Treatment with soluble CD24 attenuates COVID-19-associated systemic immunopathology

Background Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) through direct lysis of infected lung epithelial cells, which releases damage-associated molecular patterns and induces a pro-inflammatory cytokine milieu causing systemic inflammation. Anti-viral and anti-inflammatory agents have shown limited therapeutic efficacy. Soluble CD24 (CD24Fc) blunts the broad inflammatory response induced by damage-associated molecular patterns via binding to extracellular high mobility group box 1 and heat shock proteins, as well as regulating the downstream Siglec10-Src homology 2 domain–containing phosphatase 1 pathway. A recent randomized phase III trial evaluating CD24Fc for patients with severe COVID-19 (SAC-COVID; NCT04317040) demonstrated encouraging clinical efficacy. Methods Using a systems analytical approach, we studied peripheral blood samples obtained from patients enrolled at a single institution in the SAC-COVID trial to discern the impact of CD24Fc treatment on immune homeostasis. We performed high dimensional spectral flow cytometry and measured the levels of a broad array of cytokines and chemokines to discern the impact of CD24Fc treatment on immune homeostasis in patients with COVID-19. Results Twenty-two patients were enrolled, and the clinical characteristics from the CD24Fc vs. placebo groups were matched. Using high-content spectral flow cytometry and network-level analysis, we found that patients with severe COVID-19 had systemic hyper-activation of multiple cellular compartments, including CD8+ T cells, CD4+ T cells, and CD56+ natural killer cells. Treatment with CD24Fc blunted this systemic inflammation, inducing a return to homeostasis in NK and T cells without compromising the anti-Spike protein antibody response. CD24Fc significantly attenuated the systemic cytokine response and diminished the cytokine coexpression and network connectivity linked with COVID-19 severity and pathogenesis. Conclusions Our data demonstrate that CD24Fc rapidly down-modulates systemic inflammation and restores immune homeostasis in SARS-CoV-2-infected individuals, supporting further development of CD24Fc as a novel therapeutic against severe COVID-19.

Remodeling Articular Immune Homeostasis with an Efferocytosis-inspired Nanoimitator Mitigates Rheumatoid Arthritis

Massive intra-articular infiltration of the pro-inflammatory macrophages is a prominent feature of rheumatoid arthritis (RA) lesions, which are thought to underlie articular immune dysfunction, severe synovitis and ultimate joint erosion. Here we report an efferocytosis-inspired nanoimitator (EINI) for in situ targeted reprogramming of the synovial inflammatory macrophages (SIMs) and thus thwarting their autoimmune attack and reinstating articular immune homeostasis, which mitigates RA. The EINI consisted of a drug-based core with an oxidative stress-responsive phosphatidylserine (PtdSer) corona and a shell of P-selectin-blocking motif, low molecular weight heparin (LMWH). When systemically administrated, the LMWH on the EINI first bound to P-selectin overexpressed on endothelium in subsynovial capillaries, which functioned as an antagonist disrupting neutrophils synovial trafficking. Due to the high dysregulation of the synovial microvasculature, the EINI subsequently enriched in joint synovium where the shell was exfoliated upon the reactive oxygen species stimulation, and PtdSer corona was then exposed. In an efferocytosis-like manner, the PtdSer-coroneted core was in turn phagocytosed by SIMs, which synergistically terminated the SIMs-initiated pathological cascades and serially reconstructed the intra-articular immune homeostasis, conferring a chondroprotection effect. These findings demonstrate that SIMs can be precisely remodeled via the efferocytosis-mimetic strategy, which holds great potential for RA treatment.

Dietary Vegetable Powders Modulate Immune Homeostasis and Intestinal Microbiota in Mice

As the largest immune organ of the human body, the intestine also plays a vital role in nutrient digestion and absorption. Some vegetables are considered to have improvement effects on the intestine. This experiment explored the effects of freeze-dried asparagus, broccoli and cabbage powder on the intestinal immune homeostasis and microflora of mice. Thirty-two mice were divided into four groups (n = 8), including control group (fed normal diet), asparagus group (fed normal diet with 5% asparagus power), broccoli group (fed normal diet with 5% broccoli power) and cabbage group (fed normal diet with 5% cabbage power). The experiment lasted 21 days. The results showed that the serum immunoglobulin concentration (IgA and IgM) and intestinal cytokine content (like IFN-γ and TNF-α) were increased after vegetable powder supplement. The experiment also detected that vegetable powder supplementation changed intestinal flora and their metabolites (short-chain fatty acid), which showed that the abundance of Lachnospiraceae and Bacteroides were decreased, while the abundance of Firmicutes and Lactobacillus as well as propionic acid and butyric acid contents were increased. Together, these vegetable powders, especially cabbage, changed the intestinal immune response and microbial activity of mice.

