Recent studies demonstrated that inhibitors of pro-inflammatory molecular cascades triggered by rabies infection in the central nervous system (CNS) can enhance survival in mouse model and that certain antiviral compounds interfere with rabies virus replication in vitro. In this study different combinations of therapeutics were tested to evaluate their effect on survival in rabies-infected mice, as well as on viral load in the CNS. C57Bl/6 mice were infected with Silver-haired bat rabies virus (SHBRV)-18 at virus dose approaching LD50 and LD100. In one experimental group daily treatments were initiated 4 h before-, in other groups 48 or 96 h after challenge. In the first experiment therapeutic combination contained inhibitors of tumour necrosis factor-α (infliximab), caspase-1 (Ac-YVAD-cmk), and a multikinase inhibitor (sorafenib). In the treated groups there was a notable but not significant increase of survival compared to the virus infected, non-treated mice. The addition of human rabies immunoglobulins (HRIG) to the combination in the second experiment almost completely prevented mortality in the pre-exposure treatment group along with a significant reduction of viral titres in the CNS. Post-exposure treatments also greatly improved survival rates. As part of the combination with immunomodulatory compounds, HRIG had a higher impact on survival than alone. In the third experiment the combination was further supplemented with type-I interferons, ribavirin and favipiravir (T-705). As a blood-brain barrier opener, mannitol was also administered. This treatment was unable to prevent lethal consequences of SHBRV-18 infection; furthermore, it caused toxicity in treated mice, presumably due to interaction among the components. In all experiments, viral loads in the CNS were similar in mice that succumbed to rabies regardless of treatment. According to the findings, inhibitors of detrimental host response to rabies combined with antibodies can be considered among the possible therapeutic and post-exposure options in human rabies cases.

Artemis One Health Research Foundation Delft The Netherlands

Artemis One Health Research Foundation Delft The Netherlands; Research Center for Emerging Infections and Zoonoses University of Veterinary Medicine Hannover Germany

Department of Microbiology and Infectious Diseases University of Veterinary Medicine Hungária krt 23 25 1143 Budapest Hungary

Department of Microbiology and Infectious Diseases University of Veterinary Medicine Hungária krt 23 25 1143 Budapest Hungary; Viral Zoonoses Emerging and Vector Borne Infections Group Institute of Virology University of Veterinary Medicine Vienna Veterinaerplatz 1 1210 Vienna Austria

Department of Virology Veterinary Research Institute Hudcova 70 CZ 62100 Brno Czech Republic

Department of Virology Veterinary Research Institute Hudcova 70 CZ 62100 Brno Czech Republic; Institute of Parasitology Biology Centre of the Czech Academy of Sciences Branisovska 31 CZ 37005 Ceske Budejovice Czech Republic

Institute for Veterinary Medical Research Centre for Agricultural Research Hungarian Academy of Sciences Hungária krt 21 1143 Budapest Hungary

National Food Chain Safety Office Veterinary Diagnostic Directorate Tábornok u 2 1149 Budapest Hungary

Viroscience Lab Erasmus Medical Centre Wytemaweg 80 3015CN Rotterdam The Netherlands

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