bims-traimu 2024-02-25 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2024–02–25
nine papers selected by
Yantong Wan, Southern Medical University

Trained Innate Immunity in Animal Models of Cardiovascular Diseases.
Vaccines and Dementia: Part I. Non-Specific Immune Boosting with BCG: History, Ligands, and Receptors.
Vaccines and Dementia: Part II. Efficacy of BCG and Other Vaccines Against Dementia.
MV130 in the Prevention of Recurrent Respiratory Tract Infections: A Retrospective Real-World Study in Children and Adults.
A mechanism for BCG vaccine cross-protection against pulmonary viral infections.
Treatment of a MyD88 inhibitor alleviates rejection and inflammation in xenotransplantation by inhibiting dendritic cells activation and trained immunity in macrophages.
A genetically modulated Toll-like-receptor-tolerant phenotype in peripheral blood cells of children with multisystem inflammatory syndrome.
Monophosphoryl lipid A as a co-adjuvant in methicillin-resistant Staphylococcus aureus vaccine development: improvement of immune responses in a mouse model of infection.
Genetic loss of Nrf1 and Nrf2 leads to distinct metabolism reprogramming of HepG2 cells by opposing regulation of the PI3K-AKT-mTOR signalling pathway.

Int J Mol Sci. 2024 Feb 15. pii: 2312. [Epub ahead of print]25(4):

Trained Innate Immunity in Animal Models of Cardiovascular Diseases.

Patricia Kleimann, Lisa-Marie Irschfeld, Maria Grandoch, Ulrich Flögel, Sebastian Temme.

  Acquisition of immunological memory is an important evolutionary strategy that evolved to protect the host from repetitive challenges from infectious agents. It was believed for a long time that memory formation exclusively occurs in the adaptive part of the immune system with the formation of highly specific memory T cells and B cells. In the past 10-15 years, it has become clear that innate immune cells, such as monocytes, natural killer cells, or neutrophil granulocytes, also have the ability to generate some kind of memory. After the exposure of innate immune cells to certain stimuli, these cells develop an enhanced secondary response with increased cytokine secretion even after an encounter with an unrelated stimulus. This phenomenon has been termed trained innate immunity (TI) and is associated with epigenetic modifications (histone methylation, acetylation) and metabolic alterations (elevated glycolysis, lactate production). TI has been observed in tissue-resident or circulating immune cells but also in bone marrow progenitors. Risk-factors for cardiovascular diseases (CVDs) which are associated with low-grade inflammation, such as hyperglycemia, obesity, or high salt, can also induce TI with a profound impact on the development and progression of CVDs. In this review, we briefly describe basic mechanisms of TI and summarize animal studies which specifically focus on TI in the context of CVDs.

Keywords:  animal models; bone marrow; cardiovascular diseases; monocytes; trained innate immunity

DOI:  https://doi.org/10.3390/ijms25042312
J Alzheimers Dis. 2024 Feb 20.

Vaccines and Dementia: Part I. Non-Specific Immune Boosting with BCG: History, Ligands, and Receptors.

Charles L Greenblatt, Richard Lathe.

  Vaccines such as Bacille Calmette-Guérin (BCG) can apparently defer dementia onset with an efficacy better than all drugs known to date, as initially reported by Gofrit et al. (PLoS One14, e0224433), now confirmed by other studies. Understanding how and why is of immense importance because it could represent a sea-change in how we manage patients with mild cognitive impairment through to dementia. Given that infection and/or inflammation are likely to contribute to the development of dementias such as Alzheimer's disease (Part II of this work), we provide a historical and molecular background to how vaccines, adjuvants, and their component molecules can elicit broad-spectrum protective effects against diverse agents. We review early studies in which poxvirus, herpes virus, and tuberculosis (TB) infections afford cross-protection against unrelated pathogens, a concept known as 'trained immunity'. We then focus on the attenuated TB vaccine, BCG, that was introduced to protect against the causative agent of TB, Mycobacterium tuberculosis. We trace the development of BCG in the 1920 s through to the discovery, by Freund and McDermott in the 1940 s, that extracts of mycobacteria can themselves exert potent immunostimulating (adjuvant) activity; Freund's complete adjuvant based on mycobacteria remains the most potent immunopotentiator reported to date. We then discuss whether the beneficial effects of BCG require long-term persistence of live bacteria, before focusing on the specific mycobacterial molecules, notably muramyl dipeptides, that mediate immunopotentiation, as well as the receptors involved. Part II addresses evidence that immunopotentiation by BCG and other vaccines can protect against dementia development.

