bims-traimu 2023-11-12 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2023–11–12
ten papers selected by
Yantong Wan, Southern Medical University

Trained immunity: Target for prophylaxis and therapy.
"Training immunity" against nosocomial pathogens.
Neuro-HIV-New insights into pathogenesis and emerging therapeutic targets.
Liposomal Delivery of an Immunostimulatory Cpg Induces Robust Antitumor Immunity and Long-Term Immune Memory by Reprogramming Tumor-Associated Macrophages.
Sfrp1 as a Pivotal Paracrine Factor in the Trained Pericardial Stem Cells that Foster Reparative Activity.
Fumarate hydratase as a metabolic regulator of immunity.
Themis2 regulates natural killer cell memory function and formation.
Activation of Toll-like receptor 3 inhibits HIV infection of human iPSC-derived microglia.
Application of toll-like receptors (TLRs) and their agonists in cancer vaccines and immunotherapy.
Interferon signaling drives epithelial metabolic reprogramming to promote secondary bacterial infection.

Cell Host Microbe. 2023 Nov 08. pii: S1931-3128(23)00419-5. [Epub ahead of print]31(11): 1776-1791

Trained immunity: Target for prophylaxis and therapy.

Athanasios Ziogas, Mariolina Bruno, Roy van der Meel, Willem J M Mulder, Mihai G Netea.

Trained immunity is a de facto memory for innate immune responses, leading to long-term functional reprogramming of innate immune cells. In physiological conditions, trained immunity leads to adaptive states that enhance resistance against pathogens and contributes to immunosurveillance. Dysregulated trained immunity can however lead either to defective innate immune responses in severe infections or cancer or to inflammatory and autoimmune diseases if trained immunity is inappropriately activated. Here, we review the immunological and molecular mechanisms that mediate trained immunity induction and propose that trained immunity represents an important target for prophylactic and therapeutic approaches in human diseases. On the one hand, we argue that novel approaches that induce trained immunity may enhance vaccine efficacy. On the other hand, induction of trained immunity in cancer, and inhibition of exaggerated induction of trained immunity in inflammatory disorders, are viable targets amenable for new therapeutic approaches.

DOI: https://doi.org/10.1016/j.chom.2023.10.015
Sci Immunol. 2023 Nov 10. 8(89): eadl5685

"Training immunity" against nosocomial pathogens.

Alexandra Schäfer, David R Martinez.

Non-antigen vaccines that broadly activate innate immune responses reduce mortality against hospital-acquired bacterial and fungal pathogens.

DOI: https://doi.org/10.1126/sciimmunol.adl5685
FASEB J. 2023 Dec;37(12): e23301

Neuro-HIV-New insights into pathogenesis and emerging therapeutic targets.

Dmitri Sviridov, Michael Bukrinsky.

  HIV-associated neurocognitive disorders (HAND) is a term describing a complex set of cognitive impairments accompanying HIV infection. Successful antiretroviral therapy (ART) reduces the most severe forms of HAND, but milder forms affect over 50% of people living with HIV (PLWH). Pathogenesis of HAND in the ART era remains unknown. A variety of pathogenic factors, such as persistent HIV replication in the brain reservoir, HIV proteins released from infected brain cells, HIV-induced neuroinflammation, and some components of ART, have been implicated in driving HAND pathogenesis in ART-treated individuals. Here, we propose another factor-impairment of cholesterol homeostasis and lipid rafts by HIV-1 protein Nef-as a possible contributor to HAND pathogenesis. These effects of Nef on cholesterol may also underlie the effects of other pathogenic factors that constitute the multifactorial nature of HAND pathogenesis. The proposed Nef- and cholesterol-focused mechanism may provide a long-sought unified explanation of HAND pathogenesis that takes into account all contributing factors. Evidence for the impairment by Nef of cellular cholesterol balance, potential effects of this impairment on brain cells, and opportunities to therapeutically target this element of HAND pathogenesis are discussed.

