RNA viruses, in general, are deadly human pathogens, and highly efficient in evading antivirals and vaccines, due in part to their ability to mutate rapidly. The annual Flu epidemics and the recent emergence of SARS are important reminders. The long-term goal of this project is to understand the major areas of host-virus interaction in the gene expression and signal transduction of negative-strand RNA viruses, using primarily the human respiratory syncytial virus (RSV) as a model. RSV is a severe lung pathogen in children, causing respiratory diseases and asthma, and claiming nearly a million lives globally each year. In the US alone, RSV infection leads to about 100,000 hospitalizations, costing roughly $350 million to the US taxpayers. The immunopathology of RSV also is highly complex, making it difficult to formulate a reliable vaccine or antiviral. We reasoned that a prudent approach to the management of RSV should take into account the host-virus interactive pathways. In the last few years, we have shown that cellular actin is an essential transcription factor for RSV. Our recent studies using phenotypic knockdown of cellular proteins by a relatively novel strategy, known as """"""""RNA interference"""""""", have revealed an essential role of 3 cytoskeletal-regulatory proteins (CRPs) in RSV maturation. These proteins are: profilin, VASP, and zyxin. Previous studies demonstrated that these proteins were relatively non-essential for the host cell. Thus, we propose that these CRPs could be potential targets for an antiviral regimen. Moreover, an understanding of their role in RSV morphogenesis would shed light on the fundamental mechanism of how the cytoskeleton may play a critical role in RNA viral maturation. Thus, the Specific Aims of the proposal involve detailed studies of: (i) the role of actin as a viral transcription factor; and (ii) the involvement of the CRPs in viral morphogenesis. The available CRP knockout mice strains will be used to complement and extend these studies to an animal model. Together, these results should lead to a better understanding of the replication of RSV in particular and of RNA viruses in general, and pave the way for a more reliable management of the viral diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI059267-04
Application #
7393300
Study Section
Virology - A Study Section (VIRA)
Program Officer
Kim, Sonnie
Project Start
2005-07-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
4
Fiscal Year
2008
Total Cost
$237,657
Indirect Cost
Name
University of South Alabama
Department
Biochemistry
Type
Schools of Medicine
DUNS #
172750234
City
Mobile
State
AL
Country
United States
Zip Code
36688
Poddar, Darshana; Basu, Abhijit; Baldwin 3rd, William M et al. (2013) An extraribosomal function of ribosomal protein L13a in macrophages resolves inflammation. J Immunol 190:3600-12
Das, Priyanka; Basu, Abhijit; Biswas, Aditi et al. (2013) Insights into the mechanism of ribosomal incorporation of mammalian L13a protein during ribosome biogenesis. Mol Cell Biol 33:2829-42
Barik, Sailen (2012) New treatments for influenza. BMC Med 10:104
Musiyenko, Alla; Majumdar, Tanmay; Andrews, Joel et al. (2012) PRMT1 methylates the single Argonaute of Toxoplasma gondii and is important for the recruitment of Tudor nuclease for target RNA cleavage by antisense guide RNA. Cell Microbiol 14:882-901
Sikand, Kavleen; Barik, Sailen; Shukla, Girish C (2011) MicroRNAs and Androgen Receptor 3' Untranslated Region: A Missing Link in Castration-resistant Prostate Cancer? Mol Cell Pharmacol 3:107-113
Basu, Abhijit; Das, Priyanka; Chaudhuri, Sujan et al. (2011) Requirement of rRNA methylation for 80S ribosome assembly on a cohort of cellular internal ribosome entry sites. Mol Cell Biol 31:4482-99
Swedan, Samer; Andrews, Joel; Majumdar, Tanmay et al. (2011) Multiple functional domains and complexes of the two nonstructural proteins of human respiratory syncytial virus contribute to interferon suppression and cellular location. J Virol 85:10090-100
Shukla, Girish C; Singh, Jagjit; Barik, Sailen (2011) MicroRNAs: Processing, Maturation, Target Recognition and Regulatory Functions. Mol Cell Pharmacol 3:83-92
Mazumder, Barsanjit; Li, Xiaoxia; Barik, Sailen (2010) Translation control: a multifaceted regulator of inflammatory response. J Immunol 184:3311-9
Harpen, Mary; Barik, Tiasha; Musiyenko, Alla et al. (2009) Mutational analysis reveals a noncontractile but interactive role of actin and profilin in viral RNA-dependent RNA synthesis. J Virol 83:10869-76

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