bims-traimu 2022-08-14 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2022–08–14
seven papers selected by
Yantong Wan, Southern Medical University

Innate Immune Training of Human Macrophages by Cathelicidin Analogs.
Measles, mumps and rubella vaccine and heterologous immunity: a way out of the COVID-19 crisis?
Higher BCG-induced trained immunity prevalence predicts protection from COVID-19: Implications for ongoing BCG trials.
HIV and cardiovascular disease: the role of inflammation.
Human Lung Fibroblasts Exhibit Induced Inflammation Memory via Increased IL6 Gene Expression and Release.
Therapeutic applications of toll-like receptors (TLRs) agonists in AML.
Low-dose mycophenolate mofetil improves survival in a murine model of Staphylococcus aureus sepsis by increasing bacterial clearance and phagocyte function.

Front Immunol. 2022 ;13 777530

Innate Immune Training of Human Macrophages by Cathelicidin Analogs.

Albert van Dijk, Jennifer Anten, Anne Bakker, Noah Evers, Anna T Hoekstra, Jung-Chin Chang, Maaike R Scheenstra, Edwin J A Veldhuizen, Mihai G Netea, Celia R Berkers, Henk P Haagsman.

  Trained innate immunity can be induced in human macrophages by microbial ligands, but it is unknown if exposure to endogenous alarmins such as cathelicidins can have similar effects. Previously, we demonstrated sustained protection against infection by the chicken cathelicidin-2 analog DCATH-2. Thus, we assessed the capacity of cathelicidins to induce trained immunity. PMA-differentiated THP-1 (dTHP1) cells were trained with cathelicidin analogs for 24 hours and restimulated after a 3-day rest period. DCATH-2 training of dTHP-1 cells amplified their proinflammatory cytokine response when restimulated with TLR2/4 agonists. Trained cells displayed a biased cellular metabolism towards mTOR-dependent aerobic glycolysis and long-chain fatty acid accumulation and augmented microbicidal activity. DCATH-2-induced trained immunity was inhibited by histone acetylase inhibitors, suggesting epigenetic regulation, and depended on caveolae/lipid raft-mediated uptake, MAPK p38 and purinergic signaling. To our knowledge, this is the first report of trained immunity by host defense peptides.

Keywords:  Seahorse analysis; cathelicidin; host defense peptide; immunomodulation; macrophage; metabolomics; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2022.777530
Sudan J Paediatr. 2022 ;22(1): 10-18

Measles, mumps and rubella vaccine and heterologous immunity: a way out of the COVID-19 crisis?

Jahnavi Shrivastava, Manish Narang, Sunil Gomber.

  Heterologous immunity is a well-known concept in immunology wherein prior exposure to an antigen confers cross-protection against an unrelated antigen. With the surge in global COVID-19 cases, there has been significant research into the application of vaccine-induced heterologous immunity associated with measles, mumps and rubella (MMR) vaccine, Bacillus Calmette-Guérin vaccine, oral polio vaccine, and hepatitis A vaccine in curbing the worst outcomes of COVID-19 infection. Despite having specific vaccines against COVID-19, it is worthwhile exploring the application of available vaccines in the prevention of severe disease until the vaccines reach all sections of the population across the globe. In this article, we aim to outline the concept of heterologous immunity and its relevance in context to MMR vaccine and COVID-19.

Keywords:  COVID-19; Children; Heterologous immunity; MMR vaccine; Prophylaxis; Trained immunity; Vaccination

DOI:  https://doi.org/10.24911/SJP.106-1621869672
Clin Transl Discov. 2022 Jun;2(2): e60

Higher BCG-induced trained immunity prevalence predicts protection from COVID-19: Implications for ongoing BCG trials.

Samer Singh, Dhiraj Kishore, Rakesh K Singh, Chandramani Pathak, Kishu Ranjan.

