bims-traimu 2023-07-30 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2023–07–30
seven papers selected by
Yantong Wan, Southern Medical University

Routine vaccination for influenza and pneumococcal disease and its effect on COVID-19 in a population of Dutch older adults.
Streptococcus pneumoniae drives specific and lasting Natural Killer cell memory.
Protective intravenous BCG vaccination induces enhanced immune signaling in the airways.
Triad3A involved in the regulation of endotoxin tolerance and mycobactericidal activity through the NFκB-nitric oxide pathway.
Measles vaccination and reduced child mortality: Prevention of immune amnesia or beneficial non-specific effects of measles vaccine?
ATF4 knockdown in macrophage impairs glycolysis and mediates immune tolerance by targeting HK2 and HIF-1α ubiquitination in sepsis.
Acyloxyacyl hydrolase promotes pulmonary defense by preventing alveolar macrophage tolerance.

Vaccine X. 2023 Aug;14 100344

Routine vaccination for influenza and pneumococcal disease and its effect on COVID-19 in a population of Dutch older adults.

Esther J M Taks, Konstantin Föhse, Simone J C F M Moorlag, Jacobien Hoogerwerf, Reinout van Crevel, Cornelis H van Werkhoven, Mihai G Netea, Jaap Ten Oever.

   Objectives: Protective heterologous beneficial effects of vaccines have been reported, and in this study we aimed to assess the impact of routine pneumococcal and influenza vaccination on the incidence and symptom duration of COVID-19 in a population of Dutch older adults.
Methods: This cohort study is a secondary analysis of the BCG-CORONA-ELDERLY study, a randomised controlled trial on the effect of BCG vaccination on the cumulative incidence of respiratory tract infections requiring medical intervention in adults ≥60 years. The primary outcome was the cumulative incidence of a self-reported positive SARS-CoV-2 PCR test, and was assessed using a Fine-Gray competing risks model adjusted for baseline characteristics at enrolment. We analysed data from November 1st 2020 until the end of the main study in May 2021.
Results: Routine vaccination data 2020/2021 were available for 1963/2014 (97.5 %) participants; 44/1963 (2.2 %) were excluded due to COVID-19 before vaccination. 1076/1919 (56.1 %) had received the influenza vaccine and 289/1919 (15.1 %) the pneumococcal vaccine. The cumulative incidence of COVID-19 was 0.030 (95 %CI 0.021-0.041) in those vaccinated against influenza compared to 0.029 (95 %CI 0.019-0.041) in the unvaccinated group (subdistribution hazard ratio (SDHR) 1.018; 95 %CI 0.602-1.721). For pneumococcal vaccination the cumulative incidence was 0.031 (95 %CI 0.015-0.056) for the vaccinated and 0.029 (95 %CI 0.022-0.038) for non-vaccinated individuals (SDHR 0.961; 95 %CI 0.443-2.085). BCG vaccination in the previous year and sex were not significant effect modifiers in the primary analysis. Duration of fever, cough and dyspnoea was also not significantly different between treatment arms.
Conclusion: Neither influenza nor pneumococcal vaccination was associated with a lower incidence or shorter duration of COVID-19 symptoms in older adults.

Keywords:  COVID-19; Influenza vaccine; Older adults; Pneumococcal vaccine; Trained immunity

DOI:  https://doi.org/10.1016/j.jvacx.2023.100344
PLoS Pathog. 2023 Jul 24. 19(7): e1011159

Streptococcus pneumoniae drives specific and lasting Natural Killer cell memory.

Tiphaine M N Camarasa, Júlia Torné, Christine Chevalier, Orhan Rasid, Melanie A Hamon.

