NSG-Mice Reveal the Importance of a Functional Innate and Adaptive Immune Response to Overcome RVFV Infection

Lukas Mathias Michaely; Melanie Rissmann; Markus Keller; Rebecca König; Felicitas von Arnim; Martin Eiden; Karl Rohn; Wolfgang Baumgärtner; Martin Groschup; Reiner Ulrich

doi:10.3390/v14020350

NSG-Mice Reveal the Importance of a Functional Innate and Adaptive Immune Response to Overcome RVFV Infection

Viruses. 2022 Feb 8;14(2):350. doi: 10.3390/v14020350.

Authors

Affiliations

¹ Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17, 30559 Hannover, Germany.
² Center for Systems Neuroscience Hannover, University of Veterinary Medicine Hannover, Foundation, Bünteweg 2, 30559 Hannover, Germany.
³ Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, Südufer 10, 17493 Greifswald-Insel Riems, Germany.
⁴ Institute for Biometry, Epidemiology and Information Processing, University of Veterinary Medicine Hannover, Foundation, Bünteweg 2, 30559 Hannover, Germany.
⁵ Institute of Veterinary-Pathology, Faculty of Veterinary Medicine, Leipzig University, 04103 Leipzig, Germany.
⁶ Department of Experimental Animal Facilities and Biorisk Management, Friedrich-Loeffler-Institut, Südufer 10, 17493 Greifswald-Insel Riems, Germany.

Abstract

Rift Valley fever (RVF) is a zoonotic disease caused by RVF Phlebovirus (RVFV). The RVFV MP-12 vaccine strain is known to exhibit residual virulence in the case of a deficient interferon type 1 response. The hypothesis of this study is that virus replication and severity of lesions induced by the MP-12 strain in immunocompromised mice depend on the specific function of the disturbed pathway. Therefore, 10 strains of mice with deficient innate immunity (B6-IFNAR^tmAgt, C.129S7(B6)-Ifng^tm1Ts/J, B6-TLR3^tm1Flv, B6-TLR7^tm1Aki, NOD/ShiLtJ), helper T-cell- (CD4^tm1Mak), cytotoxic T-cell- (CD8^atm1Mak), B-cell- (Igh-J^tm1DhuN?+N2), combined T- and B-cell- (NU/J) and combined T-, B-, natural killer (NK) cell- and macrophage-mediated immunity (NOD.Cg-Prkdc^scidIl2rg^tm1WjI/SzJ (NSG) mice) were subcutaneously infected with RVFV MP-12. B6-IFNAR^tmAgt mice were the only strain to develop fatal disease due to RVFV-induced severe hepatocellular necrosis and apoptosis. Notably, no clinical disease and only mild multifocal hepatocellular necrosis and apoptosis were observed in NSG mice, while immunohistochemistry detected the RVFV antigen in the liver and the brain. No or low virus expression and no lesions were observed in the other mouse strains. Conclusively, the interferon type 1 response is essential for early control of RVFV replication and disease, whereas functional NK cells, macrophages and lymphocytes are essential for virus clearance.

Keywords: Rift Valley fever; adaptive immunity; immunodeficiency; innate immunity; virus persistence.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptive Immunity*
Animals
Apoptosis
Female
Humans
Immunity, Innate*
Killer Cells, Natural / immunology
Killer Cells, Natural / virology
Liver / immunology
Liver / virology
Macrophages / immunology
Macrophages / virology
Male
Mice
Mice, Inbred NOD
Rift Valley Fever / genetics
Rift Valley Fever / immunology*
Rift Valley Fever / physiopathology
Rift Valley Fever / virology
Rift Valley fever virus / genetics
Rift Valley fever virus / physiology*
T-Lymphocytes, Cytotoxic / immunology
T-Lymphocytes, Cytotoxic / virology
T-Lymphocytes, Helper-Inducer / immunology
T-Lymphocytes, Helper-Inducer / virology