M. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity.

A greater understanding of hematopoietic stem cell (HSC) regulation is required for dissecting protective versus detrimental immunity to pathogens that cause chronic infections such as Mycobacterium tuberculosis (Mtb). We have shown that systemic administration of Bacille Calmette-Guérin (BCG) or ß-glucan reprograms HSCs in the bone marrow (BM) via a type II interferon (IFN-II) or interleukin-1 (IL1) response, respectively, which confers protective trained immunity against Mtb. Here, we demonstrate that, unlike BCG or ß-glucan, Mtb reprograms HSCs via an IFN-I response that suppresses myelopoiesis and impairs development of protective trained immunity to Mtb. Mechanistically, IFN-I signaling dysregulates iron metabolism, depolarizes mitochondrial membrane potential, and induces cell death specifically in myeloid progenitors. Additionally, activation of the IFN-I/iron axis in HSCs impairs trained immunity to Mtb infection. These results identify an unanticipated immune evasion strategy of Mtb in the BM that controls the magnitude and intrinsic anti-microbial capacity of innate immunity to infection.

BCG Educates Hematopoietic Stem Cells to Generate Protective Innate Immunity against Tuberculosis.

The dogma that adaptive immunity is the only arm of the immune response with memory capacity has been recently challenged by several studies demonstrating evidence for memory-like innate immune training. However, the underlying mechanisms and location for generating such innate memory responses in vivo remain unknown. Here, we show that access of Bacillus Calmette-Guérin (BCG) to the bone marrow (BM) changes the transcriptional landscape of hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs), leading to local cell expansion and enhanced myelopoiesis at the expense of lymphopoiesis. Importantly, BCG-educated HSCs generate epigenetically modified macrophages that provide significantly better protection against virulent M. tuberculosis infection than naïve macrophages. By using parabiotic and chimeric mice, as well as adoptive transfer approaches, we demonstrate that training of the monocyte/macrophage lineage via BCG-induced HSC reprogramming is sustainable in vivo. Our results indicate that targeting the HSC compartment provides a novel approach for vaccine development.

Neonatal imprinting of alveolar macrophages via neutrophil-derived 12-HETE.

Resident-tissue macrophages (RTMs) arise from embryonic precursors1,2, yet the developmental signals that shape their longevity remain largely unknown. Here we demonstrate in mice genetically deficient in 12-lipoxygenase and 15-lipoxygenase (Alox15-/- mice) that neonatal neutrophil-derived 12-HETE is required for self-renewal and maintenance of alveolar macrophages (AMs) during lung development. Although the seeding and differentiation of AM progenitors remained intact, the absence of 12-HETE led to a significant reduction in AMs in adult lungs and enhanced senescence owing to increased prostaglandin E2 production. A compromised AM compartment resulted in increased susceptibility to acute lung injury induced by lipopolysaccharide and to pulmonary infections with influenza A virus or SARS-CoV-2. Our results highlight the complexity of prenatal RTM programming and reveal their dependency on in trans eicosanoid production by neutrophils for lifelong self-renewal.

Brain motor and fear circuits regulate leukocytes during acute stress.

The nervous and immune systems are intricately linked1. Although psychological stress is known to modulate immune function, mechanistic pathways linking stress networks in the brain to peripheral leukocytes remain poorly understood2. Here we show that distinct brain regions shape leukocyte distribution and function throughout the body during acute stress in mice. Using optogenetics and chemogenetics, we demonstrate that motor circuits induce rapid neutrophil mobilization from the bone marrow to peripheral tissues through skeletal-muscle-derived neutrophil-attracting chemokines. Conversely, the paraventricular hypothalamus controls monocyte and lymphocyte egress from secondary lymphoid organs and blood to the bone marrow through direct, cell-intrinsic glucocorticoid signalling. These stress-induced, counter-directional, population-wide leukocyte shifts are associated with altered disease susceptibility. On the one hand, acute stress changes innate immunity by reprogramming neutrophils and directing their recruitment to sites of injury. On the other hand, corticotropin-releasing hormone neuron-mediated leukocyte shifts protect against the acquisition of autoimmunity, but impair immunity to SARS-CoV-2 and influenza infection. Collectively, these data show that distinct brain regions differentially and rapidly tailor the leukocyte landscape during psychological stress, therefore calibrating the ability of the immune system to respond to physical threats.

Novel approaches to preventing phagosomal infections: timing is key.

Prophylactic vaccination strategies designed to prevent diseases caused by pathogens using the phagolysosome of innate immune cells as a site of intracellular replication and survival have been largely ineffective. These include Mycobacterium tuberculosis (Mtb), Leishmania spp., and Cryptococcus spp. These failed strategies have traditionally targeted CD4+ T helper (Th) 1 cell-mediated immune memory, deeming it crucial for vaccine efficacy. This failure warrants an investigation of alternative mediators of protection. Here, we suggest three novel approaches to activate phagocytic cells prior to or at the time of infection. We hypothesize that preventing the formation of the pathogen niche within the phagolysosome is essential for preventing disease, and a greater emphasis on the timing of phagocyte activation should generate more effective prophylactic treatment options.