NK cells are important mediators of innate immunity and play an essential role for host protection against infection, although their responses to bacteria are poorly understood. Recently NK cells were shown to display memory properties, as characterized by an epigenetic signature leading to a stronger secondary response. Although NK cell memory could be a promising mechanism to fight against infection, it has not been described upon bacterial infection. Using a mouse model, we reveal that NK cells develop specific and long-term memory following sub-lethal infection with the extracellular pathogen Streptococcus pneumoniae. Memory NK cells display intrinsic sensing and response to bacteria in vitro, in a manner that is enhanced post-bacterial infection. In addition, their transfer into naïve mice confers protection from lethal infection for at least 12 weeks. Interestingly, NK cells display enhanced cytotoxic molecule production upon secondary stimulation and their protective role is dependent on Perforin and independent of IFNγ. Thus, our study identifies a new role for NK cells during bacterial infection, opening the possibility to harness innate immune memory for therapeutic purposes.

DOI: https://doi.org/10.1371/journal.ppat.1011159
bioRxiv. 2023 Jul 18. pii: 2023.07.16.549208. [Epub ahead of print]

Protective intravenous BCG vaccination induces enhanced immune signaling in the airways.

Joshua M Peters, Edward B Irvine, Jacob M Rosenberg, Marc H Wadsworth, Travis K Hughes, Matthew Sutton, Sarah K Nyquist, Joshua D Bromley, Rajib Mondal, Mario Roederer, Robert A Seder, Patricia A Darrah, Galit Alter, JoAnne L Flynn, Alex K Shalek, Sarah M Fortune, Bryan D Bryson.

Intradermal (ID) Bacillus Calmette-Guérin (BCG) is the most widely administered vaccine in the world. However, ID-BCG fails to achieve the level of protection needed in adults to alter the course of the tuberculosis epidemic. Recent studies in non-human primates have demonstrated high levels of protection against Mycobacterium tuberculosis ( Mtb ) following intravenous (IV) administration of BCG. However, the protective immune features that emerge following IV BCG vaccination remain incompletely defined. Here we used single-cell RNA-sequencing (scRNAseq) to transcriptionally profile 157,114 unstimulated and purified protein derivative (PPD)-stimulated bronchoalveolar lavage (BAL) cells from 29 rhesus macaques immunized with BCG across routes of administration and doses to uncover cell composition-, gene expression-, and biological network-level signatures associated with IV BCG-mediated protection. Our analyses revealed that high-dose IV BCG drove an influx of polyfunctional T cells and macrophages into the airways. These macrophages exhibited a basal activation phenotype even in the absence of PPD-stimulation, defined in part by IFN and TNF-α signaling up to 6 months following BCG immunization. Furthermore, intercellular immune signaling pathways between key myeloid and T cell subsets were enhanced following PPD-stimulation in high-dose IV BCG-vaccinated macaques. High-dose IV BCG also engendered quantitatively and qualitatively stronger transcriptional responses to PPD-stimulation, with a robust Th1-Th17 transcriptional phenotype in T cells, and augmented transcriptional signatures of reactive oxygen species production, hypoxia, and IFN-γ response within alveolar macrophages. Collectively, this work supports that IV BCG immunization creates a unique cellular ecosystem in the airways, which primes and enables local myeloid cells to effectively clear Mtb upon challenge.

DOI: https://doi.org/10.1101/2023.07.16.549208
Immun Inflamm Dis. 2023 Jul;11(7): e925

Triad3A involved in the regulation of endotoxin tolerance and mycobactericidal activity through the NFκB-nitric oxide pathway.

Yongwei Qin, Jinliang Chen, Kuang Xu, Yang Lu, Feifan Xu, Jiahai Shi.

