Resistance to Rift Valley fever virus in Rattus norvegicus: genetic variability within certain ‘inbred’ strains

Marcus Ritter1, Michèle Bouloy2, Pierre Vialat2, Christian Janzen1, Otto Haller1 and Michael Frese1

Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene, Universität Freiburg, Hermann-Herder-Str. 11, D-79104 Freiburg, Germany1
Groupe des Bunyaviridés, Unité des Arbovirus et Virus des Fièvres Hèmorragiques, Institut Pasteur, 25 Rue du Dr Roux, 75724 Paris, France2

Author for correspondence: Michael Frese. Fax +49 761 203 6626. e-mail frese{at}ukl.uni-freiburg.de


   Abstract
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Abstract
Introduction
Methods
Results
Discussion
References
 
Rift Valley fever virus (RVFV) is the causative agent of Rift Valley fever, a widespread disease of domestic animals and humans in sub-Saharan Africa. Laboratory rats have frequently been used as an animal model for studying the pathogenesis of Rift Valley fever. It is shown here that Lewis rats (LEW/mol) are susceptible to infection with RVFV, whereas Wistar–Furth (WF/mol) rats are resistant to RVFV infection. LEW/mol rats developed acute hepatitis and died after infection with RVFV strain ZH548, whereas WF/mol rats survived the infection. Cross-breeding of resistant WF/mol rats with susceptible LEW/mol rats demonstrated that resistance is segregated as a single dominant gene. Primary hepatocytes but not glial cells from WF/mol rats showed the resistant phenotype in cell culture, indicating that resistance was cell type-specific. Moreover, when cultured hepatocytes were stimulated with interferon (IFN) type I there was no indication of a regulatory role of IFN in the RVFV-resistance gene expression in WF/mol rats. Interestingly, previous reports have shown that LEW rats from a different breeding stock (LEW/mai) are resistant to RVFV infections, whereas WF/mai rats are susceptible. Thus, inbred rat strains seem to differ in virus susceptibility depending on their breeding histories. A better genetic characterization of inbred rat strains and a revision in nomenclature is needed to improve animal experimentation in the future.


   Introduction
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Abstract
Introduction
Methods
Results
Discussion
References
 
Rift Valley fever (RVF) is an arthropod-borne disease that is caused by Rift Valley fever virus (RVFV), a member of thefamily Bunyaviridae, genus Phlebovirus. Epidemics and epizootics of RVFV occur periodically in sub-Saharan countries of Africa and in Egypt (reviewed by Peters & Linthicum, 1994 ). RVF has been known for many years as a devastating disease in domestic animals (Daubney & Hudson, 1931 ). Infected sheep, for example, experience high mortality ranging from 25% in adult animals to over 90 % in lambs; pregnant ewes usually abort. In humans, RVF is an influenza-like disease that is followed by complete convalescence (Laughlin et al., 1979 ). However, in a small proportion of cases (estimated to be less than 5%) the disease is more serious. Patients with severe RVF typically suffer from hepatitis associated with haemorrhagic fever, retinitis or meningoencephalitis (Laughlin et al., 1979 ).

The laboratory rat, Rattus norvegicus, has frequently been used as an animal model to study the pathogenesis of RVFV infection. Peters & Anderson (1981 ) and Peters & Slone (1982 ) observed dramatic differences in disease manifestation in experimentally infected rats of different inbred strains. They demonstrated that rats, depending on their genetic background, either survive an RVFV infection without any symptoms or die as a result of fulminant hepatitis or encephalitis. For example, Wistar–Furth rats (WF/mai) die with extensive hepatic necrosis no later than 3 to 5 days after infection with RVFV, whereas Lewis rats (LEW/mai) are highly resistant to fatal hepatic disease, although a significant percentage (about 16%) develop encephalitis later on in the infection (Peters & Slone, 1982 ; Anderson et al., 1987 ). Genetic analysis revealed that the resistance to RVFV-induced fatal hepatitis observed in LEW/mai rats is inherited by a single Mendelian dominant gene (Peters & Anderson, 1981 ), although the resistance gene has not yet been identified. However, interferon (IFN) seems to play a crucial role in the establishment of a resistant phenotype in rats (Rosebrock & Peters, 1982 ; Rosebrock et al., 1983 ; Anderson & Peters, 1988 ). Peritoneal macrophages obtained from RVFV-resistant LEW/NHsdBR rats allow RVFV to replicate efficiently, but stimulation of the cell cultures with IFN type I ({alpha}/{beta}) prior to infection inhibited RVFV growth (Rosebrock & Peters, 1982 ; Rosebrock et al., 1983 ). In contrast, IFN is not able to induce resistance in macrophages of RVFV-susceptible WF/HsdBR rats (Rosebrock & Peters, 1982 ; Rosebrock et al., 1983 ). Furthermore, injection of anti-IFN type I antibodies into LEW/mai rats led to a dramatically increased sensitivity to RVFV infections (Anderson, 1988 ).