  Endeavors to identify potentially protective variables for COVID-19 impact on certain populations have remained a priority. Multiple attempts have been made to attribute the reduced COVID-19 impact on populations to their Bacillus-Calmette-Guérin (BCG) vaccination coverage ignoring the fact that the effect of childhood BCG vaccination wanes within 5 years while most of the COVID-19 cases and deaths have occurred in aged with comorbidities. Since the supposed protection being investigated could come from heterologous 'trained immunity' (TI) conferred by exposure to Mycobacterium spp. (i.e., environmental and BCG), it is argued that the estimates of the prevalence of TI in populations currently available as latent tuberculosis infection (LTBI) prevalence would be a better variable to evaluate such assertions. Indeed, when we analyze the European populations (24), and erstwhile East and West Germany populations completely disregarding their BCG vaccination coverage, the populations with higher TI prevalence consistently display reduced COVID-19 impact as compared to their lower TI prevalence neighbors. The TI estimates of the populations not the BCG coverage per se, negatively correlated with pandemic phase-matched COVID-19 incidences (r(24): -0.79 to -0.57; p-value < .004), mortality (r(24): -0.63 to -0.45; p-value < .03), and interim case fatality rates (i-CFR) data. To decisively arrive at dependable conclusions about the potential protective benefit gained from BCG vaccination in COVID-19, the ongoing or planned randomized controlled trials should consciously consider including measures of TI as: (a) all individuals immunized do not respond equally, (b) small study groups from higher background TI could fail to indicate any protective effect.

Keywords:  Bacillus–Calmette–Guérin (BCG); COVID‐19; LTBI; SARS‐CoV‐2; trained immunity; tuberculin sensitivity test (TST)

DOI:  https://doi.org/10.1002/ctd2.60
Curr Opin HIV AIDS. 2022 Sep 01. 17(5): 286-292

HIV and cardiovascular disease: the role of inflammation.

Sahera Dirajlal-Fargo, Nicholas Funderburg.

PURPOSE OF REVIEW: HIV and antiretroviral therapy (ART) use are linked to an increased incidence of atherosclerotic cardiovascular disease (ASCVD). Immune activation persists in ART-treated people with HIV (PWH), and markers of inflammation (i.e. IL-6, C-reactive protein) predict mortality in this population. This review discusses underlying mechanisms that likely contribute to inflammation and the development of ASCVD in PWH.
RECENT FINDINGS: Persistent inflammation contributes to accelerated ASCVD in HIV and several new insights into the underlying immunologic mechanisms of chronic inflammation in PWH have been made (e.g. clonal haematopoiesis, trained immunity, lipidomics). We will also highlight potential pro-inflammatory mechanisms that may differ in vulnerable populations, including women, minorities and children.
SUMMARY: Mechanistic studies into the drivers of chronic inflammation in PWH are ongoing and may aid in tailoring effective therapeutic strategies that can reduce ASCVD risk in this population. Focus should also include factors that lead to persistent disparities in HIV care and comorbidities, including sex as a biological factor and social determinants of health. It remains unclear whether ASCVD progression in HIV is driven by unique mediators (HIV itself, ART, immunodeficiency), or if it is an accelerated version of disease progression seen in the general population.

DOI: https://doi.org/10.1097/COH.0000000000000755
Front Immunol. 2022 ;13 921728

Human Lung Fibroblasts Exhibit Induced Inflammation Memory via Increased IL6 Gene Expression and Release.

Jennifer Maries Go Yap, Takashi Ueda, Yoshihiro Kanemitsu, Norihisa Takeda, Kensuke Fukumitsu, Satoshi Fukuda, Takehiro Uemura, Tomoko Tajiri, Hirotsugu Ohkubo, Ken Maeno, Yutaka Ito, Testsuya Oguri, Shinya Ugawa, Akio Niimi.

  Fibroblasts of different origins are known to possess stromal memory after inflammatory episodes. However, there are no studies exploring human lung fibroblast memory which may predict a subsequent inflammatory response in chronic respiratory diseases and COVID-19. MRC-5 and HF19 human lung fibroblast cell lines were treated using different primary and secondary stimulus combinations: TNFα-WD-TNFα, Poly (I:C)-WD-TNFα, TNFα-WD-Poly (I:C), or LPS-WD-TNFα with a 24-h rest period (withdrawal period; WD) between the two 24-h stimulations. TLR3 and NF-κB inhibitors were used to determine pathways involved. The effect of SARS-Cov-2 spike protein to inflammatory response of lung fibroblasts was also investigated. mRNA expressions of genes and IL6 release were measured using qRT-PCR and ELISA, respectively. Statistical significance was determined by using one- or two-way ANOVA, followed by Bonferroni's post hoc analysis for comparison of multiple groups. Preexposure with Poly (I:C) significantly increased TNFα-induced IL6 gene expression and IL6 release in both cell lines, while it affected neither gene expressions of IL1B, IL2, IL8, and MMP8 nor fibrosis-related genes: ACTA2, COL1A1, POSTN, and TGFB1. Inhibition of TLR3 or NF-κB during primary stimulation significantly downregulated IL6 release. Simultaneous treatment of MRC-5 cells with SARS-CoV-2 spike protein further increased TNFα-induced IL6 release; however, preexposure to Poly (I:C) did not affect it. Human lung fibroblasts are capable of retaining inflammatory memory and showed an augmented response upon secondary exposure. These results may contribute to the possibility of training human lung fibroblasts to respond suitably on inflammatory episodes after viral infection.