Keywords:  Adjuvant; Alzheimer’s disease; Bacille Calmette–Guérin; Freund; NOD2; YB-1; immunopotentiation; muramyl dipeptide; mycobacteria; trained immunity; vaccine

DOI:  https://doi.org/10.3233/JAD-231315
J Alzheimers Dis. 2024 Feb 19.

Vaccines and Dementia: Part II. Efficacy of BCG and Other Vaccines Against Dementia.

Charles L Greenblatt, Richard Lathe.

   There is growing awareness that infections may contribute to the development of senile dementia including Alzheimer's disease (AD), and that immunopotentiation is therefore a legitimate target in the management of diseases of the elderly including AD. In Part I of this work, we provided a historical and molecular background to how vaccines, adjuvants, and their component molecules can elicit broad-spectrum protective effects against diverse agents, culminating in the development of the tuberculosis vaccine strain Bacille Calmette-Guérin (BCG) as a treatment for some types of cancer as well as a prophylactic against infections of the elderly such as pneumonia. In Part II, we critically review studies that BCG and other vaccines may offer a measure of protection against dementia development. Five studies to date have determined that intravesicular BCG administration, the standard of care for bladder cancer, is followed by a mean ∼45% reduction in subsequent AD development in these patients. Although this could potentially be ascribed to confounding factors, the finding that other routine vaccines such as against shingles (herpes zoster virus) and influenza (influenza A virus), among others, also offer a degree of protection against AD (mean 29% over multiple studies) underlines the plausibility that the protective effects are real. We highlight clinical trials that are planned or underway and discuss whether BCG could be replaced by key components of the mycobacterial cell wall such as muramyl dipeptide. We conclude that BCG and similar agents merit far wider consideration as prophylactic agents against dementia.

Keywords:  Alzheimer’s disease; Bacille Calmette–Guérin; dementia; herpes zoster; immunopotentiation; influenza; muramyl dipeptide; trained immunity; vaccine

DOI:  https://doi.org/10.3233/JAD-231323
Vaccines (Basel). 2024 Feb 07. pii: 172. [Epub ahead of print]12(2):

MV130 in the Prevention of Recurrent Respiratory Tract Infections: A Retrospective Real-World Study in Children and Adults.

Karla Montalbán-Hernández, Ana Cogollo-García, Patricia Girón de Velasco-Sada, Raquel Caballero, Miguel Casanovas, José Luis Subiza, Laura Conejero.

  Respiratory tract infections (RTIs) are among the most common and important problems in clinical medicine, making antibiotics the gold standard therapeutic option regardless of their frequent viral etiology. Their excessive and inappropriate use contributes to the rapid rise of antibiotic resistance and underscores the need for alternative strategies, especially when dealing with recurrent RTIs. Prevention is the ideal alternative, but specific vaccines targeting a wide range of respiratory pathogens are scarce. MV130 is a sublingual bacterial vaccine that induces trained immunity and provides non-specific protection against respiratory pathogens in various clinical settings according to the concept of TIbV (Trained Immunity-based Vaccine). A retrospective real-world study (RWS) was conducted to evaluate the annual incidence of RTIs and the consumption of antibiotics before and after the administration of MV130, using data sourced from the medical records of 599 patients (186 children and 413 adults) who suffered from recurrent RTIs. The median number of infectious episodes in children was significantly reduced by more than 70% from 5 episodes (interquartile range (IQR) 4.0-6.0) to 1 (IQR, 0.0-2.0) (p < 0.001) after MV130. Similarly, in adults, the median number of episodes before MV130 immunization was 5 (IQR, 4.0-6.0), which dropped by more than 80% to 1 (IQR, 0.0-1.0) during the year following MV130 immunization (p < 0.001). The median number of antibiotic courses also significantly decreased for both children and adults by over 80% (p < 0.001). This RWS showed that MV130 is an effective strategy for the prevention of respiratory infections and the reduction of associated antibiotic consumption.

Keywords:  MV130; lower respiratory tract infections; real world study; recurrent respiratory tract infections; respiratory tract infections; trained immunity-based vaccines; upper respiratory tract infections

DOI:  https://doi.org/10.3390/vaccines12020172
Nat Immunol. 2024 Feb 21.

A mechanism for BCG vaccine cross-protection against pulmonary viral infections.

DOI: https://doi.org/10.1038/s41590-024-01775-3
Int Immunopharmacol. 2024 Feb 19. pii: S1567-5769(24)00182-6. [Epub ahead of print]130 111664

Treatment of a MyD88 inhibitor alleviates rejection and inflammation in xenotransplantation by inhibiting dendritic cells activation and trained immunity in macrophages.

