bims-traimu 2024-01-21 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2024–01–21
twelve papers selected by
Yantong Wan, Southern Medical University

Implications of vaccine non-specific effects on licensure of new vaccines.
O6-methylguanine DNA methyltransferase regulates β-glucan-induced trained immunity of macrophages via farnesoid X receptor and AMPK.
Effects of Bacillus Calmette-Guérin on immunometabolism, microbiome and liver diseases⋆.
Trained immunity in recurrent Staphylococcus aureus infection promotes bacterial persistence.
BCG immunization induces CX3CR1hi effector memory T cells to provide cross-protection via IFN-γ-mediated trained immunity.
The roles of innate and adaptive immunity in inactivated viral vaccination-mediated protection against COVID-19.
Dectin-1 ligands produce distinct training phenotypes in human monocytes through differential activation of signaling networks.
Epigenetic memory.
Low-dose Olaparib improves septic cardiac function by reducing ferroptosis via accelerated mitophagy flux.
LncRNA 220, a newly discovered long non-conding RNA inhibiting apoptosis and autophagy in Kupffer cells in LPS-induced endotoxemic mice through the XBP1u-PI3K-AKT pathway.
Protein 4.1R regulates M1 macrophages polarization via glycolysis, alleviating sepsis-induced liver injury in mice.
Exposure to Mycobacterium remodels alveolar macrophages and the early innate response to Mycobacterium tuberculosis infection.

Vaccine. 2024 Jan 18. pii: S0264-410X(24)00060-4. [Epub ahead of print]

Implications of vaccine non-specific effects on licensure of new vaccines.

Grant Munkwase.

  Immune memory was for a long time thought to be an exclusive feature of the adaptive immune system. Emerging evidence has shown that the innate immune system may exhibit memory which has been termed as trained immunity or innate immune memory. Trained immunity following vaccination may produce non-specific effects leading to reduction in morbidity and mortality from heterologous pathogens. This review looked at trained immunity as a mechanism for vaccine induced non-specific effects, mechanisms underlying trained immunity and known vaccine non-specific effects. A discussion is also made on the implications these vaccine non-specific effects may have on overall risk-benefit ratio evaluation by National Medicines Regulatory Authorities (NMRAs) during licensure of new vaccines. Epigenetic remodeling and "rewiring" of cellular metabolism in the innate immune cells especially monocytes, macrophages, and Natural Killer (NK) cells have been suggested to be the mechanisms underlying trained immunity. Trained immunity in other innate cells has largely remained elusive up to date. Non-specific effects have been extensively documented with Bacille Calmette-Guerin (BCG), measles vaccine and oral polio vaccine but it remains unclear if other vaccines may exhibit similar effects. All known vaccine non-specific effects have come from observations in epidemiological studies conducted post-vaccine licensure and roll out in target populations. It remains to be seen if early identification of non-specific effects especially those with protective benefits during the clinical development of new vaccines may contribute to the overall risk-benefit ratio evaluation during licensure by NMRAs.

Keywords:  Implications; Licensure; Off-target effects; Risk–benefit ratio; Trained immunity mechanisms; Vaccine non-specific effects

DOI:  https://doi.org/10.1016/j.vaccine.2024.01.048
iScience. 2024 Jan 19. 27(1): 108733

O6-methylguanine DNA methyltransferase regulates β-glucan-induced trained immunity of macrophages via farnesoid X receptor and AMPK.

Salisa Benjaskulluecha, Atsadang Boonmee, MdFazlul Haque, Benjawan Wongprom, Thitiporn Pattarakankul, Chitsuda Pongma, Kittitach Sri-Ngern-Ngam, Pornlapat Keawvilai, Thadaphong Sukdee, Benjawan Saechue, Patipark Kueanjinda, Tanapat Palaga.