Here, we report that inbred rats from a European breeding colony (mol rats) do not respond to RVFV challenges in the same way as their American relatives (mai rats) do. WF/mol rats survived RVFV infections and LEW/mol rats died of acute hepatitis. Cross-breeding of WF/mol and LEW/mol rats revealed that resistance is segregated as a single dominant gene. It is presently not understood exactly how this gene contributes to the RVFV-resistant phenotype of WF/mol rats. However, cell culture experiments using primary hepatocytes suggest that the multiplication of RVFV is impaired in the liver of WF/mol rats. Furthermore, we have found no evidence to support the hypothesis that the resistance gene is regulated by IFN type I.


   Methods
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Abstract
Introduction
Methods
Results
Discussion
References
 
{blacksquare} Animals.
Inbred WF/mol and LEW/mol rats were obtained from M&B (formerly Mollegard Breeding & Research Centre, Ry, Denmark). Hybrid WF/molxLEW/mol rats and back cross LEW/molx(WF/molxLEW/mol) rats were bred locally.

{blacksquare} Cells.
Primary hepatocyte cultures were established from adult WF/mol and LEW/mol rats as described previously (Schramm et al., 1993 ; Schmider et al., 1996 ). Primary cultures of cortical glial cells were established from 1-day-old WF/mol and LEW/mol rats essentially as described (McCarthy & de Vellis, 1978 ). Both hepatocytes and glial cells were cultured in Dulbecco’s modified Eagle’s medium containing 200 U/ml penicillin, 200 µg/ml streptomycin and 10% foetal calf serum. Rat glioblastoma C6 cells (CCL-107) and human fibroblast MRC-5 cells (CCL-171) were obtained from the ATCC. African green monkey kidney (Vero) cells have been described previously (Frese et al., 1996 ).

{blacksquare} Viruses.
The ZH548 strain of RVFV (Meegan, 1979 ) was grown in MRC-5 cells and stock virus contained 5x106 p.f.u./ml as determined in Vero cells. The attenuated MP12 strain of RVFV (Caplen et al., 1985 ) was grown in Vero cells and contained 4·4x107 TCID50/ml as determined in Vero cells.

{blacksquare} Experimental virus infections.
Adult rats (at least 12 weeks old) of either sex were infected intraperitoneally with 103, 104 or 105 p.f.u. RVFV strain ZH548. After inoculation of the virus, the animals were monitored at least daily for clinical symptoms. Confluent primary hepatocyte cell monolayers or glial cell monolayers were infected with the MP12 strain of RVFV at a multiplicity of 0·1 TCID50 per cell, incubated for 1 h at 37 °C and washed to remove free virus. Fresh medium was added and cells were further incubated at 37 °C. Samples of the supernatant were taken at the times indicated and virus titres were then determined on Vero cells. Titres were calculated as reciprocals of the TCID50.

{blacksquare} Interferon treatment.
Primary hepatocyte cell monolayers were either stimulated overnight with 100, 1000 or 5000 IU/ml of Cytimmune rat IFN type I (Lee Biomolecular Research) or left untreated.


   Results
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Abstract
Introduction
Methods
Results
Discussion
References
 
WF/mol but not LEW/mol rats are resistant to RVFV infections
In order to confirm previous reports about a resistance gene present in LEW but not in WF rats (Peters & Slone, 1982 ; Anderson et al., 1987 ), we challenged rats of the inbred strains LEW/mol and WF/mol with RVFV. Two adult rats of either strain were infected intraperitoneally with 104 p.f.u. RVFV strain ZH548. Surprisingly, the LEW/mol rats died 3 days after infection, whereas the WF/mol rats survived (Table 1, expt 1). In view of the unexpected outcome of this first experiment and the low number of animals that were used, we performed a second challenge experiment. In this experiment, six adult animals of either strain were infected intraperitoneally with either 103, 104 or 105 p.f.u. RVFV strain ZH548 (Table 1, expt 2). Again, all LEW/mol rats became progressively ill and succumbed to an acute degenerative hepatitis within 3 days post-infection (p.i.) (M. Huerre, unpublished results). In contrast, all WF/mol rats survived infection without any symptoms of disease. These data reveal a remarkable genetic variability between inbred rats of the same strain but from different breeding colonies.


