bims-traimu 2022-09-04 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2022–09–04
seven papers selected by
Yantong Wan, Southern Medical University

Beneficial non-specific effects of live vaccines against COVID-19 and other unrelated infections.
Oral Bacille Calmette-Guérin (BCG) vaccination induces long-term potentiation of memory immune response to Ovalbumin airway challenge in mice.
HDM induces distinct immunometabolic phenotype in macrophages in TLR4-dependent manner.
Pre-exposure to mRNA-LNP inhibits adaptive immune responses and alters innate immune fitness in an inheritable fashion.
L-2-Hydroxyglutarate Protects Against Cardiac Injury via Metabolic Remodeling.
Live-attenuated YF17D-vectored COVID-19 vaccine protects from lethal yellow fever virus infection in mouse and hamster models.
Platelet Toll-Like-Receptor-2 and -4 Mediate Different Immune-Related Responses to Bacterial Ligands.

Lancet Infect Dis. 2022 Aug 26. pii: S1473-3099(22)00498-4. [Epub ahead of print]

Beneficial non-specific effects of live vaccines against COVID-19 and other unrelated infections.

Peter Aaby, Mihai G Netea, Christine S Benn.

Live attenuated vaccines could have beneficial, non-specific effects of protecting against vaccine-unrelated infections, such as BCG protecting against respiratory infection. During the COVID-19 pandemic, testing of these effects against COVID-19 was of interest to the pandemic control programme. Non-specific effects occur due to the broad effects of specific live attenuated vaccines on the host immune system, relying on heterologous lymphocyte responses and induction of trained immunity. Knowledge of non-specific effects has been developed in randomised controlled trials and observational studies with children, but examining of whether the same principles apply to adults and older adults was of interest to researchers during the pandemic. In this Personal View, we aim to define a framework for the analysis of non-specific effects of live attenuated vaccines against vaccine-unrelated infections with pandemic potential using several important concepts. First, study endpoints should prioritise severity of infection and overall patient health rather than incidence of infection only (eg, although several trials found no protection of the BCG vaccine against COVID-19 infection, it is associated with lower overall mortality than placebo). Second, revaccination of an individual with the same live attenuated vaccine could be the most effective strategy against vaccine-unrelated infections. Third, coadministration of several live attenuated vaccines might enhance beneficial non-specific effects. Fourth, the sequence of vaccine administration matters; the live attenuated vaccine should be the last vaccine administered before exposure to the pandemic infection and non-live vaccines should not be administered afterwards. Fifth, live attenuated vaccines could modify the immune response to specific COVID-19 vaccines. Finally, non-specific effects of live attenuated vaccines should always be analysed with subgroup analysis by sex of individuals receiving the vaccines.

DOI: https://doi.org/10.1016/S1473-3099(22)00498-4
Immunol Lett. 2022 Aug 25. pii: S0165-2478(22)00115-8. [Epub ahead of print]

Oral Bacille Calmette-Guérin (BCG) vaccination induces long-term potentiation of memory immune response to Ovalbumin airway challenge in mice.

Andreza Hammes, Fabíola Cardillo, Rodolfo Frota, Rosa Teixeira de Pinho, José Mengel.

  The Bacille Calmette-Guérin (BCG) is a potent immunomodulator. It was initially used by oral administration, but it is mostly used subcutaneously nowadays. This study shows that oral BCG vaccination modifies the immune response to a second non-related antigen (Ovalbumin) systemic immunization. Airway Ovalbumin challenge six months after the systemic intraperitoneal immunization resulted in a potent γδ+ T cell response in the lungs biased to IFN-γ and IL-17 production ex vivo and a mixed Th1, Th2, and Th17 T cells upon further stimulation with anti-CD3 mAb in vitro. Higher percentages of CD4+ T cells accompanied the augmented T cell response in oral BCG vaccinated mice. Also, the proportion of Foxp-3+ Tregs was diminished compared to PBS-gavaged and OVA-immunized mice. The anti-OVA-specific antibody response was also influenced by oral exposure to BCG so that these mice produced more IgG2a and less IgE detected in the sera. These results suggest that oral BCG vaccination can modify future immune responses to vaccines and improve immunity to pathogen infections, especially in the mucosal interfaces.

