Abstract
Respiratory syncytial virus (RSV), a prominent cause of airway morbidity in children, maintains an excessive hospitalization rate despite decades of research. Host factors are assumed to influence the disease severity. As a first step toward identifying the underlying resistance mechanisms, we recently showed that inbred mouse strains differ dramatically as regards their susceptibility to pneumonia virus of mice (PVM), the murine counterpart of RSV. PVM infection in mice has been shown to faithfully mimic the severe RSV disease in human infants. This study aimed at dissecting the remarkable PVM-resistance shown by the SJL/J strain. To characterize its genetic component, we assessed clinical, physiopathological, and virological resistance/susceptibility traits in large first (F1) and second (F2) generations obtained by crossing the SJL/J (resistant) and 129/Sv (susceptible) strains. Then, to acquire conclusive in vivo evidence in support of the hypothesis that certain radiosensitive hematopoietic cells might play a significant role in PVM-resistance, we monitored the same resistance/susceptibility traits in mock- and γ-irradiated SJL/J mice. Segregation analysis showed that (i) PVM-resistance is polygenic, (ii) the resistance alleles are recessive, and (iii) all resistance-encoding alleles are concentrated in SJL/J. Furthermore, there was no alteration of SJL/J PVM-resistance after immunosuppression by γ-irradiation, which suggests that adaptive immunity is not involved. We conclude that host resistance to pneumoviruses should be amenable to genetic dissection in this mouse model and that radioresistant lung epithelial cells and/or alveolar macrophages may control the clinical severity of pneumovirus-associated lung disease.
Highlights
The respiratory syncytial virus (RSV) is a major pathogen of the human species
As the great majority of children hospitalized do not belong to any of these categories [5], it has been suggested that individual factors, including genetic ones, might influence the clinical severity of the viral disease associated with RSV infection [6]
We have shown previously that in mice, the genetic background influences significantly their resistance/susceptibility to bronchiolitis and pneumonia caused by pneumonia virus of mice (PVM)
Summary
The respiratory syncytial virus (RSV) is a major pathogen of the human species. By the age of 18 months, about 85% of all infants are already seropositive, and practically all children are seropositive by the time they reach two years of age [1]. The classic strategy is to conduct population-based association studies aiming to demonstrate that certain specific allelic variants are more frequent in hospitalized children than in children with few or no symptoms [9] Such studies have demonstrated that specific haplotypes at the IL4 [10,11,12,13], IL8 [14,15,16], IL9 [17], IL10 [18,19], IL18 [20], CCR5 [21], CCL5 [22], CX3CR1 [23], IGHG2 [24], TLR4 [25,26,27], SP-A [28,29,30], SP-B [31], SP-C [32] and SP-D [33] loci are associated with the severe clinical form. The large number of candidate genes raises questions, and obtaining robust replication of population-based association study findings has proven very difficult [34]
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