Differences in lineage replacement dynamics of G1 and G2 rotavirus strains versus G9 strain over a period of 22years in Bangladesh

Group A rotaviruses (RVAs) have been a major cause of severe gastroenteritis in Bangladesh, mainly in children below the age of five. At the icddr,b, RVA strains collection and characterization dates back for more than 20years. This sample collection was used to study the molecular evolution of the VP7 gene of G1, G2 and G9 RVA strains, which have been circulating in Bangladesh for most of this study period. The evolutionary rates (95% HPD) for G1, G2 and G9 were calculated to be 0.93×10(-)(3) (0.68-1.18), 1.45×10(-)(3) (1.12-1.78) and 1.07×10(-)(3) (0.78-1.39), respectively, which is in line with previous data for the RVA VP7 outer capsid protein, which is under strong negative selective pressure. Bayesian analyses revealed that for the G1 and G2 genotypes, one or multiple lineages co-circulated for one or a few seasons, frequently followed by replacement with genetically different lineages. This can be explained by the existence of a large variety of G1 and G2 RVA lineages and the rapid dissemination of different lineages across the globe. In contrast, circulating G9 lineages were rather closely related to each other across the study period and they were usually derived from variants circulating in the previous season(s). This is consistent with the fact that G9 RVAs have circulated in the human population for less than 20years, and therefore their genetic diversity is much smaller, not resulting in the replacement of circulating G9 strains by highly divergent G9 lineages from abroad. Such different evolutionary dynamics for different RVA genotypes may alter their response to the selective pressure that might be exerted by the introduction of RVA vaccines and therefore a continued close monitoring is warranted.publisher: Elsevier articletitle: Differences in lineage replacement dynamics of G1 and G2 rotavirus strains versus G9 strain over a period of 22years in Bangladesh journaltitle: Infection, Genetics and Evolution articlelink: http://dx.doi.org/10.1016/j.meegid.2014.10.002 content_type: article copyright: Copyright © 2014 Elsevier B.V. All rights reserved.status: publishe

Differences in lineage replacement dynamics of G1 and G2 rotavirus strains versus G9 strain over a period of 22 years in Bangladesh

Group A rotaviruses (RVAs) have been a major cause of severe gastroenteritis in Bangladesh, mainly in children below the age of five. At the icddr,b, RVA strains collection and characterization dates back for more than 20years. This sample collection was used to study the molecular evolution of the VP7 gene of G1, G2 and G9 RVA strains, which have been circulating in Bangladesh for most of this study period. The evolutionary rates (95% HPD) for G1, G2 and G9 were calculated to be 0.93×10 (0.68-1.18), 1.45×10 (1.12-1.78) and 1.07×10 (0.78-1.39), respectively, which is in line with previous data for the RVA VP7 outer capsid protein, which is under strong negative selective pressure. Bayesian analyses revealed that for the G1 and G2 genotypes, one or multiple lineages co-circulated for one or a few seasons, frequently followed by replacement with genetically different lineages. This can be explained by the existence of a large variety of G1 and G2 RVA lineages and the rapid dissemination of different lineages across the globe. In contrast, circulating G9 lineages were rather closely related to each other across the study period and they were usually derived from variants circulating in the previous season(s). This is consistent with the fact that G9 RVAs have circulated in the human population for less than 20years, and therefore their genetic diversity is much smaller, not resulting in the replacement of circulating G9 strains by highly divergent G9 lineages from abroad. Such different evolutionary dynamics for different RVA genotypes may alter their response to the selective pressure that might be exerted by the introduction of RVA vaccines and therefore a continued close monitoring is warranted

Lipopolysaccharide promotes Drp1‐dependent mitochondrial fission and associated inflammatory responses in macrophages

Mitochondria have a multitude of functions, including energy generation and cell signaling. Recent evidence suggests that mitochondrial dynamics (i.e. the balance between mitochondrial fission and fusion) also regulate immune functions. Here, we reveal that lipopolysaccharide (LPS) stimulation increases mitochondrial numbers in mouse bone marrow-derived macrophages (BMMs) and human monocyte-derived macrophages. In BMMs, this response requires Toll-like receptor 4 (Tlr4) and the TLR adaptor protein myeloid differentiation primary response 88 (MyD88) but is independent of mitochondrial biogenesis. Consistent with this phenomenon being a consequence of mitochondrial fission, the dynamin-related protein 1 (Drp1) GTPase that promotes mitochondrial fission is enriched on mitochondria in LPS-activated macrophages and is required for the LPS-mediated increase in mitochondrial numbers in both BMMs and mouse embryonic fibroblasts. Pharmacological agents that skew toward mitochondrial fusion also abrogated this response. LPS triggered acute Drp1 phosphorylation at serine 635 (S635), followed by sustained Drp1 dephosphorylation at serine 656 (S656), in BMMs. LPS-induced S656 dephosphorylation was abrogated in MyD88-deficient BMMs, suggesting that this post-translational modification is particularly important for Tlr4-inducible fission. Pharmacological or genetic targeting of Tlr4-inducible fission had selective effects on inflammatory mediator production, with LPS-inducible mitochondrial fission promoting the expression and/or secretion of a subset of inflammatory mediators in BMMs and mouse embryonic fibroblasts. Thus, triggering of Tlr4 results in MyD88-dependent activation of Drp1, leading to inducible mitochondrial fission and subsequent inflammatory responses in macrophages