bims-traimu 2024-11-24 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2024–11–24
nine papers selected by
Yantong Wan, Southern Medical University

Trained innate immunity in response to nuclear antigens in systemic lupus erythematosus.
Analysis of the potential long-lasting effects of probiotic Debaryomyces hansenii CBS 8339 on trained immunity in newborn goats.
The C3-C3aR axis modulates trained immunity in alveolar macrophages.
A preliminary investigation on the protective effects of β-glucan and mannan induced trained immunity in pufferfish Takifugu obscurus.
Therapeutic BCG vaccine protects against long COVID: The BATTLE randomized clinical trial.
Randomized trial of BCG in healthcare workers to reduce absenteeism during the COVID-19 pandemic in sub-Saharan Africa.
CD38 ligation in sepsis promotes nicotinamide phosphoribosyltransferase-mediated IL-6 production in kidney stromal cells.
PDCD6 regulates lactate metabolism to modulate LC3-associated phagocytosis and antibacterial defense.
Cytosolic delivery of innate immune agonists.

J Autoimmun. 2024 Nov 14. pii: S0896-8411(24)00169-0. [Epub ahead of print]149 103335

Trained innate immunity in response to nuclear antigens in systemic lupus erythematosus.

Cansu Yanginlar, Nils Rother, Tomas G J M Post, Maaike Jacobs, Inge Jonkman, Montsy Brouns, Sybren Rinzema, Joost H A Martens, Michiel Vermeulen, Leo A B Joosten, Mihai G Netea, Luuk B Hilbrands, Zaheeb A Choudhry, Johan van der Vlag, Raphaël Duivenvoorden.

  Systemic lupus erythematosus (SLE) is an autoimmune disease directed against nuclear antigens, including those derived from apoptotic microparticles (MPs) and neutrophil extracellular traps (NETs). Here we investigated whether nuclear autoantigens can induce trained immunity in SLE patients. Trained immunity is a de facto innate immune memory elicited by an initial stimulus that induces a more vigorous long-term inflammatory response to subsequent stimuli. Isolated monocytes were stimulated with SLE-typical nuclear antigens, neutrophil extracellular traps (NETs), and apoptotic microparticles (MPs) or plasma from SLE patients. After five days of rest, cells were restimulated with Toll-like receptor (TLR) agonists, and cytokine production was measured using ELISA. Functional, transcriptomic and epigenetic changes in monocytes from SLE patients were evaluated by ex vivo stimulations, flow cytometric analysis, RNA sequencing, and chromatin immunoprecipitation (ChIP) sequencing for histone 3 lysine 4 trimethylation. We found that in vitro, both MPs and NETs, as well as plasma from SLE patients, can induce trained immunity. Furthermore, circulating monocytes from SLE patients produce increased levels of pro-inflammatory cytokines after stimulation with TLR ligands, indicating trained immunity. This is accompanied by deregulation in histone 3 lysine 4 trimethylation and increased expression of metabolism and inflammation-related genes. Our findings demonstrate that trained immunity can develop against nuclear antigens and that trained immunity is involved in the immunological dysregulation in SLE patients.

Keywords:  Innate immune cells; Monocytes; Nuclear antigens; Systemic lupus erythematosus; Trained immunity

DOI:  https://doi.org/10.1016/j.jaut.2024.103335
Dev Comp Immunol. 2024 Nov 20. pii: S0145-305X(24)00164-2. [Epub ahead of print] 105292

Analysis of the potential long-lasting effects of probiotic Debaryomyces hansenii CBS 8339 on trained immunity in newborn goats.

Miriam Angulo, Carlos Angulo.

