Rift Valley Fever Virus Non-Structural Protein S Is Associated with Nuclear Translocation of Active Caspase-3 and Inclusion Body Formation

Lukas Mathias Michaely; Melanie Rissmann; Federico Armando; Felicitas von Arnim; Markus Keller; Martin Eiden; Rebecca König; Benjamin Gutjahr; Wolfgang Baumgärtner; Martin H Groschup; Reiner Ulrich

doi:10.3390/v14112487

Rift Valley Fever Virus Non-Structural Protein S Is Associated with Nuclear Translocation of Active Caspase-3 and Inclusion Body Formation

Viruses. 2022 Nov 10;14(11):2487. doi: 10.3390/v14112487.

Authors

Lukas Mathias Michaely¹, Melanie Rissmann^{2

3

4}, Federico Armando¹, Felicitas von Arnim^{2

3}, Markus Keller^{2

3}, Martin Eiden^{2

3}, Rebecca König^{2

3}, Benjamin Gutjahr^{2

3}, Wolfgang Baumgärtner¹, Martin H Groschup^{2

3}, Reiner Ulrich^{5

6}

Affiliations

¹ Center of Systems Neuroscience, Department of Pathology, University of Veterinary Medicine Hannover, Foundation, 30559 Hannover, Germany.
² Institute of Novel and Emerging Diseases, Friedrich-Loeffler-Institute, Insel Riems, 17493 Greifswald, Germany.
³ Partner Site Hamburg-Lübeck-Borstel-Riems, German Center for Infection Research (DZIF), Insel Riems, 17493 Greifswald, Germany.
⁴ Erasmus Medical Center, Department of Viroscience, 3015 GD Rotterdam, The Netherlands.
⁵ Department of Experimental Animal Facilities and Biorisk Management, Friedrich-Loeffler-Institute, Insel Riems, 17493 Greifswald, Germany.
⁶ Institute of Veterinary Pathology, Faculty of Veterinary Medicine, Leipzig University, 04103 Leipzig, Germany.

Abstract

Rift Valley fever phlebovirus (RVFV) causes Rift Valley fever (RVF), an emerging zoonotic disease that causes abortion storms and high mortality rates in young ruminants as well as severe or even lethal complications in a subset of human patients. This study investigates the pathomechanism of intranuclear inclusion body formation in severe RVF in a mouse model. Liver samples from immunocompetent mice infected with virulent RVFV 35/74, and immunodeficient knockout mice that lack interferon type I receptor expression and were infected with attenuated RVFV MP12 were compared to livers from uninfected controls using histopathology and immunohistochemistry for RVFV nucleoprotein, non-structural protein S (NSs) and pro-apoptotic active caspase-3. Histopathology of the livers showed virus-induced, severe hepatic necrosis in both mouse strains. However, immunohistochemistry and immunofluorescence revealed eosinophilic, comma-shaped, intranuclear inclusions and an intranuclear (co-)localization of RVFV NSs and active caspase-3 only in 35/74-infected immunocompetent mice, but not in MP12-infected immunodeficient mice. These results suggest that intranuclear accumulation of RVFV 35/74 NSs is involved in nuclear translocation of active caspase-3, and that nuclear NSs and active caspase-3 are involved in the formation of the light microscopically visible inclusion bodies.

Keywords: Rift Valley fever; apoptosis; caspase-3; inclusion bodies.

Publication types

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

MeSH terms

Animals
Caspase 3
Humans
Inclusion Bodies / metabolism
Mice
Rift Valley Fever*
Rift Valley fever virus*
Ruminants
Viral Nonstructural Proteins / metabolism

Substances

Caspase 3
Viral Nonstructural Proteins

Grants and funding

This research was performed as part of the Zoonoses Anticipation and Preparedness Initiative (ZAPI project; IMI Grant Agreement no. 115760), with the assistance and financial support of IMI and the European Commission, and in-kind contributions from EFPIA partners. LMM and WB are members of the Center Systems Neuroscience of the University of Veterinary Medicine Hannover, and LMM received financial support for travel expenses.