Specific microbiota species induce serum IgA that protects against sepsis

Some 10 years ago the scientists made observation that microbiota difference between different mouse colonies is responsible for selective T_H17 expansion in the gut. Since then, field of immunology was flooded with numerous observations linking gut [and other tissue] microbiota to functional status of immune system.

One such study was recently published in journal Cell Host and Microbe. The researchers observed that serum IgA secreted by bone marrow residing plasma cells (BM PCs) were selectively enriched in mouse colony harboring members of Proteobacteria phylum. More importantly, these serum IgA protected mice during sepsis following gut damage.

Initially, the authors observed that their institute's B6 mouse colony (PENN-SPF) differed from commercial vendor B6 mice in their serum [but not small intestine] IgA status. Co-housing experiment indicated potential involvement of microbiota.

Indeed, 16S ribosomal gene sequencing showed enrichment of Proteobacteria phylum in local mouse colony (and also Deferribacteres).

Serum IgA bound microbiota and sequencing of serum IgA+/IgA- microbiota species confirmed selective enrichment of species within Proteobacteria phylum.

Development of microbiota-specific serum IgA were T cell-dependent.

Finally, serum IgA protected mice against sepsis following gut tissue damage and microbiota invasion (translocation).

In summary, serum IgA, but not intestinal IgA, is produced by bone marrow plasma cells in response to selective microbiota species, mostly from Proteobacteria phylum in mice. These serum IgA could bind microbiota, it developed in a T cell-dependent manner and protected host during gut flora invasion (translocation) in condition such as sepsis. However, it is not clear why serum IgG [in IgA KO mice] could not protect against sepsis in this study since one previous study already showed that serum IgG protected against gram negative bacteria such as E. coli. It is possible that serum IgA and IgG play non-redundant functions by protected against different microbial species.

posted by David Usharauli

IL-18 contributes to sepsis development during post-natal period

This week PNAS published new study that showed that IL-18 deficiency makes newborn mice resistant to bacterial sepsis. 

Current knowledge about pathophysiology of sepsis is incomplete. In this study, IL-18–null (IL-18−/−) newborn mice showed improved survival when exposed to sepsis-induced bacteria.

Exogenous IL-18 could increase susceptibility of newborn mice to sepsis in absence of adaptive immune system (RAG1−/− mice).

Curiously, TCRδ−/− mice lacking γδT cells [but, unlike RAG1−/− mice, have αβT cells] were resistant to IL-18 effect.

At molecular level, effect of IL-18 on sepsis was dependent of IL-1R signaling 

And also on IL-17 signaling.

In summary, this study expands our knowledge of approaches that can be taken to treat sepsis, for example, Anakinra [an interleukin-1R antagonist] and Cosentyx [anti-interleukin-17A].

David Usharauli

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

IL-3 producing innate B cells drive sepsis susceptibility

Sepsis is a life-threatening condition characterized by over-production of first line defense cytokines such as IL-1β, IL-6, TNF-α (so called cytokine storm) and leading to death due to failure of vital organs (heart, kidney, liver) and coagulation / anti-coagulation systems.

It is not clear whether immune system can defend against sepsis or contrary make it worse. From an evolutionary point of view, sepsis (as infectious overload) would represent dead-end for the host.

However, if we could understand sepsis pathophysiology we can try to manage it. In this regard, new paper in journal Science is of great interest. This study shows that a little known cytokine IL-3 drives host's susceptibility to sepsis.

The authors have studied mouse model of septic shock. They observed that IL-3 KO mice were highly resistant to septic shock. 

IL-3 KO mice were able to control bacterial counts in the blood.

Reconstitution experiments confirmed that IL-3 was driving sepsis susceptibility.

Additional experiments showed that B cells were the major source of IL-3 during sepsis in this mouse model.

Indeed, adoptive transfer of wild-type B cells into IL-3 KO hosts could increase sepsis susceptibility of the host (though the authors failed to present host survival data in this setting, as in Fig. 1A).

Finally, the authors showed that in humans, survival of sepsis patients correlated with the level of serum IL-3.

In summary, this simple study points to a new therapy for sepsis patients. In would be interesting to know whether reduced innate response in IL-3 KO mice (a) allowed the host to clear the bacteria from the blood using alternative mechanisms (complement, C-reactive protein system, etc) or whether (b) it was easier for IL-3 KO hosts to repair gut wall damage and prevent further leak of gut flora into blood.    

David Usharauli