Keywords:  BCG; IFN-γ; Tregs; foxp3; trained immunity; γδ T cells

DOI:  https://doi.org/10.1016/j.imlet.2022.08.004
Biochim Biophys Acta Mol Basis Dis. 2022 Aug 26. pii: S0925-4439(22)00202-2. [Epub ahead of print] 166531

HDM induces distinct immunometabolic phenotype in macrophages in TLR4-dependent manner.

Taisiya R Yurakova, Ekaterina O Gubernatorova, Ekaterina A Gorshkova, Maxim A Nosenko, Sergei A Nedospasov, Marina S Drutskaya.

  Asthma is one of the most common chronic diseases. In many cases it is preceded by the development of an immune response to allergens such as animal fur, dust, pollens and etc. In human population this disease is heterogeneous, and no selective drugs are available at the moment for some endotypes of asthma. The role of the adaptive immune system in the pathogenesis of asthma was extensively studied, while the role of innate immune cells, in particular myeloid cells, was not sufficiently addressed. Myeloid cells, such as macrophages and dendritic cells, are characterized by high plasticity, heterogenicity and ability to undergo polarization in response to various pathogenic stimuli, including those engaging innate immune receptors. Recently, special attention was drawn to the link between polarization of macrophages and cell metabolism. We hypothesized that immunometabolic reprogramming of myeloid cells, in particular, of macrophages and dendritic cells during sensitization with an allergen may affect further immune response and asthma development. To test this hypothesis, we generated distinct types of myeloid cells in vitro from murine bone marrow and analyzed their immunometabolic profiles upon activation with house dust mite extract (HDM) and its key active components. We found that the combination of lipopolysaccharide (LPS) and beta-glucan is sufficient to upregulate proinflammatory cytokine production as well as respiratory and glycolytic capacity of myeloid cells, comparably to HDM. This specific immunometabolic phenotype was associated with altered mitochondrial morphology and possibly with increased ROS production in macrophages. Moreover, we found that both TNF production and metabolic remodeling of macrophages in response to HDM are TLR4-dependent processes. Altogether, these results expand our understanding of molecular mechanisms underlying asthma induction and pathogenesis and may potentially lead to new therapeutic strategies for the treatment of this disease.

Keywords:  Allergy; Asthma; House dust mite; Myeloid cells; TNF

DOI:  https://doi.org/10.1016/j.bbadis.2022.166531
PLoS Pathog. 2022 Sep 02. 18(9): e1010830

Pre-exposure to mRNA-LNP inhibits adaptive immune responses and alters innate immune fitness in an inheritable fashion.

Zhen Qin, Aurélie Bouteau, Christopher Herbst, Botond Z Igyártó.

Hundreds of millions of SARS-CoV-2 mRNA-LNP vaccine doses have already been administered to humans. However, we lack a comprehensive understanding of the immune effects of this platform. The mRNA-LNP-based SARS-CoV-2 vaccine is highly inflammatory, and its synthetic ionizable lipid component responsible for the induction of inflammation has a long in vivo half-life. Since chronic inflammation can lead to immune exhaustion and non-responsiveness, we sought to determine the effects of pre-exposure to the mRNA-LNP on adaptive immune responses and innate immune fitness. We found that pre-exposure to mRNA-LNPs or LNP alone led to long-term inhibition of the adaptive immune response, which could be overcome using standard adjuvants. On the other hand, we report that after pre-exposure to mRNA-LNPs, the resistance of mice to heterologous infections with influenza virus increased while resistance to Candida albicans decreased. The diminished resistance to Candida albicans correlated with a general decrease in blood neutrophil percentages. Interestingly, mice pre-exposed to the mRNA-LNP platform can pass down the acquired immune traits to their offspring, providing better protection against influenza. In summary, the mRNA-LNP vaccine platform induces long-term unexpected immunological changes affecting both adaptive immune responses and heterologous protection against infections. Thus, our studies highlight the need for more research to determine this platform's true impact on human health.