  Trained immunity is the heightened state of innate immune memory that enhances immune response resulting in nonspecific protection. Epigenetic changes and metabolic reprogramming are critical steps that regulate trained immunity. In this study, we reported the involvement of O6-methylguanine DNA methyltransferase (MGMT), a DNA repair enzyme of lesion induced by alkylating agents, in regulation the trained immunity induced by β-glucan (BG). Pharmacological inhibition or silencing of MGMT expression altered LPS stimulated pro-inflammatory cytokine productions in BG-trained bone marrow derived macrophages (BMMs). Targeted deletion of Mgmt in BMMs resulted in reduction of the trained responses both in vitro and in vivo models. The transcriptomic analysis revealed that the dampening trained immunity in MGMT KO BMMs is partially mediated by ATM/FXR/AMPK axis affecting the MAPK/mTOR/HIF1α pathways and the reduction in glycolysis function. Taken together, a failure to resolve a DNA damage may have consequences for innate immune memory.

Keywords:  Cell biology; Immunology; Molecular biology; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2023.108733
Liver Res. 2023 Jun;7(2): 116-123

Effects of Bacillus Calmette-Guérin on immunometabolism, microbiome and liver diseases⋆.

Muhammad Umair Ijaz, Farzam Vaziri, Yu-Jui Yvonne Wan.

  Metabolic diseases have overtaken infectious diseases as the most serious public health issue and economic burden in most countries. Moreover, metabolic diseases increase the risk of having infectious diseases. The treatment of metabolic disease may require a long-term strategy of taking multiple medications, which can be costly and have side effects. Attempts to expand the therapeutic use of vaccination to prevent or treat metabolic diseases have attracted significant interest. A growing body of evidence indicates that Bacillus Calmette-Guérin (BCG) offers protection against non-infectious diseases. The non-specific effects of BCG occur likely due to the induction of trained immunity. In this regard, understanding how BCG influences the development of chronic metabolic health including liver diseases would be important. This review focuses on research on BCG, the constellation of disorders associated with metabolic health issues including liver diseases and diabetes as well as how BCG affects the gut microbiome, immunity, and metabolism.

Keywords:  Bacillus Calmette-Guérin (BCG); Diabetes; Gut microbiota; Liver disease; Metabolic diseases; Trained immunity; Vaccination

DOI:  https://doi.org/10.1016/j.livres.2023.05.001
PLoS Pathog. 2024 Jan;20(1): e1011918

Trained immunity in recurrent Staphylococcus aureus infection promotes bacterial persistence.

Xiao-Qi Lin, Zhen-Zhen Liu, Cheng-Kai Zhou, Liang Zhang, Yu Gao, Xue-Yue Luo, Jian-Gang Zhang, Wei Chen, Yong-Jun Yang.

Bacterial persister cells, a sub-population of dormant phenotypic variants highly tolerant to antibiotics, present a significant challenge for infection control. Investigating the mechanisms of antibiotic persistence is crucial for developing effective treatment strategies. Here, we found a significant association between tolerance frequency and previous infection history in bovine mastitis. Previous S. aureus infection led to S. aureus tolerance to killing by rifampicin in subsequent infection in vivo and in vitro. Actually, the activation of trained immunity contributed to rifampicin persistence of S. aureus in secondary infection, where it reduced the effectiveness of antibiotic treatment and increased disease severity. Mechanically, we found that S. aureus persistence was mediated by the accumulation of fumarate provoked by trained immunity. Combination therapy with metformin and rifampicin promoted eradication of persisters and improved the severity of recurrent S. aureus infection. These findings provide mechanistic insight into the relationship between trained immunity and S. aureus persistence, while providing proof of concept that trained immunity is a therapeutic target in recurrent bacterial infections involving persistent pathogens.

DOI: https://doi.org/10.1371/journal.ppat.1011918
Nat Immunol. 2024 Jan 15.

BCG immunization induces CX3CR1hi effector memory T cells to provide cross-protection via IFN-γ-mediated trained immunity.

Kim A Tran, Erwan Pernet, Mina Sadeghi, Jeffrey Downey, Julia Chronopoulos, Elizabeth Lapshina, Oscar Tsai, Eva Kaufmann, Jun Ding, Maziar Divangahi.