Keywords:  HAND; HIV; Nef; cholesterol; epigenetic modifications; extracellular vesicles; inflammation; lipid rafts; trained immunity

DOI:  https://doi.org/10.1096/fj.202301239RR
Adv Healthc Mater. 2023 Nov 06. e2300549

Liposomal Delivery of an Immunostimulatory Cpg Induces Robust Antitumor Immunity and Long-Term Immune Memory by Reprogramming Tumor-Associated Macrophages.

Yujin Kim, Seojung Lee, Sangyong Jon.

  Tumor-associated macrophages (TAMs)-representative immune-suppressive cells in the tumor microenvironment (TME)-are known to promote tumor progression and metastasis, and thus have been considered an attractive target for cancer therapy. However, current TAM-targeting strategies are insufficient to result in robust antitumor efficacy. Here, we report a small lipid nanoparticle encapsulating immunostimulatory CpG oligodeoxynucleotides (SLNP@CpG) as a new immunotherapeutic modality that can reprogram TAMs and further bridge innate-to-adaptive immunity. We found that SLNP@CpG treatment enhanced macrophage-mediated phagocytosis of cancer cells and tumor antigen cross-presentation and skewed the polarization state of macrophages in vitro. Intratumoral injection of SLNP@CpG into an established murine E.G7-OVA tumor model significantly suppressed tumor growth and considerably prolonged survival, completely eradicating tumors in 83.3% of mice. Furthermore, tumor-free mice resisted rechallenge with E.G7-OVA cancer cells through induction of immunological memory and long-term antitumor immunity. SLNP@CpG even exerted antitumor efficacy in an aggressive B16-F10 melanoma model by remodeling TME towards immune stimulation and tumor elimination. These findings suggest that, by modulating the function of TAMs and reshaping an immunosuppressive TME, the SLNP@CpG nanomedicine developed here may become a promising immunotherapeutic option applicable to a variety of tumors. This article is protected by copyright. All rights reserved.

Keywords:  CpG, liposomes; cancer immunotherapy; nanoparticles; tumor-associated macrophages

DOI:  https://doi.org/10.1002/adhm.202300549
Stem Cells Transl Med. 2023 Nov 04. pii: szad075. [Epub ahead of print]

Sfrp1 as a Pivotal Paracrine Factor in the Trained Pericardial Stem Cells that Foster Reparative Activity.

Hongtao Zhu, Xueqing Liu, Weili Ouyang, Yingcai Hao, Zheheng Ding, Kezhe Tan, Jianfeng Tang, Jianfeng Zhao, Xiaojun Ding, Zenghui Teng, Xiaoming Deng, Weidong Wu, Zhaoping Ding.

  Tissue damage often induces local inflammation that in turn dictates a series of subsequential responses, such as stem cell activation and growth, to maintain tissue homeostasis. The aim of the study is to testify the possibility of using inflammation-trained stem cells as optimal donor cells to augment the efficacy of cell therapy. The pericardial stem/stromal cells derived from the animals after myocardial infarction (MI-pSC) showed an enhanced myogenic potential and augmented reparative activity after transplantation in the injured hearts, as compared to the Sham-pSC. Bulk RNA-Seq analysis revealed significant upregulation of a panel of myogenic and trophic genes in the MI-pSC and, notably, Sfrp1 as an important anti-apoptotic factor induced robustly in the MI-pSC. Injection of the MI-pSC yielded measurable numbers of surviving cardiomyocytes (Tunel and Casp-3 negative) within the infarct area, but the effects were significantly diminished by siRNA-based silence of Sfrp1 gene in the pSC. Primed Sham-pSC with pericardial fluid from MI rats mimicked the upregulation of Sfrp1 and enhanced myogenic potential and reparative activity of pSC. Taken together, our results illustrated the inflammation-trained pSC favor a reparative activity through upregulation of Sfrp1 gene that confers anti-apoptotic activity in the injured cardiomyocytes. Therefore, the active form of stem cells may be used as a cardiac protective agent to boost therapeutical potential of stem cells.

Keywords:  Sfrp1; anti-apoptosis; inflammatory niche; myogenic progenitors; pericardial stromal cells

DOI:  https://doi.org/10.1093/stcltm/szad075
Trends Cell Biol. 2023 Nov 06. pii: S0962-8924(23)00209-X. [Epub ahead of print]

Fumarate hydratase as a metabolic regulator of immunity.

