bims-traimu 2023-04-02 papers

Issue of 2023–04–02
seven papers selected by
Yantong Wan, Southern Medical University

Front Immunol. 2023 ;14 1147476

Trained immunity: A "new" weapon in the fight against infectious diseases.

Amy Dagenais, Carlos Villalba-Guerrero, Martin Olivier.

Innate immune cells can potentiate the response to reinfection through an innate form of immunological memory known as trained immunity. The potential of this fast-acting, nonspecific memory compared to traditional adaptive immunological memory in prophylaxis and therapy has been a topic of great interest in many fields, including infectious diseases. Amidst the rise of antimicrobial resistance and climate change-two major threats to global health-, harnessing the advantages of trained immunity compared to traditional forms of prophylaxis and therapy could be game-changing. Here, we present recent works bridging trained immunity and infectious disease that raise important discoveries, questions, concerns, and novel avenues for the modulation of trained immunity in practice. By exploring the progress in bacterial, viral, fungal, and parasitic diseases, we equally highlight future directions with a focus on particularly problematic and/or understudied pathogens.

Keywords: host-pathogen interactions; infectious diseases; innate immune response; innate immunological memory; myeloid cells; tolerance; trained immunity; vaccines

DOI: https://doi.org/10.3389/fimmu.2023.1147476

Front Immunol. 2023 ;14 1129577

Transmission of stimulus-induced epigenetic changes through cell division is coupled to continuous transcription factor activity.

Sarah Sun, Raúl Aguirre-Gamboa, Luis B Barreiro.

Trained immunity, or innate immune memory, has been attributed to the long-term retention of stimulus-induced histone post-translational modifications (PTMs) following clearance of the initial stimulus. Yet, it remains unknown how this epigenetic memory can persist for months in dividing cells given the lack of any known mechanism for stimulus-induced histone PTMs to be directly copied from parent to daughter strand during DNA replication. Here, using time course RNA-seq, ChIP-seq, and infection assays, we find that trained macrophages are transcriptionally, epigenetically, and functionally re-programmed for at least 14 cell divisions after stimulus washout. However, the epigenetic changes observed after multiple rounds of cell division do not result from the self-sustained propagation of stimulus-induced epigenetic changes through cell division. Instead, long-lasting epigenetic differences between trained and non-trained cells are always coupled with changes in transcription factor (TF) activity, emphasizing the central role played by TFs, and gene expression changes more broadly, in driving the transmission of stimulus-induced epigenetic changes across cell divisions.

Keywords: epigenetics; histone modifications; immunogenomics; innate immune memory; macrophages; trained immunity

DOI: https://doi.org/10.3389/fimmu.2023.1129577

Biomedicines. 2023 Mar 02. pii: 766. [Epub ahead of print]11(3):

Training vs. Tolerance: The Yin/Yang of the Innate Immune System.

Trim Lajqi, Natascha Köstlin-Gille, Reinhard Bauer, Sotirios G Zarogiannis, Esra Lajqi, Valdrina Ajeti, Stefanie Dietz, Simon A Kranig, Jessica Rühle, Ardian Demaj, Janine Hebel, Maria Bartosova, David Frommhold, Hannes Hudalla, Christian Gille.

For almost nearly a century, memory functions have been attributed only to acquired immune cells. Lately, this paradigm has been challenged by an increasing number of studies revealing that innate immune cells are capable of exhibiting memory-like features resulting in increased responsiveness to subsequent challenges, a process known as trained immunity (known also as innate memory). In contrast, the refractory state of endotoxin tolerance has been defined as an immunosuppressive state of myeloid cells portrayed by a significant reduction in the inflammatory capacity. Both training as well tolerance as adaptive features are reported to be accompanied by epigenetic and metabolic alterations occurring in cells. While training conveys proper protection against secondary infections, the induction of endotoxin tolerance promotes repairing mechanisms in the cells. Consequently, the inappropriate induction of these adaptive cues may trigger maladaptive effects, promoting an increased susceptibility to secondary infections-tolerance, or contribute to the progression of the inflammatory disorder-trained immunity. This review aims at the discussion of these opposing manners of innate immune and non-immune cells, describing the molecular, metabolic and epigenetic mechanisms involved and interpreting the clinical implications in various inflammatory pathologies.

Keywords: DAMPs; PAMPs; diseases; dose; epigenetic; inflammatory; metabolic; signaling; tolerance; trained immunity

DOI: https://doi.org/10.3390/biomedicines11030766

Zhonghua Jie He He Hu Xi Za Zhi. 2023 Apr 12. 46(4): 413-418

[Progress on specific and non-specific immune effects of Bacille Calmette-Guerin].

Y Su, Y Cao, R L Wang, E J Dong, W J Zhao, J L Du.

Currently, Bacille Calmette-Guerin(BCG) is still the only admitted vaccine to prevent tuberculosis around the world. The target population is infants and children, but its protective efficacy is limited. As more and more studies have shown that re-vaccination with BCG protects against tuberculosis in adults, BCG can also induce non-specific immunity against other respiratory diseases and some chronic diseases by training immunity, especially the immune effects against COVID-19. At present, the epidemic of COVID-19 has not been effectively contained, and it is worth considering whether BCG vaccine can be used as an intervention to prevent COVID-19. The WHO and China do not have a policy to support BCG revaccination, and as more and more BCG vaccines are discovered, whether selective revaccination can be carried out in some high-risk populations and whether the vaccine can be used more widely have led to intense discussions. This article reviewed the effects of specific immunity and non-specific immunity of BCG on tuberculosis and non-tuberculous diseases.