  Trained immunity has been described as the memory capacity of the innate immune system. Several microbial components have been shown to induce trained immunity. Research on the potential of probiotics to trigger these effects has been limited to a few in vitro studies but remains completely unknown in vivo. Components from the probiotic Debaryomyces hansenii CBS 8339 (Dh) have been shown to induce innate immune memory in goat kids and calves. In the present study, stimulating innate immune cells from newborn goats with probiotic Dh increased respiratory burst activity and nitric oxide production, while cell phagocytosis was unaffected. Glucose uptake was enhanced in goat's cells stimulated with Dh, but lactate production was decreased. In newborn goats, after the training scheme (via oral probiotic administration), cell phagocytosis, nitric oxide production and glycolysis - through the upregulation of AKT and HIF1A gene expression, glucose consumption and lactate production- were enhanced. The expression of IL1B gene was similar between the D. hansenii and control groups. Moreover, the potential long-lasting effects were assessed 30 days after initiation of the training scheme. Cell phagocytosis, respiratory burst and myeloperoxidase activity were enhanced, while glycolytic parameters remained unaffected. Altogether, the results of the present study suggest that the immune training scheme may induce trained immunity by the probiotic D. hansenii in newborn goats. However, our findings were not conclusive regarding the long-lasting (one-month) effects of trained immunity by probiotics.

Keywords:  Immunological memory; beneficial microorganisms; caprine; health

DOI:  https://doi.org/10.1016/j.dci.2024.105292
bioRxiv. 2024 Nov 05. pii: 2024.11.01.621042. [Epub ahead of print]

The C3-C3aR axis modulates trained immunity in alveolar macrophages.

Alexander P Earhart, Rafael Aponte Alburquerque, Marick Starick, Aasritha Nallapu, Lorena Garnica, Ayse Naz Ozanturk, Rahul Kumar Maurya, Xiaobo Wu, Jeffrey A Haspel, Hrishikesh S Kulkarni.

Complement protein C3 is crucial for immune responses in mucosal sites such as the lung, where it aids in microbe elimination and enhances inflammation. While trained immunity - enhanced secondary responses of innate immune cells after prior exposure - is well-studied, the role of the complement system in trained immune responses remains unclear. We investigated the role of C3 in trained immunity and found that in vivo, trained wild-type mice showed significantly elevated pro-inflammatory cytokines and increased C3a levels upon a second stimulus, whereas C3-deficient mice exhibited a blunted cytokine response and heightened evidence of lung injury. Ex vivo, C3-deficient alveolar macrophages (AMs) displayed reduced chemokine and cytokine output after training, which was restored by exogenous C3 but not by C3a. Inhibiting C3aR, both pharmacologically and with a genetic C3aR knockout, prevented this restoration, indicating the necessity of C3aR engagement. Mechanistically, trained WT AMs demonstrated enhanced glycolytic activity compared to C3-deficient AMs - a defect corrected by exogenous C3 in a C3aR-dependent manner. These findings reveal that C3 modulates trained immunity in AMs through C3aR signaling, affecting cytokine production and metabolic reprogramming, and highlight a novel role for C3 in trained immunity.

DOI: https://doi.org/10.1101/2024.11.01.621042
Fish Shellfish Immunol. 2024 Nov 20. pii: S1050-4648(24)00680-6. [Epub ahead of print] 110035

A preliminary investigation on the protective effects of β-glucan and mannan induced trained immunity in pufferfish Takifugu obscurus.

Xiaorui Song, Tianying Lei, Nan Cui, Xingkun Jin, Ying Huang, Yan Shi, Zhe Zhao.