Christian G Peace, Shane M O'Carroll, Luke A J O'Neill.

  Tricarboxylic acid (TCA) cycle metabolites have been implicated in modulating signalling pathways in immune cells. Notable examples include succinate and itaconate, which have pro- and anti-inflammatory roles, respectively. Recently, fumarate has emerged as having specific roles in macrophage activation, regulating the production of such cytokines as interleukin (IL)-10 and type I interferons (IFNs). Fumarate hydratase (FH) has been identified as a control point. Notably, FH loss in different models and cell types has been found to lead to DNA and RNA release from mitochondria which are sensed by cytosolic nucleic acid sensors including retinoic acid-inducible gene (RIG)-I, melanoma differentiation-associated protein (MDA)5, and cyclic GMP-AMP synthase (cGAS) to upregulate IFN-β production. These findings may have relevance in the pathogenesis and treatment of diseases associated with decreased FH levels such as systemic lupus erythematosus (SLE) or FH-deficient kidney cancer.

Keywords:  immunometabolism; innate immunity; interferon; mitochondria

DOI:  https://doi.org/10.1016/j.tcb.2023.10.005
Nat Commun. 2023 Nov 08. 14(1): 7200

Themis2 regulates natural killer cell memory function and formation.

Tsukasa Nabekura, Elfira Amalia Deborah, Saeko Tahara, Yuya Arai, Paul E Love, Koichiro Kako, Akiyoshi Fukamizu, Masafumi Muratani, Akira Shibuya.

Immunological memory is a hallmark of the adaptive immune system. Although natural killer (NK) cells are innate immune cells important for the immediate host defence, they can differentiate into memory NK cells. The molecular mechanisms controlling this differentiation are yet to be fully elucidated. Here we identify the scaffold protein Themis2 as a critical regulator of memory NK cell differentiation and function. Themis2-deficient NK cells expressing Ly49H, an activating NK receptor for the mouse cytomegalovirus (MCMV) antigen m157, show enhanced differentiation into memory NK cells and augment host protection against MCMV infection. Themis2 inhibits the effector function of NK cells after stimulation of Ly49H and multiple activating NK receptors, though not specific to memory NK cells. Mechanistically, Themis2 suppresses Ly49H signalling by attenuating ZAP70/Syk phosphorylation, and it also translocates to the nucleus, where it promotes Zfp740-mediated repression to regulate the persistence of memory NK cells. Zfp740 deficiency increases the number of memory NK cells and enhances the effector function of memory NK cells, which further supports the relevance of the Themis2-Zfp740 pathway. In conclusion, our study shows that Themis2 quantitatively and qualitatively regulates NK cell memory formation.

DOI: https://doi.org/10.1038/s41467-023-42578-8
J Med Virol. 2023 Nov;95(11): e29217

Activation of Toll-like receptor 3 inhibits HIV infection of human iPSC-derived microglia.

Peng Wang, Jin-Biao Liu, Xu Wang, Feng-Zheng Meng, Qian-Hao Xiao, Lu Liu, Jian Zhu, Wen-Hui Hu, Wen-Zhe Ho.

  As a key immune cell in the brain, microglia are essential for protecting the central nervous system (CNS) from viral infections, including HIV. Microglia possess functional Toll-like receptor 3 (TLR3), a key viral sensor for activating interferon (IFN) signaling pathway-mediated antiviral immunity. We, therefore, studied the effect of poly (I:C), a synthetic ligand of TLR3, on the activation of the intracellular innate immunity against HIV in human iPSC-derived microglia (iMg). We found that poly (I:C) treatment of iMg effectively inhibits HIV infection/replication at both mRNA and protein levels. Investigations of the mechanisms revealed that TLR3 activation of iMg by poly (I:C) induced the expression of both type I and type III IFNs. Compared with untreated cells, the poly (I:C)-treated iMg expressed significantly higher levels of IFN-stimulated genes (ISGs) with known anti-HIV activities (ISG15, MxB, Viperin, MxA, and OAS-1). In addition, TLR3 activation elicited the expression of the HIV entry coreceptor CCR5 ligands (CC chemokines) in iMg. Furthermore, the transcriptional profile analysis showed that poly (I:C)-treated cells had the upregulated IFN signaling genes (ISG15, ISG20, IFITM1, IFITM2, IFITM3, IFITM10, APOBEC3A, OAS-2, MxA, and MxB) and the increased CC chemokine signaling genes (CCL1, CCL2, CCL3, CCL4, and CCL15). These observations indicate that TLR3 is a potential therapy target for activating the intracellular innate immunity against HIV infection/replication in human microglial cells. Therefore, further studies with animal models and clinical specimens are necessary to determine the role of TLR3 activation-driven antiviral response in the control and elimination of HIV in infected host cells.