DOI: https://doi.org/10.1371/journal.ppat.1010830
Circ Res. 2022 Aug 31. 101161CIRCRESAHA122321227

L-2-Hydroxyglutarate Protects Against Cardiac Injury via Metabolic Remodeling.

Huamei He, Ryan M Mulhern, William M Oldham, Wusheng Xiao, Yi-Dong Lin, Ronglih Liao, Joseph Loscalzo.

   BACKGROUND: L-2-hydroxyglutarate (L2HG) couples mitochondrial and cytoplasmic energy metabolism to support cellular redox homeostasis. Under oxygen-limiting conditions, mammalian cells generate L2HG to counteract the adverse effects of reductive stress induced by hypoxia. Very little is known, however, about whether and how L2HG provides tissue protection from redox stress during low-flow ischemia (LFI) and ischemia-reperfusion injury. We examined the cardioprotective effects of L2HG accumulation against LFI and ischemia-reperfusion injury and its underlying mechanism using genetic mouse models.
METHODS AND RESULTS: L2HG accumulation was induced by homozygous (L2HGDH [L-2-hydroxyglutarate dehydrogenase]-/-) or heterozygous (L2HGDH+/-) deletion of the L2HGDH gene in mice. Hearts isolated from these mice and their wild-type littermates (L2HGDH+/+) were subjected to baseline perfusion or 90-minute LFI or 30-minute no-flow ischemia followed by 60- or 120-minute reperfusion. Using [13C]- and [31P]-NMR spectroscopy, high-performance liquid chromatography, real-time quantitative real-time polymerase chain reaction, ELISA, triphenyltetrazolium staining, colorimetric/fluorometric spectroscopy, and echocardiography, we found that L2HGDH deletion induces L2HG accumulation at baseline and under stress conditions with significant functional consequences. In response to LFI or ischemia-reperfusion, L2HG accumulation shifts glucose flux from glycolysis towards the pentose phosphate pathway. These key metabolic changes were accompanied by enhanced cellular reducing potential, increased elimination of reactive oxygen species, attenuated oxidative injury and myocardial infarction, preserved cellular energy state, and improved cardiac function in both L2HGDH-/- and L2HGDH+/- hearts compared with L2HGDH+/+ hearts under ischemic stress conditions.
CONCLUSION: L2HGDH deletion-induced L2HG accumulation protects against myocardial injury during LFI and ischemia-reperfusion through a metabolic shift of glucose flux from glycolysis towards the pentose phosphate pathway. L2HG offers a novel mechanism for eliminating reactive oxygen species from myocardial tissue, mitigating redox stress, reducing myocardial infarct size, and preserving high-energy phosphates and cardiac function. Targeting L2HG levels through L2HGDH activity may serve as a new therapeutic strategy for cardiovascular diseases related to oxidative injury.

Keywords:  glycolysis; ischemia; pentose phosphate pathway; reactive oxygen species; reperfusion

DOI:  https://doi.org/10.1161/CIRCRESAHA.122.321227
EBioMedicine. 2022 Aug 27. pii: S2352-3964(22)00422-4. [Epub ahead of print]83 104240

Live-attenuated YF17D-vectored COVID-19 vaccine protects from lethal yellow fever virus infection in mouse and hamster models.

Ji Ma, Michael Bright Yakass, Sander Jansen, Bert Malengier-Devlies, Dominique Van Looveren, Lorena Sanchez-Felipe, Thomas Vercruysse, Birgit Weynand, Mahadesh Prasad Arkalagud Javarappa, Osbourne Quaye, Patrick Matthys, Tania Roskams, Johan Neyts, Hendrik Jan Thibaut, Kai Dallmeier.