  Immune stimuli are able to trigger long-term protective effects through mechanisms of trained immunity, which has attracted increasing attention. Although the existence of trained immunity has evidenced in teleost fish, while there were no such reports in pufferfish (Takifugu obscurus) so far. Therefore, the present study aimed to evaluate the induction of β-glucan and mannan on the trained immunity and their protective efficacy against Vibrio harveyi re-stimulation in pufferfish. β-glucan and mannan induction of trained immunity in head-kidney primary leukocytes is accompanied by a strong increase in immediate ROS burst, cumulative NO production and lactate concentrations after V. harveyi re-stimulation. In addition, β-glucan and mannan-treated pufferfish exhibited reduced bacterial loads in multiple tissues, a rapid and long-term elevated inflammatory response in head kidney during secondary V. harveyi infection. Notably, immune receptors dectin-1 and dectin-2, and cytokines tnfsf14 and il-1β exhibited comparatively upregulation to the β-glucan training, while NK-lysin and faslg showed stronger response to the mannan training post V. harveyi stimulation, implying the different signaling pathway activated post β-glucan and mannan training. Subsequent markers for immune training including abundance of genes encoding glycolytic enzymes (hk1, pfkla, and ldha) and transcription factors (mtor and hif-1α), as well as increased acetylation levels were elevated in the β-glucan and mannan trained pufferfish, depicting heightened glycolysis following β-glucan and mannan training. These results collectively demonstrated that β-glucan and mannan both induced protective responses against V. harveyi infection probably through mediating distinct signaling pathway in pufferfish, and studies are underway to harness its potential applicability for prime and boost vaccination strategies.

Keywords:  Acetylation level; Mannan; Pufferfish (Takifugu obscurus); Trained immunity; β-glucan

DOI:  https://doi.org/10.1016/j.fsi.2024.110035
J Intern Med. 2024 Nov 19.

Therapeutic BCG vaccine protects against long COVID: The BATTLE randomized clinical trial.

Mehrsa Jalalizadeh, Keini Buosi, Cristiane F Giacomelli, Patricia A F Leme, Karen L Ferrari, Franciele A V Dionato, Wandrey R S Brito, Natália S Brunetti, Aline R Maia, Joseane Morari, Ana C Pagliarone, Alessandro S Farias, Licio A Velloso, Maria A F Queiroz, Antonio C R Vallinoto, Marcio C Bajgelman, Leonardo O Reis.

   BACKGROUND: Bacillus Calmette-Guérin (BCG) injected during the COVID-19 convalescence period was safe and enhanced recovery from anosmia and dysgeusia in the acute phase.
OBJECTIVES: To report the long-term results of the BATTLE trial, BCG vaccine in adults with mild COVID-19.
METHODS: Design: Double-blind, placebo-controlled, randomized (1:1) clinical trial.
INTERVENTION: BCG intradermal vaccine and placebo.
PATIENTS: A total of 157 BCG and 142 placebo recipients participated in the 6-month follow-up, and 97 BCG and 95 placebo recipients participated in the 12-month follow-up.
MEASUREMENTS: Long COVID symptoms and mechanistic analyses.
RESULTS: BCG reduced hearing problems at 6 months (odds ratio [OR] = 0.26) and sleeping, concentration, memory, and vision problems at 12 months (OR = 0.45, 0.36, 0.38, and 0.36, respectively). Sensitivity analyses confirmed that long COVID-19 symptoms were reduced at the 6- and 12-month follow-ups (p = 0.010 and 0.031, respectively). BCG's crossover interaction paradoxically increased hair loss in women and decreased it in men at 6 months (p = 0.032). BCG immunomodulation is likely mediated through inhibition of Fas ligand expression in the blood and increased induction of IL6, IL10, interferon-induced transmembrane protein 3, and angiotensin-converting enzyme 2 in cultured human macrophages.
CONCLUSION: Long-term follow-up of the BATTLE trial participants revealed that BCG protects against long COVID development if administered within the COVID-19 convalescence period. The response to BCG was subject-specific, including a paradoxical crossover interaction based on sex.
LIMITATIONS: Not tested for previous mycobacterial exposure; loss to follow-up, particularly at 12 months.

Keywords:  SARS‐CoV‐2; convalescent patients; immunomodulation; safety; trained immunity

DOI:  https://doi.org/10.1111/joim.20033
Trans R Soc Trop Med Hyg. 2024 Nov 20. pii: trae108. [Epub ahead of print]

Randomized trial of BCG in healthcare workers to reduce absenteeism during the COVID-19 pandemic in sub-Saharan Africa.