Zeyang Li, Minghui Zhao, Yang Yang, Zhimiao Zou, Limin Zhang, Fengchao Jiang, Dunfeng Du, Ping Zhou.

BACKGROUND: Acute vascular rejection (AVR) and systemic inflammation in xenograft recipients (SIXR) negatively impact the xenografts survival, and novel immunosuppressants are required to improve survival outcomes. We previously reported that TJ-M2010-5, a myeloid differentiation factor 88 (MyD88) inhibitor, exerts excellent anti-rejection effects in allogeneic transplantation. The aim of the present study was to evaluate the efficacy of TJ-M2010-5 in preventing AVR and SIXR and to investigate whether combined treatment of TJ-M2010-5 with anti-CD154 antibody (MR1) could prolong xenograft survival furthermore.
METHODS: A model involving heart transplantation from Sprague-Dawley rats to BALB/c mice was established in vivo, and the xenografts developed typical AVR. Bone marrow-derived dendritic cells and macrophages were cultured to study the underlying mechanisms induced by rat cardiomyocyte lysate stimulation in vitro.
RESULTS: TJ-M2010-5 monotherapy prolonged xenograft survival, although combination treatment with MR1 further enhanced the anti-AVR and anti-SIXR effects with about 21 days graft survival, compared to monotherapy. TJ-M2010-5 reduced dendritic cell and macrophage activation induced by xenotransplantation, downregulated CD80/CD86 expression, suppressed B-cell activation and anti-donor antibody generation, reduced pro-inflammatory cytokine production and tissue factor expression, and attenuated epigenetic modifications underlying interleukin-6 and tumor necrosis factor-α production in macrophages by inhibiting nuclear factor kappa B nuclear translocation.
CONCLUSIONS: TJ-M2010-5 attenuated AVR and SIXR and contributed to xenograft survival by inhibiting dendritic cell and macrophage activation. A dual-system inhibition strategy combining TJ-M2010-5 with anti-CD154 antibody achieved better results in xenotransplantation.

DOI: https://doi.org/10.1016/j.intimp.2024.111664
medRxiv. 2024 Feb 05. pii: 2024.02.02.24301686. [Epub ahead of print]

A genetically modulated Toll-like-receptor-tolerant phenotype in peripheral blood cells of children with multisystem inflammatory syndrome.

Rehan Khan, Weizhen Ji, Jeisac Guzman-Rivera, Abhilasha Madhvi, Tracy Andrews, Benjamin Richlin, Christian Suarez, Sunanda Gaur, William Cuddy, Aalok R Singh, Hulya Bukulmez, David Kaelber, Yukiko Kimura, Usha Ganapathi, Ioannis E Michailidis, Rahul Ukey, Sandra Moroso-Fela, John K Kuster, Myriam Casseus, Jason Roy, Lawrence C Kleinman, Daniel B Horton, Saquib A Lakhani, Maria Laura Gennaro.

Dysregulated innate immune responses contribute to multisystem inflammatory syndrome in children (MIS-C), characterized by gastrointestinal, mucocutaneous, and/or cardiovascular injury occurring weeks after SARS-CoV-2 exposure. To investigate innate immune functions in MIS-C, we stimulated ex vivo peripheral blood cells from MIS-C patients with agonists of Toll-like receptors (TLR), key innate immune response initiators. We found severely dampened cytokine responses and elevated gene expression of negative regulators of TLR signaling. Increased plasma levels of zonulin, a gut leakage marker, were also detected. These effects were also observed in children enrolled months after MIS-C recovery. Moreover, cells from MIS-C children carrying rare genetic variants of lysosomal trafficking regulator ( LYST ) were less refractory to TLR stimulation and exhibited lysosomal and mitochondrial abnormalities with altered energy metabolism. Our results strongly suggest that MIS-C hyperinflammation and/or excessive or prolonged stimulation with gut-originated TLR ligands drive immune cells to a lasting refractory state. TLR hyporesponsiveness is likely beneficial, as suggested by excess lymphopenia among rare LYST variant carriers. Our findings point to cellular mechanisms underlying TLR hyporesponsiveness; identify genetic determinants that may explain the MIS-C clinical spectrum; suggest potential associations between innate refractory states and long COVID; and highlight the need to monitor long-term consequences of MIS-C.

DOI: https://doi.org/10.1101/2024.02.02.24301686
Immunol Res. 2024 Feb 21.

Monophosphoryl lipid A as a co-adjuvant in methicillin-resistant Staphylococcus aureus vaccine development: improvement of immune responses in a mouse model of infection.