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Table 1. WF/mol but not LEW/mol rats are resistant to RVFV infections

 
Resistance is segregated as a single Mendelian dominant locus
Breeding experiments were performed to elucidate the genetic background of the RVFV-resistant phenotype of WF/mol rats. First, WF/mol and LEW/mol rats were cross-bred to generate WF/molxLEW/mol hybrid rats. Then, these hybrid rats were back crossed to RVFV-susceptible LEW/mol rats and the resulting offspring were challenged with RVFV in order to study the segregation of resistance. We infected 16 adult LEW/molx(WF/molxLEW/mol) rats intraperitoneally with 104 p.f.u. RVFV strain ZH548. On day 5 after infection, eight animals, two females and six males, were dead (Table 1, expt 3). Histopathological examination of the livers indicated an acute degenerative hepatitis, similar to that observed in RVFV-infected LEW/mol rats (M. Huerre, unpublished results). The eight surviving animals, four females and four males, remained healthy until day 21 when the experiment was terminated. Taken together, the results indicate that an autosomally inherited single dominant gene locus is responsible for RVFV resistance in WF/mol rats.

Multiplication of RVFV in unstimulated hepatocyte and glial cell cultures
A rapid invasion of the liver is characteristic of RVFV infections in rats (McGavran & Easterday, 1963 ; Peters & Slone, 1982 ). The multiplication of RVFV in hepatocytes is responsible for liver necrosis and contributes mainly to the high-titre plasma viraemia (Anderson et al., 1987 ; Anderson & Smith, 1987 ). Host defence mechanisms that protect the liver against RVFV infection or slow down virus replication in hepatocytes would have a huge impact on the development of the disease. To compare the multiplication of RVFV in hepatocytes from LEW/mol and WF/mol rats, primary hepatocyte cultures were established from both rat strains and infected with RVFV strain MP12 at 0·1 TCID50 per cell. Hepatocytes obtained from susceptible LEW/mol rats produced large amounts of RVFV (Fig. 1A). About 36 h p.i., virus titres in the cell culture supernatant reached a peak of 2·4x106 TCID50/ml (mean titre of four experiments). At the same time-point, reduced virus titres (1·7x104 TCID50/ml) were detected in supernatants of hepatocytes derived from WF/mol rats. A virus-induced cytopathic effect (CPE) was observed in hepatocytes from both rat strains, but CPE was delayed and less pronounced in hepatocytes from WF/mol rats (data not shown).



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Fig. 1. Enhanced RVFV resistance in primary hepatocytes from WF/mol rats. Confluent monolayers of primary hepatocytes (A) and glial cells (B) obtained from WF/mol and LEW/mol rats were infected with RVFV strain MP12 at 0·1 TCID50 per cell and virus titres in the cell culture supernatant were determined at the times indicated. Mean titres from four separate experiments (A) or results of a single representative experiment (B) are shown. Error bars represent 95% confident intervals.

 
Rats resistant to RVFV-induced hepatitis frequently develop a multifocal necrotizing encephalitis 2 to 3 weeks p.i. (Peters & Slone, 1982 ; Anderson et al., 1987 ). In addition, rats of any strain die from acute brain lesions after intracerebral inoculation of RVFV. Therefore, we studied the multiplication of RVFV in cells of the central nervous system. First, we infected C6 rat glioblastoma cells (Benda et al., 1968 ) with RVFV strain MP12. About 36 h p.i., the virus had multiplied to high titres (up to 3·2x108 TCID50/ml) and caused severe CPE (data not shown), indicating that glial cells are highly permissive to RVFV. Next, primary glial cell cultures obtained from LEW/mol and WF/mol rats were infected with RVFV strain MP12 at a multiplicity of 0·1 TCID50 per cell and the production of progeny virus was measured. RVFV multiplied in glial cells of both rat strains to titres greater than 1x108 TCID50/ml with almost the same growth characteristics (Fig. 1B). Furthermore, RVFV induced a strong CPE in glial cells of both rat strains 36 h p.i. (data not shown).

Taken together, the results indicate that WF/mol rats possess an innate resistance mechanism to RVFV that inhibits virus multiplication in hepatocytes but not in glial cells.

