Reovirus nonstructural protein sigma1s is required for establishment of viremia and systemic dissemination.
Serotype-specific patterns of reovirus disease in the CNS of newborn mice segregate with the viral S1 gene segment, which encodes attachment protein sigma1 and nonstructural protein sigma1s. The importance of receptor recognition in target cell selection by reovirus implicates the sigma1 protein as the primary effector of disease outcome. However, the contribution of sigma1s to reovirus disease is unknown. To define the function of sigma1s in reovirus pathogenesis, we generated a sigma1s-deficient virus by altering a single nucleotide to disrupt the sigma1s translational start site. Viruses were recovered that contain nine gene segments from strain type 3 Dearing and either the wild-type or sigma1s-null S1 gene segment from strain type 1 Lang. Following peroral inoculation of newborn mice, both viruses replicated in the intestine, although the wild-type virus achieved higher yields than the sigma1s-null virus. However, unlike the wild-type virus, the sigma1s-deficient virus failed to disseminate to sites of secondary viral replication, including the brain, heart, and liver. Within the small intestine, both viruses were detected in Peyer's patches, but only the wild-type virus reached the mesenteric lymph node. Concordantly, wild-type virus, but not sigma1s-deficient virus, was detected in the blood of infected animals. Wild-type and sigma1s-null viruses produced equivalent titers following intracranial inoculation, indicating that sigma1s is dispensable for viral growth in the murine CNS. These results suggest a key role for sigma1s in virus spread from intestinal lymphatics to the bloodstream, thereby allowing the establishment of viremia and dissemination to sites of secondary replication within the infected host.
Boehme
Karl W
KW
Department of Pediatrics, and the Elizabeth B. Lamb Center for Pediatric Research, D7235 Medical Center North, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Guglielmi
Kristen M
KM
Dermody
Terence S
TS
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000821:virology; D002478:Cells, Cultured; D012089:Mammalian orthoreovirus 3 / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D030102:Orthoreovirus, Mammalian / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D012088:Reoviridae Infections / Q000821:virology*; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*; D014766:Viremia; D014779:Virus Replication
D017361:Viral Nonstructural Proteins; C071901:sigma 1NS protein, Reovirus