   BACKGROUND: The live-attenuated yellow fever vaccine YF17D holds great promise as alternative viral vector vaccine platform, showcased by our previously presented potent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine candidate YF-S0. Besides protection from SARS-CoV-2, YF-S0 also induced strong yellow fever virus (YFV)-specific immunity, suggestive for full dual activity. A vaccine concomitantly protecting from SARS-CoV-2 and YFV would be of great benefit for those living in YFV-endemic areas with limited access to current SARS-CoV-2 vaccines. However, for broader applicability, pre-existing vector immunity should not impact the potency of such YF17D-vectored vaccines.
METHODS: The immunogenicity and efficacy of YF-S0 against YFV and SARS-CoV-2 in the presence of strong pre-existing YFV immunity were evaluated in mouse and hamster challenge models.
FINDINGS: Here, we show that a single dose of YF-S0 is sufficient to induce strong humoral and cellular immunity against YFV as well as SARS-CoV-2 in mice and hamsters; resulting in full protection from vigorous YFV challenge in either model; in mice against lethal intracranial YF17D challenge, and in hamsters against viscerotropic infection and liver disease following challenge with highly pathogenic hamster-adapted YFV-Asibi strain. Importantly, strong pre-existing immunity against the YF17D vector did not interfere with subsequent YF-S0 vaccination in mice or hamsters; nor with protection conferred against SARS-CoV-2 strain B1.1.7 (Alpha variant) infection in hamsters.
INTERPRETATION: Our findings warrant the development of YF-S0 as dual SARS-CoV-2 and YFV vaccine. Contrary to other viral vaccine platforms, use of YF17D does not suffer from pre-existing vector immunity.
FUNDING: Stated in the acknowledgments.

Keywords:  Anti-vector immunity; Dual vaccine; SARS-CoV-2 vaccine; Yellow fever vaccine

DOI:  https://doi.org/10.1016/j.ebiom.2022.104240
TH Open. 2022 Jul;6(3): e156-e167

Platelet Toll-Like-Receptor-2 and -4 Mediate Different Immune-Related Responses to Bacterial Ligands.

Marius Niklaus, Philipp Klingler, Katja Weber, Angela Koessler, Sabine Kuhn, Markus Boeck, Anna Kobsar, Juergen Koessler.

  Background Like immune cells, platelets express toll-like receptors (TLRs) on their surface membrane. TLR2 and TLR4 are able to recognize bacterial antigens and have the potential to influence hemostatic functions and classical intracellular signaling pathways. This study investigated the role of TLR2 and TLR4 for immune-related functions in human platelets. Materials and Methods Washed platelets and neutrophils were prepared from fresh human peripheral blood. Basal-, Pam3CSK4- (as TLR2 agonist) and Lipopolysaccharides (LPS; as TLR4 agonist) -induced CD62P expression, fibrinogen binding and TLR2 or TLR4 expression, intracellular reactive oxygen species (ROS) production in H 2 DCFDA-loaded platelets and uptake of fluorescence-labeled TLR ligands, and fluorophore-conjugated fibrinogen were evaluated by flow cytometry. Analysis of platelet-neutrophil complexes was performed after coincubation of washed platelets and neutrophils in the presence and absence of TLR2 or TLR4 agonists on poly-L-lysine coated surfaces, followed by immunostaining and immunofluorescence imaging. Results Pam3CSK4 rapidly and transiently increased TLR2 and TLR4 expression. Over the course of 30 minutes after activation with Pam3CSK4 and LPS, the expression of both receptors decreased. Pam3CSK4-stimulated intracellular ROS production and the uptake of TLR ligands or fibrinogen much stronger than LPS. Besides, TLR4 activation led to a significant increase of platelet-neutrophil contacts. Conclusion Stimulation leads to rapid mobilization of TLR2 or TLR4 to the platelet surface, presumably followed by receptor internalization along with bound TLR ligands. After activation, platelet TLR2 and TLR4 mediate different immune-related reactions. In particular, TLR2 induces intracellular responses in platelets, whereas TLR4 initiates interactions with other immune cells such as neutrophils.

Keywords:  cell-cell interactions; immunity; platelet physiology; receptors

DOI:  https://doi.org/10.1055/a-1827-7365