Keywords:  Poly (I:C); SARS-CoV-2; fibroblasts; inflammatory memory; interleukin-6; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2022.921728
Clin Transl Oncol. 2022 Aug 13.

Therapeutic applications of toll-like receptors (TLRs) agonists in AML.

Ye Peng, Yanzhong Wang, Manling Wang, Jianping Lan, Yirui Chen.

  Acute myeloid leukemia (AML) is an aggressive type of blood cancer affecting bone marrow (BM). In AML, hematopoietic precursors are arrested in the early stages of development and are defined as the presence of ≥ 20% blasts (leukemia cells) in the BM. Toll-like receptors (TLR) are major groups of pattern recognition receptors expressed by almost all innate immune cells that enable them to detect a wide range of pathogen-associated molecular patterns and damage-associated molecular patterns to prime immune responses toward adaptive immunity. Because TLRs are commonly expressed on transformed immune system cells (ranging from blasts to memory cells), they can be a potential option for developing efficient clinical alternatives in hematologic tumors. This is because several in vitro and in vivo investigations have demonstrated that TLR signaling increased the immunogenicity of AML cells, making them more vulnerable to T cell-mediated invasion. This study aimed to review the current knowledge in this field and provide some insight into the therapeutic potentials of TLRs in AML.

Keywords:  AML; Hematological malignancy; Immunotherapy; Leukemia; TLR

DOI:  https://doi.org/10.1007/s12094-022-02917-5
Front Immunol. 2022 ;13 939213

Low-dose mycophenolate mofetil improves survival in a murine model of Staphylococcus aureus sepsis by increasing bacterial clearance and phagocyte function.

Fanny Alby-Laurent, Nadia Belaïdouni, Benoit Blanchet, Christophe Rousseau, Jean-François Llitjos, Sylvia Sanquer, Jean-Paul Mira, Frédéric Pène, Julie Toubiana, Jean-Daniel Chiche.

  Regulators of TLRs signaling pathways play an important role in the control of the pro-inflammatory response that contributes to sepsis-induced tissue injury. Mycophenolate mofetil, an immunosuppressive drug inhibiting lymphocyte proliferation, has been reported to be a regulator of TLRs signaling pathways. Whether MMF used at infra-immunosuppressive doses has an impact on survival and on innate immune response in sepsis is unknown. C57BL/6J mice were infected intraperitoneally with 108 CFU Staphylococcus aureus, and treated or not with low-dose of MMF (20mg/kg/day during 4 days). Survival rate and bacterial clearance were compared. Cytokine levels, quantitative and qualitative cellular responses were assessed. S. aureus - infected mice treated with MMF exhibited improved survival compared to non-treated ones (48% vs 10%, p<0.001). With the dose used for all experiments, MMF did not show any effect on lymphocyte proliferation. MMF treatment also improved local and systemic bacterial clearance, improved phagocytosis activity of peritoneal macrophages resulting in decreased inflammatory cytokines secretion. MMF-treated mice showed enhanced activation of NF-κB seemed with a suspected TLR4-dependent mechanism. These results suggest that infra-immunosuppressive doses of MMF improve host defense during S. aureus sepsis and protects infected mice from fatal outcome by regulating innate immune responses. The signaling pathways involved could be TLR4-dependent. This work brings new perspectives in pathogenesis and therapeutic approaches of severe infections.

Keywords:  NF-κB; innate immunity; macrophages; mycophenolate mofetil; phagocytosis; sepsis; staphylococcus aureus; toll-like receptor 4

DOI:  https://doi.org/10.3389/fimmu.2022.939213