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. 2005 Jan;79(2):1036-44.
doi: 10.1128/JVI.79.2.1036-1044.2005.

Natural history of a recurrent feline coronavirus infection and the role of cellular immunity in survival and disease

Jolanda D F de Groot-Mijnes  1 , Jessica M van Dun, Robbert G van der Most, Raoul J de Groot
Affiliations

Natural history of a recurrent feline coronavirus infection and the role of cellular immunity in survival and disease

Jolanda D F de Groot-Mijnes et al. J Virol. 2005 Jan.

Abstract

We describe the natural history, viral dynamics, and immunobiology of feline infectious peritonitis (FIP), a highly lethal coronavirus infection. A severe recurrent infection developed, typified by viral persistence and acute lymphopenia, with waves of enhanced viral replication coinciding with fever, weight loss, and depletion of CD4+ and CD8+ T cells. Our combined observations suggest a model for FIP pathogenesis in which virus-induced T-cell depletion and the antiviral T-cell response are opposing forces and in which the efficacy of early T-cell responses critically determines the outcome of the infection. Rising amounts of viral RNA in the blood, consistently seen in animals with end-stage FIP, indicate that progression to fatal disease is the direct consequence of a loss of immune control, resulting in unchecked viral replication. The pathogenic phenomena described here likely bear relevance to other severe coronavirus infections, in particular severe acute respiratory syndrome, for which multiphasic disease progression and acute T-cell lymphopenia have also been reported. Experimental FIP presents a relevant, safe, and well-defined model to study coronavirus-mediated immunosuppression and should provide an attractive and convenient system for in vivo testing of anticoronaviral drugs.

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Figures

FIG. 1.
FIG. 1.
Survival time and mortality after experimental FIPV infection. Bars indicate the number of animals succumbing to FIP per day. The labels A through E indicate groups of cats with distinct patterns of disease progression (see text).
FIG. 2.
FIG. 2.
Kinetics of neutralizing antibody titers in FIPV-infected cats with different types of disease progression. The virus-neutralizing antibody titers were determined weekly and are expressed as the reciprocal log10 plasma dilution causing 50% virus neutralization. The average titers of the rapid and intermediate (▪, types A and B; 10 cats) and the delayed (•, type C; 3 cats) progressors and the prolonged (▴, type D; 2 cats) and long-term (□, type E, 5 cats) survivors are plotted on the y axis. Curves for types A and B were virtually identical and were therefore combined.
FIG. 3.
FIG. 3.
Disease progression in rapid (A), intermediate (B), and delayed (C) progressors and in prolonged (D) and long-term (E) FIPV survivors. Cats, inoculated oronasally with FIPV 79-1146, were monitored for up to 126 days for fever, body weight, and viral RNA in white blood cells and plasma (top graphs). In addition, total lymphocyte counts and CD4+ and CD8+ T-cells counts (black, red and blue lines, respectively) were determined (bottom graphs). Periods of fever are indicated by pink shading and color coding as follows: blue, ≤37°C; green, 37 to 39.7°C; orange, 39.7 to 40°C; red, 40 to 41°C; magenta, ≥41°C. Body weight (black line, open circles) is expressed as the percentage of weight at day 0. Viral RNA titers as determined by real-time RT-PCR are expressed as CT values on an inverted y axis (red line, white blood cells; blue line, plasma). Total lymphocyte and T-cell counts are presented as percentages of the cell counts determined at day 0. For groups A to C, data acquired for animals with highly similar disease progression were averaged (n = 7, 3, and 3 cats, respectively) to obtain trend curves (left-hand panels). Results obtained for individual animals are shown on the right. For groups D and E, only data for individual animals are presented; for group E, two representative examples are shown. (F) Disease progression in persistently infected cats 085 and 155. The animals were sacrificed at days 58 and 42, respectively.
FIG. 4.
FIG. 4.
rVV expression library of the FIPV 79-1146 proteome. The viral genome is shown schematically. Depicted as boxes are the coding sequences for polyprotein pp1ab (ORF1a and ORF1b), the spike protein (S), the small membrane protein (E), the membrane protein (M), the nucleocapsid protein (N), and those for the accessory proteins 3a to 3c, 7a, and 7b. Indicated below are the regions expressed by the various rVVs (Table 2).
FIG. 5.
FIG. 5.
FIPV-specific T-cell responses in persistently infected, partially protected cats and in a long-term survivor. Splenocytes were stimulated with autologous fibroblast cultures (10), which had been infected with rVVs expressing the various FIPV proteins. An rVV with lacZ inserted into the TK locus (rVV-TK) served as a negative control. Only the results obtained with rVV-TK, rVV-S, rVV-M, and rVV-N are shown. Virus-specific CD4+ and CD8+ T cells were identified by intracellular expression of TNF-α by three-color flow cytometry. Results obtained for partially protected animals 085 and 155 and for long-term survivor 291 are shown as dot-plot representations, with frequencies of antigen-specific T cells given as percentages of the total CD4+ or CD8+ populations.
FIG. 6.
FIG. 6.
FIPV-specific T-cell responses in persistently infected, partially protected cats and in long-term survivors. Splenocytes were stimulated with autologous fibroblast cultures (10), which had been mock infected or infected with rVVs expressing FIPV proteins (A through 7b; 3 indicates 3E7a) (see Fig. 4). rVV-TK served as a negative control (TK). Virus-specific T cells were identified by intracellular expression of TNF-α by three-color flow cytometry. The results are presented as bar graphs, depicting the antigen-specific CD4+ and CD8+ T-cell responses in persistently infected animals (cats 085 and 155) and in long-term survivors (cats 249, 281, and 291). Frequencies of antigen-specific T cells (y axis) are given as percentages of the total CD4+ or CD8+ populations.
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