Mehdi Mirshekar, Setareh Haghighat, Zahra Mousavi, Amir Hossein Abdolghaffari, Mohammad Hossein Yazdi.

  To increase the effectiveness of methicillin-resistant Staphylococcus aureus vaccines (MRSA), a new generation of immune system stimulating adjuvants is necessary, along with other adjuvants. In some vaccines, monophosphoryl lipid A (MPLA) as a toll-like receptor 4 agonist is currently used as an adjuvant or co-adjuvant. MPLA could increase the immune response and vaccine immunogenicity. The current investigation assessed the immunogenicity and anti-MRSA efficacy of recombinant autolysin formulated in MPLA and Alum as co-adjuvant/adjuvant. r-Autolysin was expressed and purified by Ni-NTA affinity chromatography and characterized by SDS-PAGE. Then, the vaccine candidate formulation in MPLAs and Alum was prepared. To investigate the immunogenic responses, total IgG, isotype (IgG1 and IgG2a) levels, and cytokines (IL-4, IL-12, TNF-α, and IFN-γ) profiles were evaluated by ELISA. Also, the bacterial burden in internal organs, opsonophagocytosis, survival rate, and pathobiology changes was compared among the groups. Results demonstrated that mice immunized with the r-Autolysin + Alum + MPLA Synthetic and r-Autolysin + Alum + MPLA Biologic led to increased levels of opsonic antibodies, IgG1, IgG2a isotype as well as increased levels of cytokines profiles, as compared with other experimental groups. More importantly, mice immunized with MPLA and r-Autolysin exhibited a decrease in mortality and bacterial burden, as compared with the control group. The highest level of survival was seen in the r-Autolysin + Alum + MPLA Synthetic group. We concluded that both MPLA forms, synthetic and biological, are reliable candidates for immune response improvement against MRSA infection.

Keywords:  Co-adjuvant; Immunogenicity; Monophosphoryl lipid A; Mouse model; Staphylococcus aureus; r-Autolysin

DOI:  https://doi.org/10.1007/s12026-024-09456-x
Bioorg Chem. 2024 Feb 13. pii: S0045-2068(24)00117-2. [Epub ahead of print]145 107212

Genetic loss of Nrf1 and Nrf2 leads to distinct metabolism reprogramming of HepG2 cells by opposing regulation of the PI3K-AKT-mTOR signalling pathway.

Rongzhen Deng, Yuping Zhu, Keli Liu, Qun Zhang, Shaofan Hu, Meng Wang, Yiguo Zhang.

  As a vital hallmarker of cancer, the metabolic reprogramming has been shown to play a pivotal role in tumour occurrence, metastasis and drug resistance. Amongst a vast variety of signalling molecules and metabolic enzymes involved in the regulation of cancer metabolism, two key transcription factors Nrf1 and Nrf2 are required for redox signal transduction and metabolic homeostasis. However, the regulatory effects of Nrf1 and Nrf2 (both encoded by Nfe2l1 and Nfe2l2, respectively) on the metabolic reprogramming of hepatocellular carcinoma cells have been not well understood to date. Here, we found that the genetic deletion of Nrf1 and Nrf2 from HepG2 cells resulted in distinct metabolic reprogramming. Loss of Nrf1α led to enhanced glycolysis, reduced mitochondrial oxygen consumption, enhanced gluconeogenesis and activation of the pentose phosphate pathway in the hepatocellular carcinoma cells. By striking contrast, loss of Nrf2 attenuated the glycolysis and gluconeogenesis pathways, but with not any significant effects on the pentose phosphate pathway. Moreover, knockout of Nrf1α also caused fat deposition and increased amino acid synthesis and transport, especially serine synthesis, whilst Nrf2 deficiency did not cause fat deposition, but attenuated amino acid synthesis and transport. Further experiments revealed that such distinctive metabolic programming of between Nrf1α-/- and Nrf2-/- resulted from substantial activation of the PI3K-AKT-mTOR signalling pathway upon the loss of Nrf1, leading to increased expression of critical genes for the glucose uptake, glycolysis, the pentose phosphate pathway, and the de novo lipid synthesis, whereas deficiency of Nrf2 resulted in the opposite phenomenon by inhibiting the PI3K-AKT-mTOR pathway. Altogether, these provide a novel insight into the cancer metabolic reprogramming and guide the exploration of a new strategy for targeted cancer therapy.

Keywords:  AKT; HIF1; Liver cancer; Metabolic reprogramming; Nrf1; Nrf2; PI3K; SREBP; Signal transduction pathway; Transcriptional regulation; mTOR

DOI:  https://doi.org/10.1016/j.bioorg.2024.107212