHF virus strains isolated from human patients. In humanized mice, lethal disease develops, characterized by histopathological change in the liver and brain. To date, targets of neurological infection and disease have not been investigated in CCHF. CNS disease in humanized mice was characterized by gliosis, meningitis, and meningoencephalitis, and glial cells were identified as principal targets of infection. Humanized mice represent a novel lethal model for studies of CCHF countermeasures, and CCHF-associated CNS disease. Our data suggest a role for astrocyte dysfunction in neurological disease and identify key regions of infection in the CNS for future investigations of CCHF.

Vesicular Stomatitis Virus-Based Vaccine Protects Mice against Crimean-Congo Hemorrhagic Fever

“…At 35 days post prime, all mice were challenged with 50 pfu of CCHFV strain Turkey2004 and were monitored for clinical signs, weights, and temperatures. We challenged with a human/clinical strain, Turkey200406546, designated throughout this work as Turkey2004; which has previously been published in GenBank with the accession numbers KY362517 (S-segment), KY362519 (M-segment), and KY362515 (L-segment) 41 . Mean time-to-death (MTD) was 5.6 days post infection (dpi), with a standard deviation (SD) +/− 0.55 dpi as demonstrated with the PBS control group (Fig.…”

“…In selecting the CCHFV challenge isolate, we chose an isolate with low passage history and demonstrated clinical relevance (i.e., documented history of disease in humans). The Turkey2004 isolate, came from a clinical case 41 .…”

Nucleocapsid protein-based vaccine provides protection in mice against lethal Crimean-Congo hemorrhagic fever virus challenge

“…The only CCHF disease models are certain immunocompromised and/or humanized mouse strains [2]. The mouse strains include the interferon signaling deficient IFNAR -/and STAT1 -/mouse strains and the humanized Hu-NSG-SGM3 mice [10][11][12]29]. The Hu-NSG-SGM3 express certain human cytokines and human leukocytes, however the disease progression is somewhat atypical as the disease is primarily neurological [29].…”

“…The mouse strains include the interferon signaling deficient IFNAR -/and STAT1 -/mouse strains and the humanized Hu-NSG-SGM3 mice [10][11][12]29]. The Hu-NSG-SGM3 express certain human cytokines and human leukocytes, however the disease progression is somewhat atypical as the disease is primarily neurological [29]. Both the STAT1 -/and IFNAR -/mice possess complete sets of murine immune systems, but their cells either have altered response to interferon signaling or do not respond to type I interferon signaling, respectively, leading to rapid disease more reminiscent of human hemorrhagic fever [10][11][12].…”

A Hitchhiker's guide to humanized mice: new pathways to studying viral infections

“…In humanized HLA‐A2 mice, Hantavirus infection induces a dramatic decrease in total platelet count and infiltration of lymphocytes into the lungs, and increases weight loss . Similarly, in Crimean–Congo haemorrhagic fever infection, there is distinct strain variability observed, liver and brain pathological changes, increased polyfunctionality of CD8 + T cells and viral RNA observed in the blood and tissues of infected mice …”