Keywords:  HIV; TLR3; iPSC-derived microglia; interferon; poly (I:C)

DOI:  https://doi.org/10.1002/jmv.29217
Front Immunol. 2023 ;14 1227833

Application of toll-like receptors (TLRs) and their agonists in cancer vaccines and immunotherapy.

Samik Chakraborty, Juan Ye, Herui Wang, Mitchell Sun, Yaping Zhang, Xueyu Sang, Zhengping Zhuang.

  Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) expressed in various immune cell types and perform multiple purposes and duties involved in the induction of innate and adaptive immunity. Their capability to propagate immunity makes them attractive targets for the expansion of numerous immunotherapeutic approaches targeting cancer. These immunotherapeutic strategies include using TLR ligands/agonists as monotherapy or combined therapeutic strategies. Several TLR agonists have demonstrated significant efficacy in advanced clinical trials. In recent years, multiple reports established the applicability of TLR agonists as adjuvants to chemotherapeutic drugs, radiation, and immunotherapies, including cancer vaccines. Cancer vaccines are a relatively novel approach in the field of cancer immunotherapy and are currently under extensive evaluation for treating different cancers. In the present review, we tried to deliver an inclusive discussion of the significant TLR agonists and discussed their application and challenges to their incorporation into cancer immunotherapy approaches, particularly highlighting the usage of TLR agonists as functional adjuvants to cancer vaccines. Finally, we present the translational potential of rWTC-MBTA vaccination [irradiated whole tumor cells (rWTC) pulsed with phagocytic agonists Mannan-BAM, TLR ligands, and anti-CD40 agonisticAntibody], an autologous cancer vaccine leveraging membrane-bound Mannan-BAM, and the immune-inducing prowess of TLR agonists as a probable immunotherapy in multiple cancer types.

Keywords:  TLR - toll-like receptor; TLR agonists; adjuvant; cancer immuno therapy; cancer vaccine; immunotherapy

DOI:  https://doi.org/10.3389/fimmu.2023.1227833
PLoS Pathog. 2023 Nov;19(11): e1011719

Interferon signaling drives epithelial metabolic reprogramming to promote secondary bacterial infection.

Grace P Carreno-Florez, Brian R Kocak, Matthew R Hendricks, Jeffrey A Melvin, Katrina B Mar, Jessica Kosanovich, Rachel L Cumberland, Greg M Delgoffe, Sruti Shiva, Kerry M Empey, John W Schoggins, Jennifer M Bomberger.

Clinical studies report that viral infections promote acute or chronic bacterial infections at multiple host sites. These viral-bacterial co-infections are widely linked to more severe clinical outcomes. In experimental models in vitro and in vivo, virus-induced interferon responses can augment host susceptibility to secondary bacterial infection. Here, we used a cell-based screen to assess 389 interferon-stimulated genes (ISGs) for their ability to induce chronic Pseudomonas aeruginosa infection. We identified and validated five ISGs that were sufficient to promote bacterial infection. Furthermore, we dissected the mechanism of action of hexokinase 2 (HK2), a gene involved in the induction of aerobic glycolysis, commonly known as the Warburg effect. We report that HK2 upregulation mediates the induction of Warburg effect and secretion of L-lactate, which enhances chronic P. aeruginosa infection. These findings elucidate how the antiviral immune response renders the host susceptible to secondary bacterial infection, revealing potential strategies for viral-bacterial co-infection treatment.

DOI: https://doi.org/10.1371/journal.ppat.1011719