bims-traimu 2022-08-07 papers

Issue of 2022–08–07
five papers selected by
Yantong Wan, Southern Medical University

Sci Adv. 2022 Aug 05. 8(31): eabn4002

Neonatal BCG vaccination is associated with a long-term DNA methylation signature in circulating monocytes.

Samantha Bannister, Bowon Kim, Jorge Domínguez-Andrés, Gizem Kilic, Brendan R E Ansell, Melanie R Neeland, Simone J C F M Moorlag, Vasiliki Matzaraki, Amanda Vlahos, Rebecca Shepherd, Susie Germano, Melanie Bahlo, Nicole L Messina, Richard Saffery, Mihai G Netea, Nigel Curtis, Boris Novakovic.

Trained immunity describes the capacity of innate immune cells to develop heterologous memory in response to certain exogenous exposures. This phenomenon mediates, at least in part, the beneficial off-target effects of the BCG vaccine. Using an in vitro model of trained immunity, we show that BCG exposure induces a persistent change in active histone modifications, DNA methylation, transcription, and adenosine-to-inosine RNA modification in human monocytes. By profiling DNA methylation of circulating monocytes from infants in the MIS BAIR clinical trial, we identify a BCG-associated DNA methylation signature that persisted more than 12 months after neonatal BCG vaccination. Genes associated with this epigenetic signature are involved in viral response pathways, consistent with the reported off-target protection against viral infections in neonates, adults, and the elderly. Our findings indicate that the off-target effects of BCG in infants are accompanied by epigenetic remodeling of circulating monocytes that lasts more than 1 year.

DOI: https://doi.org/10.1126/sciadv.abn4002

Front Cardiovasc Med. 2022 ;9 854421

Mechanisms of Post-critical Illness Cardiovascular Disease.

Andrew Owen, Jaimin M Patel, Dhruv Parekh, Mansoor N Bangash.

Prolonged critical care stays commonly follow trauma, severe burn injury, sepsis, ARDS, and complications of major surgery. Although patients leave critical care following homeostatic recovery, significant additional diseases affect these patients during and beyond the convalescent phase. New cardiovascular and renal disease is commonly seen and roughly one third of all deaths in the year following discharge from critical care may come from this cluster of diseases. During prolonged critical care stays, the immunometabolic, inflammatory and neurohumoral response to severe illness in conjunction with resuscitative treatments primes the immune system and parenchymal tissues to develop a long-lived pro-inflammatory and immunosenescent state. This state is perpetuated by persistent Toll-like receptor signaling, free radical mediated isolevuglandin protein adduct formation and presentation by antigen presenting cells, abnormal circulating HDL and LDL isoforms, redox and metabolite mediated epigenetic reprogramming of the innate immune arm (trained immunity), and the development of immunosenescence through T-cell exhaustion/anergy through epigenetic modification of the T-cell genome. Under this state, tissue remodeling in the vascular, cardiac, and renal parenchymal beds occurs through the activation of pro-fibrotic cellular signaling pathways, causing vascular dysfunction and atherosclerosis, adverse cardiac remodeling and dysfunction, and proteinuria and accelerated chronic kidney disease.

Keywords: CKD; atherosclerosis; chronicity; critical illness; heart failure; immune aging; inflammation; insulin resistance

DOI: https://doi.org/10.3389/fcvm.2022.854421

Front Immunol. 2022 ;13 963627

The SARS-CoV-2 Nucleoprotein Induces Innate Memory in Human Monocytes.

Patricia Urbán, Paola Italiani, Diana Boraschi, Sabrina Gioria.