Multiplication of RVFV in IFN-treated hepatocyte cultures
Previous reports suggest differences between RVFV-resistant LEW/mai and susceptible WF/mai rats concerning the IFN-induced antiviral response (Rosebrock & Peters, 1982 ; Rosebrock et al., 1983 ; Anderson & Peters, 1988 ). Therefore, we investigated the effect of IFN type I on the multiplication of RVFV in cultured hepatocytes from LEW/mol and WF/mol rats. Primary hepatocytes were isolated from both rat strains and were either stimulated overnight with 100, 1000 or 5000 IU/ml of rat IFN type I or were left untreated. Subsequently, the cells were challenged with RVFV strain MP12 at an m.o.i. 0·1 and virus titre in the cell culture supernatant was determined 24 h p.i. Hepatocytes from both rat strains responded to the IFN treatment by inhibiting RVFV multiplication in a dose-dependent manner (Fig. 2). Compared to untreated cells, hepatocytes from LEW/mol and WF/mol rats that were stimulated with 5000 IU/ml of IFN produced only 2% and 1% progeny virus, respectively. These results indicate that hepatocytes from RVFV-resistant WF/mol rats do not exhibit a stronger IFN-induced antiviral response than hepatocytes from susceptible LEW/mol rats. We suggest, therefore, that the resistance gene is not regulated by IFN type I.



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Fig. 2. RVFV multiplication in hepatocytes from WF/mol and LEW/mol rats after treatment with IFN. Confluent monolayers of primary hepatocyte cell cultures from WF/mol (A) and LEW/mol (B) rats were either stimulated overnight with 100, 1000, or 5000 IU/ml rat IFN type I or left untreated. Cell monolayers were subsequently infected with RVFV strain MP12 at a multiplicity of 0·1 TCID50 per cell and virus titres in the cell culture supernatant were determined 24 h p.i. The result of a single representative experiment is shown.

 

   Discussion
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Abstract
Introduction
Methods
Results
Discussion
References
 
The pathogenesis of RVF has been intensively studied in experimentally infected mice and rats (reviewed by Gonzalez-Scarano & Nathanson, 1996 ). After subcutaneous or intraperitoneal inoculation of RVFV, the liver is rapidly invaded and the virus quickly spreads into the hepatic parenchyma (McGavran & Easterday, 1963 ). RVFV-induced CPE causes a massive destruction of liver tissue, resulting in fatal liver failure (McGavran & Easterday, 1963 ; Anderson et al., 1987 ). Furthermore, infected hepatocytes are probably the major source of the high-titre plasma viraemia that is observed in susceptible animals (Anderson et al., 1987 ; Anderson & Smith, 1987 ). It is, therefore, of great importance for the host organism to prevent or inhibit virus multiplication in hepatocytes in order to survive an RVFV infection. We observed that RVFV-infected hepatocytes from resistant WF/mol rats produced less than 1% progeny virus when compared to RVFV-infected hepatocytes from susceptible LEW/mol rats, strongly suggesting that WF/mol rats possess a potent innate resistance mechanism to inhibit RVFV multiplication in the liver. Interestingly, Anderson & Smith (1987 ) have shown that hepatocytes from RVFV-resistant LEW/mai rats are less permissive to an RVFV infection than hepatocytes from RVFV-susceptible WF/mai rats. Therefore, it is tempting to speculate that WF/mol and LEW/mai rats may have the same resistance gene that protects the liver against RVFV.

Other observations, however, seem to indicate that the IFN-induced antiviral response is involved in the resistance of certain rat strains to RVFV infections. These observations are (i) the injection of IFN type I-specific antibodies into LEW/mai rats leads to a dramatically increased sensitivity to RVFV infections (Anderson, 1988 ); (ii) macrophages from RVFV-resistant LEW/NHsdBR rats but not from RVFV-susceptible WF/HsdBR rats exhibit resistance to RVFV after stimulation with IFN type I (Rosebrock & Peters, 1982 ; Rosebrock et al., 1983 ), suggesting that an IFN-induced antiviral mechanism is responsible for the RVFV-resistant phenotype; (iii) the multiplication of RVFV is inhibited by MxA, a human IFN-induced GTPase (Frese et al., 1996 ); and (iv) preliminary data indicates that the rat Mx2 protein also possesses antiviral activity against bunyaviruses, including RVFV (M. Sandrock, M. Frese, G. Kochs and O. Haller, unpublished results). These findings clearly demonstrate that the IFN-induced antiviral defence is indispensable for resistance to RVFV infections. A similar conclusion applies for the mouse model since genetically targeted ‘knockout’ mice, lacking the {beta}-subunit of the IFN-{alpha}/{beta} receptor, are highly susceptible to attenuated strains of RVFV that do not normally kill mice (Bouloy et al., 1999 ). Although the genetic resistance against RVFV described here seems not to rely on an IFN response, IFN is certainly important for the outcome of the disease in both RVFV-susceptible rats and RVFV-resistant rats. Spontaneously transformed embryonic thymus cells derived from both LEW/mai and WF/mai rats, for example, are able to inhibit the formation of RVFV-plaques after exposure to IFN type I (Anderson & Peters, 1988 ). Furthermore, the treatment of susceptible WF/mai rats with IFN improves the chances of surviving an RVFV infection (Anderson, 1988 ). Since RVFV was inhibited in hepatocytes from both resistant WF/mol and susceptible LEW/mol rats following IFN treatment, we support the view that at least a part of the IFN-induced antiviral defence against RVFV also operates in susceptible rats. Furthermore, the present data provide no evidence for an IFN-regulated expression of the RVFV resistance gene in WF/mol rats.