DOI: https://doi.org/10.3760/cma.j.cn112147-20220711-00589

mBio. 2023 Mar 28. e0035623

BCG Vaccination of Health Care Workers Does Not Reduce SARS-CoV-2 Infections nor Infection Severity or Duration: a Randomized Placebo-Controlled Trial.

BCG-Corona Study Group

Bacillus Calmette-Guerin (BCG) vaccination has been hypothesized to reduce severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, severity, and/or duration via trained immunity induction. Health care workers (HCWs) in nine Dutch hospitals were randomized to BCG or placebo vaccination (1:1) in March and April 2020 and followed for 1 year. They reported daily symptoms, SARS-CoV-2 test results, and health care-seeking behavior via a smartphone application, and they donated blood for SARS-CoV-2 serology at two time points. A total of 1,511 HCWs were randomized and 1,309 analyzed (665 BCG and 644 placebo). Of the 298 infections detected during the trial, 74 were detected by serology only. The SARS-CoV-2 incidence rates were 0.25 and 0.26 per person-year in the BCG and placebo groups, respectively (incidence rate ratio, 0.95; 95% confidence interval, 0.76 to 1.21; P = 0.732). Only three participants required hospitalization for SARS-CoV-2. The proportions of participants with asymptomatic, mild, or moderate infections and the mean infection durations did not differ between randomization groups. In addition, unadjusted and adjusted logistic regression and Cox proportional hazards models showed no differences between BCG and placebo vaccination for any of these outcomes. The percentage of participants with seroconversion (7.8% versus 2.8%; P = 0.006) and mean SARS-CoV-2 anti-S1 antibody concentration (13.1 versus 4.3 IU/mL; P = 0.023) were higher in the BCG than placebo group at 3 months but not at 6 or 12 months postvaccination. BCG vaccination of HCWs did not reduce SARS-CoV-2 infections nor infection duration or severity (ranging from asymptomatic to moderate). In the first 3 months after vaccination, BCG vaccination may enhance SARS-CoV-2 antibody production during SARS-CoV-2 infection. IMPORTANCE While several BCG trials in adults were conducted during the 2019 coronavirus disease epidemic, our data set is the most comprehensive to date, because we included serologically confirmed infections in addition to self-reported positive SARS-CoV-2 test results. We also collected data on symptoms for every day during the 1-year follow-up period, which enabled us to characterize infections in detail. We found that BCG vaccination did not reduce SARS-CoV-2 infections nor infection duration or severity but may have enhanced SARS-CoV-2 antibody production during SARS-CoV-2 infection in the first 3 months after vaccination. These results are in agreement with other BCG trials that reported negative results (but did not use serological endpoints), except for two trials in Greece and India that reported positive results but had few endpoints and included endpoints that were not laboratory confirmed. The enhanced antibody production is in agreement with prior mechanistic studies but did not translate into protection from SARS-CoV-2 infection.

Keywords: Bacillus Calmette-Guerin vaccine; COVID-19; SARS-CoV-2; health care workers; randomized placebo-controlled clinical trial

DOI: https://doi.org/10.1128/mbio.00356-23

J Inflamm Res. 2023 ;16 1195-1207

Metabolic Reprogramming and Its Regulatory Mechanism in Sepsis-Mediated Inflammation.

Wenzhang Liu, Tianyi Liu, Yongjun Zheng, Zhaofan Xia.

Sepsis is a systemic inflammatory disease caused by an infection that can lead to multiple organ failure. Sepsis alters energy metabolism, leading to metabolic reprogramming of immune cells, which consequently disrupts innate and adaptive immune responses, triggering hyperinflammation and immunosuppression. This review summarizes metabolic reprogramming and its regulatory mechanism in sepsis-induced hyperinflammation and immunosuppression, highlights the significance and intricacies of immune cell metabolic reprogramming, and emphasizes the pivotal role of mitochondria in metabolic regulation and treatment of sepsis. This review provides an up-to-date overview of the relevant literature to inform future research directions in understanding the regulation of sepsis immunometabolism. Metabolic reprogramming has great promise as a new target for sepsis treatment in the future.

Keywords: hyperinflammation; immune cell; immunometabolism; immunosuppression; mitochondria

DOI: https://doi.org/10.2147/JIR.S403778

bioRxiv. 2023 Mar 22. pii: 2023.03.22.533820. [Epub ahead of print]

Assessing vaccine-mediated protection in an ultra-low dose Mycobacterium tuberculosis murine model.

C R Plumlee, H W Barrett, D E Shao, K A Lien, L M Cross, S B Cohen, P T Edlefsen, K B Urdahl.

Despite widespread immunization with Bacille-Calmette-Guerin (BCG), the only currently licensed tuberculosis (TB) vaccine, TB remains a leading cause of mortality globally. There are many TB vaccine candidates in the developmental pipeline, but the lack of a robust animal model to assess vaccine efficacy has hindered our ability to prioritize candidates for human clinical trials. Here we use a murine ultra-low dose (ULD) Mycobacterium tuberculosis (Mtb) challenge model to assess protection conferred by BCG vaccination. We show that BCG confers a durable reduction in lung bacterial burdens, curbs Mtb dissemination to the contralateral lung, and prevents detectable infection in a small percentage of mice. These findings are consistent with the ability of human BCG vaccination to mediate protection, particularly against disseminated disease, in specific human populations and clinical settings. Overall, our findings demonstrate that the ultra-low dose Mtb infection model can measure distinct parameters of immune protection that cannot be assessed in conventional dose murine infection models and could provide an improved platform for TB vaccine testing.

DOI: https://doi.org/10.1101/2023.03.22.533820