After a century of using the Bacillus Calmette-Guérin (BCG) vaccine, our understanding of its ability to provide protection against homologous (Mycobacterium tuberculosis) or heterologous (for example, influenza virus) infections remains limited. Here we show that systemic (intravenous) BCG vaccination provides significant protection against subsequent influenza A virus infection in mice. We further demonstrate that the BCG-mediated cross-protection against influenza A virus is largely due to the enrichment of conventional CD4+ effector CX3CR1hi memory αβ T cells in the circulation and lung parenchyma. Importantly, pulmonary CX3CR1hi T cells limit early viral infection in an antigen-independent manner via potent interferon-γ production, which subsequently enhances long-term antimicrobial activity of alveolar macrophages. These results offer insight into the unknown mechanism by which BCG has persistently displayed broad protection against non-tuberculosis infections via cross-talk between adaptive and innate memory responses.

DOI: https://doi.org/10.1038/s41590-023-01739-z
Clin Transl Med. 2024 Jan;14(1): e1530

The roles of innate and adaptive immunity in inactivated viral vaccination-mediated protection against COVID-19.

Shanhe Yu, Shijun Chen, Jiang Zhu, Jieming Qu.



Keywords:  COVID-19; inactivated viral vaccination; innate and adaptive immunity; trained immunity

DOI:  https://doi.org/10.1002/ctm2.1530
Sci Rep. 2024 01 17. 14(1): 1454

Dectin-1 ligands produce distinct training phenotypes in human monocytes through differential activation of signaling networks.

Quen J Cheng, Kylie Farrell, Jeffrey Fenn, Zuchao Ma, Sara K Makanani, Jonathan Siemsen.

Cells of the innate immune system retain memory of prior exposures through a process known as innate immune training. β-glucan, a Dectin-1 ligand purified from the Candida albicans cell wall, has been one of the most widely utilized ligands for inducing innate immune training. However, many Dectin-1 ligands exist, and it is not known whether these all produce the same phenotype. Using a well-established in vitro model of innate immune training, we compared two commercially available Dectin-1 agonists, zymosan and depleted zymosan, with the gold standard β-glucan in the literature. We found that depleted zymosan, a β-glucan purified from Saccharomyces cerevisiae cell wall through alkali treatment, produced near identical effects as C. albicans β-glucan. However, untreated zymosan produced a distinct training effect from β-glucans at both the transcript and cytokine level. Training with zymosan diminished, rather than potentiated, induction of cytokines such as TNF and IL-6. Zymosan activated NFκB and AP-1 transcription factors more strongly than β-glucans. The addition of the toll-like receptor (TLR) ligand Pam3CSK4 was sufficient to convert the training effect of β-glucans to a phenotype resembling zymosan. We conclude that differential activation of TLR signaling pathways determines the phenotype of innate immune training induced by Dectin-1 ligands.

DOI: https://doi.org/10.1038/s41598-024-51620-8
Nat Rev Cancer. 2024 Jan 15.

Epigenetic memory.

Gabrielle Brewer.

DOI: https://doi.org/10.1038/s41568-024-00667-w
Pharmacol Res. 2024 Jan 14. pii: S1043-6618(23)00412-7. [Epub ahead of print] 107056

Low-dose Olaparib improves septic cardiac function by reducing ferroptosis via accelerated mitophagy flux.

Ruixue Liu, Fengjuan Li, Shuai Hao, Dongyao Hou, Xue Zeng, He Huang, Gautam Sethi, Jun Guo, Chenyang Duan.