I Silva, L Nhamússua, E Ca, F Schaltz-Buchholzer, A Nhama, M Cumbe, A P Delgado, M L Lima Mendonça, P Fontoura, M Sidat, P Ferrinho, I I Araújo, P Aide, C Benn, I Fronteira, S Nielsen.

   BACKGROUND: We tested whether providing BCG vaccine to healthcare workers (HCWs) could reduce non-planned absenteeism and thereby reduce the potential impact of the COVID-19 pandemic on healthcare systems in Africa.
METHODS: We conducted a multicenter, single-blinded, placebo-controlled randomized trial in Guinea-Bissau and Mozambique between December 2020 and June 2022. Participants were randomized 1:1 to BCG vaccine or placebo (saline) and followed by biweekly telephone calls for 6 mo. The incidence of unplanned absenteeism due to illness was analyzed using Bayesian negative binomial regression yielding relative RRs. Secondary outcomes included infectious disease episodes, COVID-19 infection and all-cause hospitalizations.
RESULTS: We enrolled 668 HCWs (Guinea-Bissau, n=503; Mozambique, n=165). The RR for absenteeism of BCG vs placebo was 1.29 (0.81 to 1.94) with comparable effects by country. No protection against infectious disease episodes (HR=1.18 [0.97 to 1.45]) or COVID-19 infection (HR=1.19 [0.80 to 1.75]) was observed. Two trial deaths (1 BCG, 1 control) were registered and nine admissions (3 BCG, 6 control), the all-cause admission HR being 0.51 (0.13 to 2.03).
CONCLUSIONS: With 64% of the planned sample size and unplanned absenteeism rates lower than expected, BCG did not reduce self-reported absenteeism due to illness. Rather, BCG tended to increase the risk of self-reported absenteeism, infectious disease episodes and COVID-19 infections.
SHORT SUMMARY: This was a randomized control trial assessing non-specific effects of BCG vaccination in healthcare workers. There was no beneficial effect on self-reported absenteeism due to illness within 6 mo of follow-up during the COVID-19 pandemic, but a trend towards fewer all-cause hospital admissions.

Keywords:  COVID-19 pandemic; bacillus Calmette-Guérin (BCG); healthcare workers; non-specific effects of vaccines; sub-Saharan Africa

DOI:  https://doi.org/10.1093/trstmh/trae108
Nephrol Dial Transplant. 2024 Nov 20. pii: gfae269. [Epub ahead of print]

CD38 ligation in sepsis promotes nicotinamide phosphoribosyltransferase-mediated IL-6 production in kidney stromal cells.

Yuya Suzuki, Tadashi Otsuka, Yusuke Takahashi, Shingo Maruyama, Alexey Annenkov, Yasuhiro Kanda, Tomoya Katakai, Hirofumi Watanabe, Riuko Ohashi, Yoshikatsu Kaneko, Ichiei Narita.

