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. 2013 Aug;87(15):8307-16.
doi: 10.1128/JVI.00619-13. Epub 2013 May 22.

Permissive replication of homologous murine rotavirus in the mouse intestine is primarily regulated by VP4 and NSP1

Ningguo Feng  1 , Linda L Yasukawa, Adrish Sen, Harry B Greenberg
Affiliations

Permissive replication of homologous murine rotavirus in the mouse intestine is primarily regulated by VP4 and NSP1

Ningguo Feng et al. J Virol. 2013 Aug.

Abstract

Homologous rotaviruses (RV) are, in general, more virulent and replicate more efficiently than heterologous RV in the intestine of the homologous host. The genetic basis for RV host range restriction is not fully understood and is likely to be multigenic. In previous studies, RV genes encoding VP3, VP4, VP7, nonstructural protein 1 (NSP1), and NSP4 have all been implicated in strain- and host species-specific infection. These studies used different RV strains, variable measurements of host range, and different animal hosts, and no clear consensus on the host range restriction determinants emerged. We used a murine model to demonstrate that enteric replication of murine RV EW is 1,000- to 10,000-fold greater than that of a simian rotavirus (RRV) in suckling mice. Intestinal replication of a series of EW × RRV reassortants was used to identify several RV genes that influenced RV replication in the intestine. The role of VP4 (encoded by gene 4) in enteric infection was strain specific. RRV VP4 reduced murine RV infectivity only slightly; however, a reassortant expressing VP4 from a bovine RV strain (UK) severely restricted intestinal replication in the suckling mice. The homologous murine EW NSP1 (encoded by gene 5) was necessary but not sufficient for promoting efficient enteric growth. Efficient enteric replication required a constellation of murine genes encoding VP3, NSP2, and NSP3 along with NSP1.

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Figures

Fig 1
Fig 1
(A) EW or RRV titers in the intestine in orally infected 5-day-old suckling 129sv mice. Five-day-old suckling mice were orally inoculated with wild-type EW (104 DD50) or cell culture-adapted RRV (107 PFU). At different days postinfection, mice (n = 3) were sacrificed and intestinal tissues collected. Virus titers in intestines were determined by qRT-PCR and expressed as PFU equivalent per gram of tissue. The virus titers in EW-infected mice were significantly higher than in RRV-infected mice at all time points (P < 0.01). (B and C) Tissues from small intestines were collected at day 3 postinfection with EW (B) or RRV (C) and were stained with Texas Red-labeled anti-RV VP6 monoclonal antibody (MAb), 1E11 (red), and the cell nucleus was stained with DAPI (blue).
Fig 2
Fig 2
Intestinal titers of indicated RV in suckling 129sv mice infected with EW or EW × RRV monoreassortant D6/2. Five-day-old suckling 129sv mice were orally inoculated with wild-type EW (104 DD50) or D6/2 (104 PFU). At different days postinfection, mice (n = 3) were sacrificed and intestinal tissues collected. Virus titers in intestines were determined by qRT-PCR and are expressed as PFU equivalents per gram of tissue. *, the virus titers in EW-infected mice were significantly higher than in D6/2-infected mice at days 4 and 6 postinfection (P < 0.01).
Fig 3
Fig 3
Comparison of the titers of various RVs in the intestine of wild-type and STAT1 KO 129 suckling mice. Five-day-old wild-type 129sv or STAT1 KO mice were orally inoculated with wild-type EW (104 PFU), RRV (104 PFU), or EW × RRV reassortants (104 PFU). At day 3 postinfection, mice (n = 4 to 13 per virus strain) were sacrificed and intestinal tissues were collected. Virus titers in intestines were determined by qRT-PCR (EW) or plaque assay (RRV or EW × RRV reassortants) and expressed as PFU equivalent (EW) or PFU (RRV or EW × RRV reassortants) per gram of tissue. The geometric means were calculated for each growth phenotype group. *, the virus titers were significantly different for RRV, the RRV-like phenotypic group, and the intermediate phenotypic group in wild-type versus STAT1 KO mice (P < 0.05); there was no significant difference between titers in wild-type and STAT1 KO mice for EW or the EW-like phenotypic group (P > 0.05).
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