title: The C proteins of human parainfluenza virus type 1 (HPIV1) control the transcription of a broad array of cellular genes that would otherwise respond to HPIV1 infection.
abstract: Human parainfluenza virus type 1 (HPIV1) is an important respiratory pathogen in children and the most common cause of viral croup. We performed a microarray-based analysis of gene expression kinetics to examine how wild-type (wt) HPIV1 infection altered gene expression in human respiratory epithelial cells and what role beta interferon played in this response. We similarly evaluated HPIV1-P(C-), a highly attenuated and apoptosis-inducing virus that does not express any of the four C proteins, and HPIV1-C(F170S), a less attenuated mutant that contains a single point mutation in C and, like wt HPIV1, does not efficiently induce apoptosis, to examine the role of the C proteins in controlling host gene expression. We also used these data to investigate whether the phenotypic differences between the two C mutants could be explained at the transcriptional level. Mutation or deletion of the C proteins of HPIV1 permitted the activation of over 2,000 cellular genes that otherwise would be repressed by HPIV1 infection. Thus, the C proteins profoundly suppress the response of human respiratory cells to HPIV1 infection. Cellular pathways targeted by the HPIV1 C proteins were identified and their transcriptional control was analyzed using bioinformatics. Transcription factor binding sites for IRF and NF-kappaB were overrepresented in some of the C protein-targeted pathways, but other pathways were dominated by less-known factors, such as forkhead transcription factor FOXD1. Surprisingly, the host responses to the P(C-) and C(F170S) mutants were very similar, and only subtle differences in the expression kinetics of caspase 3 and TRAIL receptor 2 were observed. Thus, changes in host cell transcription did not reflect the striking phenotypic differences observed between these two viruses.
authors.affiliation: Laboratory of Infectious Diseases, Respiratory Viruses Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-8007, USA.
authors.forename: Jim B
authors.initials: JB
authors.lastname: Boonyaratanakornkit
authors.forename: Emmalene J
authors.initials: EJ
authors.lastname: Bartlett
authors.forename: Emerito
authors.initials: E
authors.lastname: Amaro-Carambot
authors.forename: Peter L
authors.initials: PL
authors.lastname: Collins
authors.forename: Brian R
authors.initials: BR
authors.lastname: Murphy
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Schmidt
mesh_terms: D002460:Cell Line; D004847:Epithelial Cells / Q000821:virology; D017353:Gene Deletion; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D010222:Parainfluenza Virus 1, Human / Q000235:genetics / Q000502:physiology*; D017354:Point Mutation; D020545:Respiratory Mucosa / Q000821:virology; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D014764:Viral Proteins; C068856:C protein, human parainfluenza virus type 1