The interaction of SARS-CoV-2 with the human immune system is at the basis of the positive or negative outcome of the infection. Monocytes and macrophages, which are major innate immune/inflammatory effector cells, are not directly infected by SARS-CoV-2, however they can react to the virus and mount a strong reaction. Whether this first interaction and reaction may bias innate reactivity to re-challenge, a phenomenon known as innate memory, is currently unexplored and may be part of the long-term sequelae of COVID-19. Here, we have tested the capacity of SARS-CoV-2 and some of its proteins to induce innate memory in human monocytes in vitro. Our preliminary results show that the Spike protein subunits S1 and S2 and the entire heat-inactivated virus have no substantial effect. Conversely, monocytes pre-exposed to the nucleocapsid N protein react to subsequent viral or bacterial challenges with an increased production of anti-inflammatory IL-1Ra, a response profile suggesting a milder response to new infections.

Keywords: SARS-CoV-2; cytokines; innate immunity; innate memory; monocytes; nucleoprotein

DOI: https://doi.org/10.3389/fimmu.2022.963627

Trends Immunol. 2022 Jul 28. pii: S1471-4906(22)00138-7. [Epub ahead of print]

Innate antiviral immunity: how prior exposures can guide future responses.

Jeffrey A Tomalka, Mehul S Suthar, Michael S Diamond, Rafick P Sekaly.

Innate immunity is an intrinsic baseline defense in cells, with its earliest origins in bacteria, and with key roles in defense against pathogens and in the activation of B and T cell responses. In mammals, the efficacy of innate immunity in initiating the cascades that lead to pathogen control results from the interplay of transcriptomic, epigenomic, and proteomic responses regulating immune activation and long-lived pathogen-specific memory responses. Recent studies suggest that intrinsic innate immunity is modulated by individual exposure histories - prior infections, vaccinations, and metabolites of microbial origin - and this promotes, or impairs, the development of efficacious innate immune responses. Understanding how environmental factors regulate innate immunity and boost protection from infection or response to vaccination could be a valuable tool for pandemic preparedness.

Keywords: antiviral immunity; innate immunity; metabolites; microbiome

DOI: https://doi.org/10.1016/j.it.2022.07.001

Am J Respir Cell Mol Biol. 2022 Aug 04.

CXCL14 Protects Against Polymicrobial Sepsis by Enhancing Antibacterial Functions of Macrophages.

Xiaofei Lai, Hao Ding, Renlin Yu, Haobo Bai, Yi Liu, Ju Cao.

Rapid and effective control of bacterial infection is critical for the treatment of bacterial sepsis. CXCL14 is an important chemokine involved in infection and immunity, which can bind to CXCR4. However, the contribution of CXCL14/CXCR4 chemokine axis to bacterial clearance in sepsis remains unknown. Here the impact of CXCL14/CXCR4 blockade or CXCL14 administration on sepsis was assessed using murine and cell models, as well as human samples. CXCL14 protein levels were elevated in mice after cecal ligation and puncture (CLP)-induced sepsis. In vivo, CXCL14 blockade using anti-CXCL14 antibody or CXCL14 knockdown by adeno-associated virus carrying-CXCL14 shRNA significantly increased mortality and bacterial burden, which was paralleled by significantly decreased macrophage influx and M2 macrophage polarization at the site of infection after CLP. Therapeutic administration of CXCL14 improved mortality and bacterial clearance after CLP in a CXCR4-dependent manner, and macrophages, but not neutrophils, were important for the protective effect of CXCL14 in sepsis. In vitro, CXCL14 directly enhanced bacterial phagocytosis and killing of macrophages, and it also increased phagosome formation and reactive oxygen species (ROS) production in macrophages. Furthermore, inhibiting the activation of PI3K/Akt and NF-κB signaling pathways, but not STAT1, abrogated the enhanced antibacterial effects of CXCL14 on macrophages. Finally, circulating CXCL14 levels were significantly up-regulated in the patients with sepsis. CXCL14 could enhance bacterial phagocytosis and killing in human monocyte-derived macrophages, which was dependent on CXCR4. Therefore, our results indicate a previously undescribed role of CXCL14/CXCR4 axis and suggest CXCL14 as a potential adjunct therapy in bacterial sepsis.

Keywords: CXCL14; CXCR4; macrophages; sepsis; therapy

DOI: https://doi.org/10.1165/rcmb.2022-0249OC