  Sepsis is a dysregulated response to infection that can result in life-threatening organ failure, and septic cardiomyopathy is a serious complication involving ferroptosis. Olaparib, a classic targeted drug used in oncology, has demonstrated potential protective effects against sepsis. However, the exact mechanisms underlying its action remain to be elucidated. In our study, we meticulously screened ferroptosis genes associated with sepsis, and conducted comprehensive functional enrichment analyses to delineate the relationship between ferroptosis and mitochondrial damage. Eight sepsis-characterized ferroptosis genes were identified in sepsis patients, including DPP4, LPIN1, PGD, HP, MAPK14, POR, GCLM, and SLC38A1, which were significantly correlated with mitochondrial quality imbalance. Utilizing DrugBank and molecular docking, we demonstrated a robust interaction of Olaparib with these genes. Lipopolysaccharide (LPS)-stimulated HL-1 cells and monocytes were used to establish an in vitro sepsis model. Additionally, an in vivo model was developed using mice subjected to cecal ligation and perforation (CLP). Intriguingly, low-dose Olaparib (5mg/kg) effectively targeted and mitigated markers associated with ferroptosis, concurrently improving mitochondrial quality. This led to a marked enhancement in cardiac function and a significant increase in survival rates in septic mice (p < 0.05). The mechanism through which Olaparib ameliorates ferroptosis in cardiac and leukocyte cells post-sepsis is attributed to its facilitation of mitophagy, thus favoring mitochondrial integrity. In conclusion, our findings suggest that low-dose Olaparib can improve mitochondrial quality by accelerating mitophagy flux, consequently inhibiting ferroptosis and preserving cardiac function after sepsis.

Keywords:  Olaparib; cardiac function; ferroptosis; mitophagy; sepsis

DOI:  https://doi.org/10.1016/j.phrs.2023.107056
Int Immunopharmacol. 2024 Jan 18. pii: S1567-5769(24)00015-8. [Epub ahead of print]128 111497

LncRNA 220, a newly discovered long non-conding RNA inhibiting apoptosis and autophagy in Kupffer cells in LPS-induced endotoxemic mice through the XBP1u-PI3K-AKT pathway.

Ying Yang, Tian Tian, Zhenqi Wang, Shan Li, Nanhong Li, Haihua Luo, Yong Jiang.

  Sepsis is recognized as a potentially fatal condition characterized by acute organ dysfunction resulting from an imbalanced immune response to infection. Acute liver injury (ALI) arises as an inflammatory outcome of immune response dysregulation associated with sepsis. Kupffer cells, which are liver-specific macrophages, are known to have a significant impact on ALI, although the precise regulatory mechanism remains unclear. Numerous studies have showcased the regulatory impact of long non-coding RNAs (lncRNAs) on the progression of diverse ailments, yet their precise regulatory mechanisms remain predominantly unexplored. In this study, a novel long non-coding RNA (lncRNA), referred to as lncRNA 220, was discovered using high-throughput sequencing. The expression of lncRNA 220 was found to be significantly elevated in the livers of mice with lipopolysaccharide (LPS)-induced endotoxemia, specifically during the 8-hour time period. Furthermore, in Kupffer cells treated with LPS, lncRNA 220 was observed to inhibit apoptosis and autophagy by activating the PI3K-AKT-mTORC1 pathway. This effect was achieved through the reduction of X-box protein 1 unspliced (Xbp1u) mRNA stability and suppression of its translation in the context of endoplasmic reticulum stress (ERS). Ultimately, this intervention mitigated the progression of LPS-induced ALI. To summarize, our study establishes lncRNA 220 as a newly identified regulator that suppresses apoptosis and autophagy in Kupffer cells subjected to LPS treatment, indicating its potential as a molecular target for ALI in endotoxemic mice.

Keywords:  Acute liver injury; Apoptosis; Autophagy; Endoplasmic reticulum stress; Long non-coding RNA; Sepsis

DOI:  https://doi.org/10.1016/j.intimp.2024.111497
Int Immunopharmacol. 2024 Jan 17. pii: S1567-5769(24)00064-X. [Epub ahead of print]128 111546

Protein 4.1R regulates M1 macrophages polarization via glycolysis, alleviating sepsis-induced liver injury in mice.

Si-Yao Sang, Yuan-Jiao Wang, Taotao Liang, Yan Liu, Jiao-Jiao Liu, Hui Li, Xin Liu, Qiao-Zhen Kang, Ting Wang.

