Genetic analysis of HA1 domain of influenza A/H3N2 viruses isolated in Kenya during the 2007-2013 seasons reveal significant divergence from WHO-recommended vaccine strains.

BACKGROUND: Influenza viruses evolve rapidly and cause regular seasonal epidemics in humans challenging effective vaccination. The virus surface HA glycoprotein is the primary target for the host immune response. Here, we investigated the vaccine efficacy and evolution patterns of human influenza A/H3N2 viruses that circulated in Kenyan in the period before and after the 2009 A/H1N1 pandemic, targeting the HA1 domain. MATERIALS AND METHODS: A hundred and fifteen HA sequences of Kenyan virus viruses were analyzed relative to the corresponding WHO vaccine reference strains using bioinformatics approaches. RESULTS: Our analyses revealed varied amino acid substitutions at all the five antigenic sites (A-E) of the HA1 domain, with a majority the changes occurring at sites A and B. The Kenyan A/H3N2 viruses isolated during 2007/2008 seasons belonged to A/Brisbane/10/2007-like viruses lineage, while those circulating in 2009-2012 belonged to the lineage of A/Victoria/361/2011-like viruses. The 2013 viruses clustered in clade 3C.3 of the A/Samara/73/2013-like viruses. The mean evolutionary rate of the A/H3N2 viruses analyzed in the study was at 4.17×10-3 (95% HPD=3.09×10-3-5.31×10-3) nucleotide substitutions per site per year, whereas the TMRCA was estimated at 11.18 (95% HPD=9.00-14.12) years ago from 2013. The prediction of vaccine efficacy revealed modest vaccine efficaciousness during 2008, and 2010 influenza seasons, whilst sub-optimal effectiveness was registered in 2007, 2009, 2012 and 2013. Further, the overall selective pressure acting on the HA1 domain was estimated at 0.56 (ω<1), suggesting that a majority of codon sites in the HA1 epitopes were evolving under purifying selection. CONCLUSIONS: Generally, our results highlight the genetic plasticity of A/H3N2 viruses and reveal considerable disparity in vaccine efficaciousness against the A/H3N2 viruses that circulated in Kenya, specifically during 2007, 2009, 2012, and 2013 influenza seasons. Our findings underscore the importance and need for consistent surveillance and molecular characterization of influenza viruses, to inform decision making and enhance early of detection of strains with epidemic/pandemic potential as well as benefit in guiding decisions regarding the appropriate annual influenza vaccine formulations.

Targeted disruption of guanylyl cyclase-A/natriuretic peptide receptor-A gene provokes renal fibrosis and remodeling in null mutant mice: role of proinflammatory cytokines.

Binding of atrial and brain natriuretic peptides to guanylyl cyclase-A/natriuretic peptide receptor-A produces second messenger cGMP, which plays an important role in maintaining renal and cardiovascular homeostasis. Mice carrying a targeted disruption of the Npr1 gene coding for guanylyl cyclase-A/natriuretic peptide receptor-A exhibit changes that are similar to those that occur in untreated human hypertension, including elevated blood pressure, cardiac hypertrophy, and congestive heart failure. The objective of this study was to determine whether disruption of the Npr1 gene in mice provokes kidney fibrosis, remodeling, and derangement. We found that systemic disruption of the Npr1 gene causes increased renal tubular damage characterized by dilation, flattening of epithelium, and expansion of interstitial spaces in Npr1(-/-) (0-copy) mice. Significant increases occurred in the expression levels of TNF-α (4-fold), IL-6 (4.5-fold), and TGF-ß1 (2-fold) in 0-copy null mutant mice compared with 2-copy wild-type mice. An increased epithelial-to-mesenchymal transition indicated by increased expression of α-smooth muscle actin, was observed in Npr1(-/-) mouse kidneys. Treatment with captopril and losartan showed a 38 and 46% attenuation in fibrosis and 30 and 42% reduction in α-smooth muscle actin immunoexpression, respectively, in 1-copy and 0-copy mice compared with 2-copy mice. Although bendroflumethiazide treatment did not show any effect. The present results demonstrate that the disruption of Npr1 gene activates proinflammatory cytokines leading to fibrosis, hypertrophic growth, and remodeling of the kidneys of mutant mice.