   INTRODUCTION: Sepsis is characterized by an endotoxin tolerance phenotype that occurs in the stage of infection. Persistent bacterial infection can lead to immune cell exhaustion. Triad3A, an E3 ubiquitin ligase, negatively regulates its activation by TLR4. However, the effect of Triad3A on endotoxin tolerance and bactericidal ability in the state of endotoxin tolerance remains unclear.
METHODS: Using single dose LPS and repeated LPS stimulated macrophage cell lines at indicated times, we investigated miR-191, Tirad3A, TRAF3, TLR4, p-P65, TNF-α, IL-1β, and iNOS expression, the effect of miR-191 on Triad3A and TRAF3, gene loss-of-function analyses, the effect of Triad3A on TLR4, p-P65, cytokine, and mycobactericidal activity in endotoxin tolerant cells infected with Mycobacterium marinum.
RESULTS: Here we found that Triad3A is involved in regulating endotoxin tolerance. Our result also displayed that miR-191 expression is downregulated in macrophages in the state of endotoxin tolerance. miR-191 can directly bind to Triad3A and TRAF3. Additionally, knockdown of Triad3A can reverse the effect of decreasing TNF-α and IL-1β in endotoxin tolerant macrophages. Furthermore, we demonstrated that the TLR4-NF-κB-NO pathway was associated with Triad3A and responsible for the killing of intracellular mycobacteria in a tuberculosis sepsis model.
CONCLUSIONS: These results provide new insight into the mechanisms of Triad3A induced tolerogenic phenotype in macrophages, which can help the better comprehension of the pathogenesis involved in septic shock with infection of Mycobacterium tuberculosis, and suggest that Triad3A may be a potential drug target for the treatment of severe septic tuberculosis.

Keywords:  Triad3A; antimycobacterial activity; endotoxin tolerance; immune cell exhaustion; miRNA; tuberculosis sepsis

DOI:  https://doi.org/10.1002/iid3.925
J Infect. 2023 Jul 21. pii: S0163-4453(23)00382-1. [Epub ahead of print]

Measles vaccination and reduced child mortality: Prevention of immune amnesia or beneficial non-specific effects of measles vaccine?

Christine S Benn, Peter Aaby.

  Measles vaccine (MV) has been observed to reduce all-cause mortality more than explained by prevention of measles infection. Recently, prevention of "measles-induced immune amnesia" (MIA) has been proposed as an explanation for this larger-than-anticipated beneficial effect of measles vaccine (MV). According to the "MIA hypothesis", immune amnesia leads to excess non-measles morbidity and mortality, that may last up to five years after measles infection, but may be prevented by MV. However, the benefits of MV-vaccinated children could also be due to beneficial non-specific effects (NSEs) of MV, reducing the risk of non-measles infections (The "NSE hypothesis"). The epidemiological studies do provide some support for MIA, as exposure to measles infection before 6 months of age causes long-term MIA, and over 6 months of age for 2-3 months. However, in children over 6 months of age, the MIA hypothesis is contradicted by several epidemiological patterns: First, in community studies that adjusted for MV status, children surviving acute measles infection had lower mortality than uninfected controls (44%(95%CI: 0-69%)). Second, in six randomised trials and six observational studies comparing MV-vaccinated and MV-unvaccinated children, the benefit of MV changed minimally from 54%(43-63%) to 49%(37-59%) when measles cases were censored in the survival analysis, making it unlikely that prevention of measles and its long-term consequences explained much of the reduced mortality. Third, several studies conducted in measles-free contexts still showed significantly lower mortality after MV (55%(40-67%)). Fourth, administration of MV in the presence of maternal measles antibody (MatAb) is associated with much stronger beneficial effect for child survival than administration of MV in the absence of MatAb (55%(35-68%) lower mortality). The MIA hypothesis alone cannot explain the strongly beneficial effects of MV on child survival. Conversely, the hypothesis that MV has beneficial non-specific immune training effects is compatible with all available data. Consideration should be given to continuing MV even when measles has been eradicated.

Keywords:  child survival; measles immune amnesia; measles infection; measles vaccination; non-specific effects of vaccines

DOI:  https://doi.org/10.1016/j.jinf.2023.07.010
Clin Immunol. 2023 Jul 20. pii: S1521-6616(23)00461-8. [Epub ahead of print]254 109698

ATF4 knockdown in macrophage impairs glycolysis and mediates immune tolerance by targeting HK2 and HIF-1α ubiquitination in sepsis.

Tiantian Liu, Zhenliang Wen, Lujing Shao, Yun Cui, Xiaomeng Tang, Huijie Miao, Jingyi Shi, Linlin Jiang, Shuyun Feng, Yilin Zhao, Hong Zhang, Qiming Liang, Dechang Chen, Yucai Zhang, Chunxia Wang.

