Browsing by Author "Deventhiran, Jagadeeswaran"

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    Influenza A Virus PB1-F2 Protein: its Role in Pathogenesis
    Deventhiran, Jagadeeswaran (Virginia Tech, 2015-07-31)
    Influenza A virus (IAV) causes annual seasonal epidemics and occasional pandemics resulting in significant levels of mortality and socio-economic costs worldwide. PB1-F2 is a small non-structural protein encoded by an alternate +1 open reading frame in the PB1 gene. PB1-F2 is considered to play important roles in primary influenza virus infection and post-influenza secondary bacterial pneumonia in mice. It is a multifunctional and enigmatic protein with diverse functions attributed to it and the precise contribution of PB1-F2 to the IAV life cycle in avian and mammalian hosts remains largely unknown. In the triple-reassortant H3N2 (TR H3N2) swine influenza virus (SIV) background, we found that PB1-F2 expression did not affect nasal shedding, lung viral load, immunophenotypes, and lung pathology in pigs. On the other hand, in turkeys, deletion of PB1-F2 resulted in early induction of clinical disease and effective transmission among the turkey poults. Interestingly, the virulence associated 66S mutation in PB1-F2 abolished the ability of the IAV to successfully infect turkeys and transmit to in-contacts. These results highlight the strain- and species-specific role of PB1-F2 protein. We also demonstrated that specific amino acid residues in the C-terminal of PB1-F2 determine the pathogenicity of 2009 swine-origin pandemic H1N1 virus in a mouse model. The C-terminal residues 73K, 75R, and 79R together with 66S increased virus replication, decreased type I interferon response, increased infiltration of neutrophils and myeloperoxidase production in lungs resulting in acute respiratory distress syndrome (ARDS) in mice with characteristic clinical and pathological features of acute lung injury (ALI). Further, we found that PB1-F2 induces mitochondrial superoxide production and mitochondrial damage in a sequence dependent manner in IAV-infected lung epithelial cells. PB1-F2-mediated mitochondrial damage promotes Parkin-mediated mitophagy but suppresses the autophagic degradation of damaged mitochondria in the infected lung epithelial cells. Accumulated dysfunctional mitochondria likely to aggravate host cell death and inflammatory responses. Taken together, the present findings enhance our understanding of PB1-F2 protein as a virulence determinant in IAV infection in a species- and strain-specific manner and provide new insights into the impact of genetic changes in PB1-F2 on the host pathogenesis of virulent IAV strains.
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    A Novel Pathogenic Mammalian Orthoreovirus from Diarrheic Pigs and Swine Blood Meal in the United States
    Narayanappa, Athmaram Thimmasandra; Sooryanarain, Harini; Deventhiran, Jagadeeswaran; Cao, Dianjun; Venkatachalam, Backiyalakshmi Ammayappan; Kambiranda, Devaiah; LeRoith, Tanya; Heffron, C. Lynn; Lindstrom, Nicole; Hall, Karen; Jobst, Peter; Sexton, Cary; Meng, Xiang-Jin; Elankumaran, Subbiah (American Society for Microbiology, 2015-05)
    Since May 2013, outbreaks of porcine epidemic diarrhea have devastated the U.S. swine industry, causing immense economic losses. Two different swine enteric coronaviruses (porcine epidemic diarrhea virus and Delta coronavirus) have been isolated from the affected swine population. The disease has been reported from at least 32 states of the United States and other countries, including Mexico, Peru, Dominican Republic, Canada, Columbia, Ecuador, and Ukraine, with repeated outbreaks in previously infected herds. Here we report the isolation and characterization of a novel mammalian orthoreovirus 3 (MRV3) from diarrheic feces of piglets from these outbreaks in three states and ring-dried swine blood meal from multiple sources. MRV3 could not be isolated from healthy or pigs that had recovered from epidemic diarrhea from four states. Several MRV3 isolates were obtained from chloroform-extracted pig feces or blood meal in cell cultures or developing chicken embryos. Biological characterization of two representative isolates revealed trypsin resistance and thermostability at 90 degrees C. NextGen sequencing of ultrapurified viruses indicated a strong homology of the S1 segment to mammalian and bat MRV3. Neonatal piglets experimentally infected with these viruses or a chloroform extract of swine blood meal developed severe diarrhea and acute gastroenteritis with 100% mortality within 3 days postinfection. Therefore, the novel porcine MRV3 may contribute to enteric disease along with other swine enteric viruses. The role of MRV3 in the current outbreaks of porcine epidemic diarrhea in the United States remains to be determined, but the pathogenic nature of the virus warrants further investigations on its epidemiology and prevalence. IMPORTANCE Porcine orthoreoviruses causing diarrhea have been reported in China and Korea but not in the United States. We have isolated and characterized two pathogenic reassortant MRV3 isolates from swine fecal samples from porcine epidemic diarrhea outbreaks and ring-dried swine blood meal in the United States. These fecal and blood meal isolates or a chloroform extract of blood meal induced severe diarrhea and mortality in experimentally infected neonatal pigs. Genetic and phylogenetic analyses of two MRV3 isolates revealed that they are identical but differed significantly from nonpathogenic mammalian orthoreoviruses circulating in the United States. The present study provides a platform for immediate development of suitable vaccines and diagnostics to prevent and control porcine orthoreovirus diarrhea.
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    A Time Course for Susceptibility to Staphylococcus aureus Respiratory Infection during Influenza in a Swine Model.
    Smith, E. A.; Kumar, S. R.; Deventhiran, Jagadeeswaran; Cecere, Thomas E.; LeRoith, Tanya; McGilliard, M.; Elankumaran, Subbiah; Mullarky, Isis K. (2011)
    Bacterial superinfections following influenza A virus (IAV) are predominant causes of morbidity in humans. The recent emergence of methicillin-resistant Staphylococcus aureus (MRSA) and highly virulent IAV strains has reduced treatment options. Development of an appropriate animal model to study secondary S. aureus infections may provide important information regarding disease pathogenesis. Pigs are natural hosts to both IAV and S. aureus and have respiratory physiology and immune response comparable to humans. To establish a time course of susceptibility to S. aureus after IAV infection, nursery pigs infected intranasally with IAV were challenged with MRSA at different time points. Lung pathology scores and MRSA CFU were evaluated in dual-infected animals after IAV infection. Flow cytometric analysis of bronchoalveolar lavage fluid indicated differences between treatments. These results demonstrate the appropriateness of an intranasal challenge model in nursery pigs for studying the pathogenesis of IAV and S. aureus coinfection and provide insights into the timeframe for susceptibility of IAV-infected pigs to secondary S. aureus infection.