   BACKGROUND AND HYPOTHESIS: Activated macrophages, pivotal for driving the immune response in sepsis, express high levels of CD38. Although the circulating levels of its ligand, CD31, increase in sepsis, the functions of CD38 and its ligation remain elusive. This study aimed to elucidate the impact of CD38 ligation on sepsis using single-cell and single-nucleus RNA sequencing (scRNA-seq and snRNA-seq, respectively) to identify a novel therapeutic target for severe sepsis.
METHODS: We performed scRNA-seq analysis of mouse peritoneal immune cells to precisely identify cell types exhibiting increased CD38 expression upon exposure to lipopolysaccharide (LPS). Subsequently, we induced CD38 ligation using a well-established agonistic anti-CD38 antibody in a mouse model of LPS-induced sepsis. We analyzed its pathophysiological effects using kidney snRNA-seq. Finally, we performed histological analysis of septic tissues collected from patients to ensure consistency of our findings between mice and humans.
RESULTS: LPS stimulation upregulated CD38 expression in peritoneal macrophages. CD38 ligation significantly exacerbated LPS-induced inflammation in vivo, particularly in the kidneys. Kidney snRNA-seq analysis revealed that CD38 ligation induced interleukin (IL)-6 production in renal stromal cells via nicotinamide phosphoribosyltransferase (NAMPT) signaling originating from CD38-positive macrophages. NAMPT inhibition significantly ameliorated LPS-induced IL-6 production and kidney injury. Histological analysis of human septic tissues demonstrated upregulation of IL6 mRNA and NAMPT in renal stromal cells and CD38-positive macrophages, respectively.
CONCLUSION: Our findings elucidate the implications of CD38 ligation in an LPS-induced sepsis model and uncover shared signaling pathways between mice and human sepsis. NAMPT signaling identified in this study may be a novel therapeutic target for mitigating systemic inflammation and kidney injury associated with severe sepsis.

Keywords:  AKI; IL-6; NAMPT; renal stromal cell; sepsis

DOI:  https://doi.org/10.1093/ndt/gfae269
Nat Commun. 2024 Nov 23. 15(1): 10157

PDCD6 regulates lactate metabolism to modulate LC3-associated phagocytosis and antibacterial defense.

Lulu Sun, Sijin Wu, Hui Wang, Tianyu Zhang, Mengyu Zhang, Xuepeng Bai, Xiumei Zhang, Bingqing Li, Cai Zhang, Yan Li, Jun Zhou, Tianliang Li.

LC3-associated phagocytosis (LAP) is critical in host defense against invading pathogens, but the molecular mechanism for LAP activation is still unclear. Here, we find programmed cell death 6 (PDCD6) as a negative regulator of LAP. PDCD6 deficiency in mice and macrophages induces enhanced bactericidal activity and LAP formation. In parallel, lactate dehydrogenase A (LDHA) activity and lactate production is induced in macrophages challenged with bacteria, Zymosan or Pam3CSK4, while genetic ablation or pharmacological inhibition of LDHA reduces lactate levels and impairs bactericidal activity in vivo and in vitro. Mechanistically, PDCD6 interacts with LDHA to downregulate lactate metabolism, leading to reduced RUBCN lactylation at lysine33 (K33). By contrast, PDCD6-deficiency increases RUBCN lactylation, thereby promotes RUBCN interaction with VPS34, LAP formation, and protective responses. Our results thus suggest a PDCD6-LDHA-lactate-RUBCN axis of innate immunity regulation that may both contribute to protection from infectious diseases and serve as targets for therapeutic development.

DOI: https://doi.org/10.1038/s41467-024-54377-w
Trends Immunol. 2024 Nov 19. pii: S1471-4906(24)00253-9. [Epub ahead of print]

Cytosolic delivery of innate immune agonists.

Ravi Bharadwaj, Swati Jaiswal, Neal Silverman.

  Solute carrier proteins (SLCs) are pivotal for maintaining cellular homeostasis by transporting small molecules across cellular membranes. Recent discoveries have uncovered their involvement in modulating innate immunity, particularly within the cytosol. We review emerging evidence that links SLC transporters to cytosolic innate immune recognition and highlight their role in regulating inflammation. We explore how SLC transporters influence the activation of endosomal Toll-like receptors, cytosolic NODs, and STING sensors. Understanding the contribution of SLCs to innate immune recognition provides insight into their fundamental biological functions and opens new avenues to develop possible therapeutic interventions for autoimmune and inflammatory diseases. This review aims to discuss current knowledge and identify key gaps in this rapidly evolving field.

Keywords:  NOD receptors; SLC15; SLC46; STING agonists; cGAMP; muropeptides

DOI:  https://doi.org/10.1016/j.it.2024.10.007