Amino acid availability determines plant immune homeostasis in the rhizosphere microbiome

Microbes possess conserved microbe-associated molecular patterns (MAMPs) such as flagellin that are recognized by plant receptors to induce immunity. Despite containing the same MAMPs as pathogens, commensals thrive in the plant rhizosphere microbiome indicating they must suppress or evade host immunity. The beneficial bacteria Pseudomonas capeferrum WCS358 can suppress Arabidopsis root immunity via acidification by secreting gluconic acid. While gluconic acid is sufficient to suppress immunity, we found that it is not necessary in a second beneficial strain Pseudomonas simiae WCS417, which produces more gluconic acid than WCS358. To uncover mechanisms that contribute to the suppression of Arabidopsis immunity, we performed a forward genetic screen in EMS-mutagenized P. simiae WCS417 using a flagellin-inducible CYP71A12 pro:GUS reporter as an Arabidopsis immune readout. We identified a mutant that cannot suppress flagellin-elicited CYP71A12 pro:GUS expression or acidify the rhizosphere. Next generation sequencing revealed a mutation in the catabolic site of an ornithine carbamoyltransferase argF, which is required for arginine biosynthesis. The mutant could be complemented by expression of argF from a plasmid, and a ΔargF mutant could not suppress immunity. Fungal pathogens can use alkalization through production of ammonia and glutamate, the arginine biosynthetic precursors, to promote their own growth and virulence. Therefore, we hypothesized that the biosynthesis of specific amino acids may be necessary to reduce levels of ammonia and glutamate to prevent rhizosphere alkalization and bacterial overgrowth. Genetically blocking arginine, glutamine, or proline biosynthesis, or by adding corresponding exogenous amino acids, resulted in rhizosphere alkalization. Interestingly, exogenous amino acids caused bacterial overgrowth in a gluconic acid-deficient mutants. Our findings show that bacterial amino acid biosynthesis contributes to acidification by preventing accumulation of glutamate precursors and the resulting alkalization. Collectively this work shows that by regulating nutrient availability, plants have the potential to regulate their immune homeostasis in the rhizosphere microbiome.

Impact of Food-Derived Bioactive Compounds on Intestinal Immunity

The gastrointestinal system is responsible for the digestion and the absorption of nutrients. At the same time, it is essentially involved in the maintenance of immune homeostasis. The strongest antigen contact in an organism takes place in the digestive system showing the importance of a host to develop mechanisms allowing to discriminate between harmful and harmless antigens. An efficient intestinal barrier and the presence of a large and complex part of the immune system in the gut support the host to implement this task. The continuous ingestion of harmless antigens via the diet requires an efficient immune response to reliably identify them as safe. However, in some cases the immune system accidentally identifies harmless antigens as dangerous leading to various diseases such as celiac disease, inflammatory bowel diseases and allergies. It has been shown that the intestinal immune function can be affected by bioactive compounds derived from the diet. The present review provides an overview on the mucosal immune reactions in the gut and how bioactive food ingredients including secondary plant metabolites and probiotics mediate its health promoting effects with regard to the intestinal immune homeostasis.

Gut Immune System and the Implications of Oral-Administered Immunoprophylaxis in Finfish Aquaculture

The gastrointestinal immune system plays an important role in immune homeostasis regulation. It regulates the symbiotic host-microbiome interactions by training and developing the host’s innate and adaptive immunity. This interaction plays a vital role in host defence mechanisms and at the same time, balancing the endogenous perturbations of the host immune homeostasis. The fish gastrointestinal immune system is armed with intricate diffused gut-associated lymphoid tissues (GALTs) that establish tolerance toward the enormous commensal gut microbiome while preserving immune responses against the intrusion of enteric pathogens. A comprehensive understanding of the intestinal immune system is a prerequisite for developing an oral vaccine and immunostimulants in aquaculture, particularly in cultured fish species. In this review, we outline the remarkable features of gut immunity and the essential components of gut-associated lymphoid tissue. The mechanistic principles underlying the antigen absorption and uptake through the intestinal epithelial, and the subsequent immune activation through a series of molecular events are reviewed. The emphasis is on the significance of gut immunity in oral administration of immunoprophylactics, and the different potential adjuvants that circumvent intestinal immune tolerance. Comprehension of the intestinal immune system is pivotal for developing effective fish vaccines that can be delivered orally, which is less labour-intensive and could improve fish health and facilitate disease management in the aquaculture industry.