  Strengthened glycolysis is crucial for the macrophage pro-inflammatory response during sepsis. Activating transcription factor 4 (ATF4) plays an important role in regulating glucose and lipid metabolic homeostasis in hepatocytes and adipocytes. However, its immunometabolic role in macrophage during sepsis remains largely unknown. In the present study, we found that the expression of ATF4 in peripheral blood mononuclear cells (PBMCs) was increased and associated with glucose metabolism in septic patients. Atf4 knockdown specifically decreased LPS-induced spleen macrophages and serum pro-inflammatory cytokines levels in mice. Moreover, Atf4 knockdown partially blocked LPS-induced pro-inflammatory cytokines, lactate accumulation and glycolytic capacity in RAW264.7. Mechanically, ATF4 binds to the promoter region of hexokinase II (HK2), and interacts with hypoxia inducible factor-1α (HIF-1α) and stabilizes HIF-1α through ubiquitination modification in response to LPS. Furthermore, ATF4-HIF-1α-HK2-glycolysis axis launches pro-inflammatory response in macrophage depending on the activation of mammalian target of rapamycin (mTOR). Importantly, Atf4 overexpression improves the decreased level of pro-inflammatory cytokines and lactate secretion and HK2 expression in LPS-induced tolerant macrophages. In conclusion, we propose a novel function of ATF4 as a crucial glycolytic activator contributing to pro-inflammatory response and improving immune tolerant in macrophage involved in sepsis. So, ATF4 could be a potential new target for immunotherapy of sepsis.

Keywords:  Activating transcription factor 4; Glycolysis; Hexokinase II; Hypoxia inducible factor-1α; Pro-inflammatory response; sepsis

DOI:  https://doi.org/10.1016/j.clim.2023.109698
PLoS Pathog. 2023 Jul 27. 19(7): e1011556

Acyloxyacyl hydrolase promotes pulmonary defense by preventing alveolar macrophage tolerance.

Xiaofang Cheng, Wei Jiang, Yeying Chen, Benkun Zou, Zhiyan Wang, Lu Gan, Zeling Xiao, Changshun Li, Cheng-Yun Yu, Yimeng Lu, Zeyao Han, Jiashun Zeng, Jie Gu, Tianqing Chu, Mingsheng Fu, Yiwei Chu, Wenhong Zhang, Jianguo Tang, Mingfang Lu.

Although alveolar macrophages (AMs) play important roles in preventing and eliminating pulmonary infections, little is known about their regulation in healthy animals. Since exposure to LPS often renders cells hyporesponsive to subsequent LPS exposures ("tolerant"), we tested the hypothesis that LPS produced in the intestine reaches the lungs and stimulates AMs, rendering them tolerant. We found that resting AMs were more likely to be tolerant in mice lacking acyloxyacyl hydrolase (AOAH), the host lipase that degrades and inactivates LPS; isolated Aoah-/- AMs were less responsive to LPS stimulation and less phagocytic than were Aoah+/+ AMs. Upon innate stimulation in the airways, Aoah-/- mice had reduced epithelium- and macrophage-derived chemokine/cytokine production. Aoah-/- mice also developed greater and more prolonged loss of body weight and higher bacterial burdens after pulmonary challenge with Pseudomonas aeruginosa than did wildtype mice. We also found that bloodborne or intrarectally-administered LPS desensitized ("tolerized") AMs while antimicrobial drug treatment that reduced intestinal commensal Gram-negative bacterial abundance largely restored the innate responsiveness of Aoah-/- AMs. Confirming the role of LPS stimulation, the absence of TLR4 prevented Aoah-/- AM tolerance. We conclude that commensal LPSs may stimulate and desensitize (tolerize) alveolar macrophages in a TLR4-dependent manner and compromise pulmonary immunity. By inactivating LPS in the intestine, AOAH promotes antibacterial host defenses in the lung.

DOI: https://doi.org/10.1371/journal.ppat.1011556