  Acute liver injury (ALI) is a common clinical disease caused by sepsis, metabolic syndrome, hepatitis virus. Macrophage plays an important role in the development of ALI, which is characterized by polarization and inflammatory regulation. The polarization process of macrophages is related to membrane binding proteins and adaptors. Protein 4.1R acts as an adaptor, linking membrane proteins to the cytoskeleton, and is involved in cell activation and cytokine secretion. However, whether protein 4.1R is involved in regulating macrophage polarization and inflammation-induced liver injury remains unknown. In this study, protein 4.1R is identified with the special effect on macrophage M1 polarization. And it is further demonstrated that protein 4.1R deficiency significantly enhance glycolytic metabolism. Mechanistically, the regulation of protein 4.1R on pyruvate kinase M2 (PKM2) plays a key role in glycolysis metabolism. In addition, we found that protein 4.1R directly interacts with toll-like receptor 4 (TLR4), inhibits the activation of the AKT/HIF-1α signaling pathway. In conclusion, protein 4.1R targets HIF-1α mediated glycolysis regulates M1 macrophage polarization, indicating that protein 4.1R is a candidate for regulating macrophage mediated inflammatory response. In conclusion, we have revealed a novel function of protein 4.1R in macrophage polarization and ALI, providing important insights into the metabolic reprogramming, which is important for ALI therapy. We have revealed a novel function of protein 4.1R in macrophage polarization and ALI, providing important insights into the metabolic reprogramming, which is important for ALI therapy.

Keywords:  AKT/HIF-1α signal pathway; Acute liver injury; Glycolysis; M1 macrophage polarization; Protein 4.1R

DOI:  https://doi.org/10.1016/j.intimp.2024.111546
PLoS Pathog. 2024 Jan;20(1): e1011871

Exposure to Mycobacterium remodels alveolar macrophages and the early innate response to Mycobacterium tuberculosis infection.

Dat Mai, Ana Jahn, Tara Murray, Michael Morikubo, Pamelia N Lim, Maritza M Cervantes, Linh K Pham, Johannes Nemeth, Kevin Urdahl, Alan H Diercks, Alan Aderem, Alissa C Rothchild.

Alveolar macrophages (AMs) play a critical role during Mycobacterium tuberculosis (Mtb) infection as the first cells in the lung to encounter bacteria. We previously showed that AMs initially respond to Mtb in vivo by mounting a cell-protective, rather than pro-inflammatory response. However, the plasticity of the initial AM response was unknown. Here, we characterize how previous exposure to Mycobacterium, either through subcutaneous vaccination with Mycobacterium bovis (scBCG) or through a contained Mtb infection (coMtb) that mimics aspects of concomitant immunity, impacts the initial response by AMs. We find that both scBCG and coMtb accelerate early innate cell activation and recruitment and generate a stronger pro-inflammatory response to Mtb in vivo by AMs. Within the lung environment, AMs from scBCG vaccinated mice mount a robust interferon-associated response, while AMs from coMtb mice produce a broader inflammatory response that is not dominated by Interferon Stimulated Genes. Using scRNAseq, we identify changes to the frequency and phenotype of airway-resident macrophages following Mycobacterium exposure, with enrichment for both interferon-associated and pro-inflammatory populations of AMs. In contrast, minimal changes were found for airway-resident T cells and dendritic cells after exposures. Ex vivo stimulation of AMs with Pam3Cys, LPS and Mtb reveal that scBCG and coMtb exposures generate stronger interferon-associated responses to LPS and Mtb that are cell-intrinsic changes. However, AM profiles that were unique to each exposure modality following Mtb infection in vivo are dependent on the lung environment and do not emerge following ex vivo stimulation. Overall, our studies reveal significant and durable remodeling of AMs following exposure to Mycobacterium, with evidence for both AM-intrinsic changes and contributions from the altered lung microenvironments. Comparisons between the scBCG and coMtb models highlight the plasticity of AMs in the airway and opportunities to target their function through vaccination or host-directed therapies.

DOI: https://doi.org/10.1371/journal.ppat.1011871