RVFV is able to cross the blood–brain barrier and infect neurons and glial cells. In humans, RVF is sometimes associated with retinitis and meningoencephalitis (Laughlin et al., 1979 ; Siam et al., 1980 ). In rats infected via peripheral routes, RVFV may enter the central nervous system and cause encephalitis, even in genetically resistant animals that do not develop hepatitis (Peters & Slone, 1982 ; Anderson et al., 1987 ). Moreover, intracerebral inoculation kills resistant as well as susceptible animals as a result of an acute encephalitis. Here, we show that rat C6 glioblastoma cells and primary glial cells from both WF/mol and LEW/mol rats were fully permissive to RVFV. These data may explain why the central nervous system of resistant rats is susceptible to RVFV infection.

Finally, a word of caution to researchers using rats as animal models seems appropriate. In an attempt to characterize a gene locus that confers resistance to RVFV, we discovered that two inbred strains did not exhibit the resistant phenotype described previously in the literature. It had been reported that LEW/mai but not WF/mai rats are resistant to RVFV-induced hepatitis (Peters & Slone, 1982 ; Anderson et al., 1987 ). The present data show, however, that LEW and WF rats obtained from the Danish breeder M&B behaved differently, i.e. LEW/mol rats were highly susceptible to RVFV infections whereas WF/mol rats were resistant to RVFV infections (Table 2). The ZH501 strain of RVFV (Meegan, 1979 ) was used in previous challenge experiments with LEW/mai and WF/mai rats, whereas we used strain ZH548 to infect LEW/mol and WF/mol rats. Therefore, it might be argued that the observed differences in host resistance may be attributed to specific pathogenic properties of the two virus strains rather than to genetic differences of the rat strains used. This is very unlikely as no substantial differences were found between RVFV strain ZH501 and strain ZH548 concerning (i) virulence for susceptible WF/mai rats; (ii) ability to form plaques in hepatocytes from resistant LEW/mai rats or susceptible WF/mai rats; and (iii) sensitivity to IFN in cell culture (Anderson & Peters, 1988 ). Thus, rats that seemingly represent the same inbred rat strain may show quite opposite phenotypes upon RVFV infection, depending on the breeding stocks from which they are derived. The observation that LEW/NIco and WF/Ico rats from the French breeder IFFA CREDO (L’Arbresle, France) are both resistant to RVFV infections (M. Bouloy, unpublished results) further complicates the picture and indicates a high degree of genetic variability among the ‘inbred’ rat strains LEW and WF. The results are in line with a previous genetic characterization of 156 rat substrains using 39 markers (Bender et al., 1994 ). Interestingly, Bender and colleagues reported that 12 out of 13 LEW substrains have identical markers but LEW/mol rats differ from the other LEW rats by several gene loci. Furthermore, extensive substrain differences were found among WF rat markers (Bender et al., 1994 ). Therefore, a revision of the nomenclature and a better genetic characterization of rat breeding stocks is needed in order to improve the standardization of animal experiments in the future.


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Table 2. RVFV resistance in rats from different breeding colonies but from the same inbred strain

 

   Acknowledgments
 
We thank George W. Anderson, Jonathan F. Smith, Fritz v. Weizsäcker, Poul H. Jørgensen and Georg Kochs for helpful discussions and advice; Michel Huerre for histopathological examinations; Simone Gruber and Sabine McNelly for expert technical assistance; and Kathrin Hagmaier for critical reading of the manuscript. This work was supported by grant HA 1582 from the Deutsche Forschungsgemeinschaft.


   References
Top
Abstract
Introduction
Methods
Results
Discussion
References
 
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Received 26 April 2000; accepted 2 August 2000.



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