Novel strategies for targeting innate immune responses to influenza.

We previously reported that TLR4(-/-) mice are refractory to mouse-adapted A/PR/8/34 (PR8) influenza-induced lethality and that therapeutic administration of the TLR4 antagonist Eritoran blocked PR8-induced lethality and acute lung injury (ALI) when given starting 2 days post infection. Herein we extend these findings: anti-TLR4- or -TLR2-specific IgG therapy also conferred significant protection of wild-type (WT) mice from lethal PR8 infection. If treatment is initiated 3 h before PR8 infection and continued daily for 4 days, Eritoran failed to protect WT and TLR4(-/-) mice, implying that Eritoran must block a virus-induced, non-TLR4 signal that is required for protection. Mechanistically, we determined that (i) Eritoran blocks high-mobility group B1 (HMGB1)-mediated, TLR4-dependent signaling in vitro and circulating HMGB1 in vivo, and an HMGB1 inhibitor protects against PR8; (ii) Eritoran inhibits pulmonary lung edema associated with ALI; (iii) interleukin (IL)-1β contributes significantly to PR8-induced lethality, as evidenced by partial protection by IL-1 receptor antagonist (IL-1Ra) therapy. Synergistic protection against PR8-induced lethality was achieved when Eritoran and the antiviral drug oseltamivir were administered starting 4 days post infection. Eritoran treatment does not prevent development of an adaptive immune response to subsequent PR8 challenge. Overall, our data support the potential of a host-targeted therapeutic approach to influenza infection

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Sepsis definitions: Time for change

SCOPUS: sh.jinfo:eu-repo/semantics/publishe

Niche models tell half the story:spatial context and life-history traits influence species responses to global change

Aim While niche models are typically used to assess the vulnerability of species to climate change, they have been criticized for their limited assessment of threats other than climate change. We attempt to evaluate this limitation by combining niche models with life-history models to investigate the relative influence of climate change and a range of fire regimes on the viability of a long-lived plant population. Specifically, we investigate whether range shift due to climate change is a greater threat to an obligate seeding fire-prone shrub than altered fire frequency and how these two threatening processes might interact. Location Australian sclerophyll woodland and heathland. Methods The study species is Leucopogon setiger, an obligate seeding fire-prone shrub. A spatially explicit stochastic matrix model was constructed for this species and linked with a dynamic niche model and fire risk functions representing a suite of average fire return intervals. We compared scenarios with a variety of hypothetical patches, a patch framework based upon current habitat suitability and one with dynamic habitat suitability based on climate change scenarios A1FI and A2. Results Leucopogon setiger was found to be sensitive to fire frequency, with shorter intervals reducing expected minimum abundances (EMAs). Spatial decoupling of fires across the landscape reduced the vulnerability of the species to shortened fire frequencies. Shifting habitat, while reducing EMAs, was less of a threat to the species than frequent fire. Main conclusions Altered fire regime, in particular more frequent fires relative to the historical regime, was predicted to be a strong threat to this species, which may reflect a vulnerability of obligate seeders in general. Range shifts induced by climate change were a secondary threat when habitat reductions were predicted. Incorporating life-history traits into habitat suitability models by linking species distribution models with population models allowed for the population-level evaluation of multiple stressors that affect population dynamics and habitat, ultimately providing a greater understanding of the impacts of global change than would be gained by niche models alone. Further investigations of this type could elucidate how particular bioecological factors can affect certain types of species under global change. ?? 2012 Blackwell Publishing Ltd