Mycobacterium tuberculosis infection drives differential responses in the bone marrow hematopoietic stem and progenitor cells.

Hematopoietic stem and progenitor cells (HSPCs) play a vital role in the host response to infection through the rapid and robust production of mature immune cells. These HSPC responses can be influenced, directly and indirectly, by pathogens as well. Infection with Mycobacterium tuberculosis (Mtb) can drive lymphopoiesis through modulation of type I interferon (IFN) signaling. We have previously found that the presence of a drug resistance (DR)-conferring mutation in Mtb drives altered host-pathogen interactions and heightened type I IFN production in vitro. But the impacts of this DR mutation on in vivo host responses to Mtb infection, particularly the hematopoietic compartment, remain unexplored. Using a mouse model, we show that, while drug-sensitive Mtb infection induces expansion of HSPC subsets and a skew toward lymphopoiesis, DR Mtb infection fails to induce an expansion of these subsets and an accumulation of mature granulocytes in the bone marrow. Using single-cell RNA sequencing, we show that the HSCs from DR Mtb-infected mice fail to upregulate pathways related to cytokine signaling across all profiled HSC subsets. Collectively, our studies report a novel finding of a chronic infection that fails to induce a potent hematopoietic response that can be further investigated to understand pathogen-host interaction at the level of hematopoiesis.

Aspects of Chemical Entropy Generation in Flow of Casson Nanofluid between Radiative Stretching Disks.

The appropriate utilization of entropy generation may provoke dipping losses in the available energy of nanofluid flow. The effects of chemical entropy generation in axisymmetric flow of Casson nanofluid between radiative stretching disks in the presence of thermal radiation, chemical reaction, and heat absorption/generation features have been mathematically modeled and simulated via interaction of slip boundary conditions. Shooting method has been employed to numerically solve dimensionless form of the governing equations, including expressions referring to entropy generation. The impacts of the physical parameters on fluid velocity components, temperature and concentration profiles, and entropy generation number are presented. Simulation results revealed that axial component of velocity decreases with variation of Casson fluid parameter. A declining variation in Bejan number was noticed with increment of Casson fluid constant. Moreover, a progressive variation in Bejan number resulted due to the impact of Prandtl number and stretching ratio constant.

Predominance of M2 macrophages in gliomas leads to the suppression of local and systemic immunity.

Glioblastoma is a highly prevalent and aggressive form of primary brain tumor. It represents approximately 56% of all the newly diagnosed gliomas. Macrophages are one of the major constituents of tumor-infiltrating immune cells in the human gliomas. The role of immunosuppressive macrophages is very well documented in correlation with the poor prognosis of patients suffering from breast, prostate, bladder and cervical cancers. The current study highlights the correlation between the tumor-associated macrophage phenotypes and glioma progression. We observed an increase in the pool of M2 macrophages in high-grade gliomas, as confirmed by their CD68 and CD163 double-positive phenotype. In contrast, less M1 macrophages were noticed in high-grade gliomas, as evidenced by the down-regulation in the expression of CCL3 marker. In addition, we observed that higher gene expression ratio of CD163/CCL3 is associated with glioma progression. The Kaplan-Meier survival plots indicate that glioma patients with lower expression of M2c marker (CD163), and higher expression of M1 marker (CCL3) had better survival. Furthermore, we examined the systemic immune response in the peripheral blood and noted a predominance of M2 macrophages, myeloid-derived suppressor cells and PD-1+ CD4 T cells in glioma patients. Thus, the study indicates a high gene expression ratio of CD163/CCL3 in high-grade gliomas as compared to low-grade gliomas and significantly elevated frequency of M2 macrophages and PD-1+ CD4 T cells in the blood of tumor patients. These parameters could be used as an indicator of the early diagnosis and prognosis of the disease.

T-cell exhaustion in tuberculosis: pitfalls and prospects.

T-cells play an important role in immunity but when these cells are overexposed to specific antigens, their function may decline. This state is usually referred to as exhaustion and the T-cells show reduced proliferation and functions such as cytokine release. T-cell exhaustion has been observed in several cancers as well as in chronic infections such as tuberculosis (TB). In chronic Mycobacterium tuberculosis (Mtb) infection, T-cells may express the exhaustion phenotype and show a progressive loss of secretion of IL-2, IFN-γ and TNF-α. In some cancers and chronic infection models, blocking the exhaustion phenotype can be achieved with the so-called checkpoint inhibitors. This results in tumor control and more effective immunity. However, in the case of TB, the T-cell exhaustion results are quite ambiguous. Hence, there is a need to investigate and explain the contribution of checkpoint at a molecular level to the outcome of events in chronic TB. Such information could help to guide the success of new therapies against chronic TB. This review highlights the mechanism through which T-cells undergo exhaustion and the approaches that can avert such events. This will help to design immunotherapies that can reinvigorate T-cell potency to protect patients from TB.

