Sialic acid decorated multi-valent nanoparticles prevent sepsis mortality in mice

Sepsis is an uncontrolled tissue-immune [hyper]response that leads to the organ failure and frequently patients' death. At present, there is no specific treatment for sepsis, just supporting care. Obviously, sepsis represents important unmet medical condition.

New study in Science Translational Medicine provided evidence that sialic acid coated nanoparticles could prevent sepsis-induced death in mice model of acute sepsis.  

This study is based on prior evidence that binding of sialic acid (type of sugar) to its receptors called Siglecs on macrophages or neutrophils could inhibit inflammatory pathways. Here, the authors showed that unlike bi-valent anti-Siglec antibodies, administration of multi-valent sialic acid coated nanoparticles (in a form of α2,8 sacharide linkage), at both T= 0h or T= +2h, prevented endotoxin induced animal death (i.p. injection).

Similar protection was observed in anesthetized mice undergoing cecal ligation and puncture (CLP) procedure (here too, α2,8-NANO was administered i.p.).

Additionally, intra-lung administration of α2,8-NANO showed significant (but not as impressive) protection against lung inflammation (a secondary complication following cecal ligation and puncture procedure).

The authors showed that protection provided by α2,8-NANO was IL-10 dependent in endotoxin injection model (though, for some reason, the authors had used 1mg α2,8-NANO here, not 2mg α2,8-NANO, as in other figures). Also, application of exogenous IL-10 in IL-10KO mice would have provided more clear role of IL-10 here. 

Finally, the authors tried to show that α2,8-NANO application could be useful for human condition as well. They showed that α2,8-NANO could reduce inflammatory cytokine secretion from primary monocytes stimulated with endotoxin in vitro (but for some reason the authors decided to show "processed", not raw data, implying that data were either not consistent or showed too much variability).

In summary, this study suggests that sialic acid decorated multi-valent nanoparticles may play beneficial role in sepsis management (I want to note here that I am against conducting such distressing experiments on lab animals as are i.p. injection of endotoxin or CLP. We must find better alternative models).

As mention earlier, this study comes with 2 major drawbacks (that make this study not easily "translational"):

(1) while animal studies, shown here, were quite impressive, primary human cells showed less sensitivity towards α2,8-NANO application.
(2) even in animal models, α2,8-NANO was applied through i.p. injection. This route of injection is completely non-applicable for human use and I am puzzled that labs still continuing using it. Why not just use injection via i.v. route?

David Usharauli

Foxp3+ Treg-derived IL-10 stabilizes anti-viral CD8 T cell memory formation

CD8 T cells can eliminate infected or tumor cells. Vaccine formulation that could improve CD8 T cell effector function and memory formation would be highly beneficial against intracellular infections such as HIV, TB, malaria or against tumors.

New study in Nature Immunology provided evidence that Foxp3⁺ T_reg-derived IL-10 modulates CD8 T_cm memory formation.

Initially, the authors showed the proportion of central memory CD8 T cells (T_cm) generated after acute viral infection in IL-10KO mice were significantly reduced. No data are shown about actual T_cm numbers, though. No data are shown about actual viral titre or its clearance, either. Not cool.

Interestingly, presence of IL-10 was only relevant between day 8-15 post-infection (during CD8 T effector cell contraction phase). Here the authors have used PBS, rather than isotype antibody, as a control for anti-IL-10 antibody blockade. Not cool.

Next, the authors found that it was IL-10 derived from Foxp3⁺ T_reg cells that influenced T_cm formation.

Conditional ablation of Foxp3⁺ T_reg cells during early stages of infection had the same effect.

More importantly, viral antigen-specific CD8 memory T cells harvested from IL-10 fl/fl Foxp3-Cre mice (that selectively lacks IL-10 in Foxp3⁺ T_regs) showed reduced survival and reduced protection upon secondary antigen exposure in naive recipients.

Mechanistically, the authors hypothesized that hyper-inflammatory milieu found in IL-10 fl/fl Foxp3-Cre hosts at day 15 post viral infection could contribute to reduced T_cm formation. However, the authors did not try to actually test this hypothesis.

Finally, adoptive transfer of WT Foxp3⁺ T_reg cells at day 8 post infection could rescue T_cm phenotype.

In summary, these results suggest that at some point (day 8-15) post viral infection Foxp3⁺ T_reg-derived IL-10 reduces overall host's activation status and enables T_cm phenotype formation.

David Usharauli