Triggering through Toll-like receptor 2 limits chronically stimulated T-helper type 1 cells from undergoing exhaustion.

Chronic infections result in T-cell exhaustion, a state of functional unresponsiveness. To control the infection, it is important to salvage the exhausted T cells. In this study, we delivered signals through Toll-like receptor 2 (TLR-2) to reinvigorate functionality in chronically activated T-helper type 1 (Th1) cells. This process significantly augmented the expression of T-bet, interferon γ, interleukin 2, and the antiapoptotic molecule Bcl-2, whereas it dampened the display of the exhaustion markers programmed death receptor 1 (PD-1) and lymphocyte activation gene 3 (Lag-3). Additionally, TLR-2 signaling bolstered the ability of chronically stimulated Th1 cells to activate B cells. Finally, the results were substantiated by observing reduced lung pathology upon administration of TLR-2 agonist in the chronic infection model of tuberculosis. These data demonstrated the importance of TLR-2 in rescuing chronically activated Th1 cells from undergoing exhaustion. This study will pave a way for targeting TLR-2 in developing therapeutic strategies to treat chronic diseases involving loss of Th1 cell function.

Latency-associated protein Acr1 impairs dendritic cell maturation and functionality: a possible mechanism of immune evasion by Mycobacterium tuberculosis.

Mycobacterium tuberculosis (M. tuberculosis) in latently infected individuals survives and thwarts the attempts of eradication by the immune system. During latency, Acr1 is predominantly expressed by the bacterium. However, whether M. tuberculosis exploits its Acr1 in impairing the host immunity remains widely unexplored. Hence, currently we have investigated the role of Acr1 in influencing the differentiation and function of dendritic cells (DCs), which play a cardinal role in innate and adaptive immunity. Therefore, for the first time, we have revealed a novel mechanism of mycobacterial Acr1 in inhibiting the maturation and differentiation of DCs by inducing tolerogenic phenotype by modulating the expression of PD-L1; Tim-3; indoleamine 2, 3-dioxygenase (IDO); and interleukin 10. Furthermore, Acr1 interferes in the differentiation of DCs by targeting STAT-6 and STAT-3 pathways. Continuous activation of STAT-3 inhibited the translocation of NF-κB in Acr1-treated DCs. Furthermore, Acr1 also augmented the induction of regulatory T cells. These DCs displayed decline in their antigen uptake capacity and reduced ability to help T cells. Interestingly, M. tuberculosis exhibited better survival in Acr1-treated DCs. Thus, this study provides a crucial insight into a strategy adopted by M. tuberculosis to survive in the host by impairing the function of DCs.

Manipulation of costimulatory molecules by intracellular pathogens: veni, vidi, vici!!

Some of the most successful pathogens of human, such as Mycobacterium tuberculosis (Mtb), HIV, and Leishmania donovani not only establish chronic infections but also remain a grave global threat. These pathogens have developed innovative strategies to evade immune responses such as antigenic shift and drift, interference with antigen processing/presentation, subversion of phagocytosis, induction of immune regulatory pathways, and manipulation of the costimulatory molecules. Costimulatory molecules expressed on the surface of various cells play a decisive role in the initiation and sustenance of immunity. Exploitation of the "code of conduct" of costimulation pathways provides evolutionary incentive to the pathogens and thereby abates the functioning of the immune system. Here we review how Mtb, HIV, Leishmania sp., and other pathogens manipulate costimulatory molecules to establish chronic infection. Impairment by pathogens in the signaling events delivered by costimulatory molecules may be responsible for defective T-cell responses; consequently organisms grow unhindered in the host cells. This review summarizes the convergent devices that pathogens employ to tune and tame the immune system using costimulatory molecules. Studying host-pathogen interaction in context with costimulatory signals may unveil the molecular mechanism that will help in understanding the survival/death of the pathogens. We emphasize that the very same pathways can potentially be exploited to develop immunotherapeutic strategies to eliminate intracellular pathogens.

Friendly pathogens: prevent or provoke autoimmunity.

The gut microflora is an immense health asset for human beings. The mammalian gut harbors trillions of commensals. These microbes not only modulate local but also systemic immunity. Recently, various reports are evolving, which signify that the gut microbes can modulate, tune and tame the host immune response. Consequently, it advocates the significance of the microbial composition. Further, the microbiota provides a fine equilibrium to host by regulating immune homeostasis. Furthermore, disturbance in this population can incite imbalance in immune system, leading to molecular mimicry and therefore autoimmunity. Hence, it is imperative to understand the influence of these bugs in preventing or provoking immune system against the self-components. In this article, we highlight the interaction between different gut microbes and cells of immune system and the mechanism involved in controlling and curtailing various autoimmune diseases.

Deciphering KDM8 dysregulation and CpG methylation in hepatocellular carcinoma using multi-omics and machine learning.

Aim: This study investigates the altered expression and CpG methylation patterns of histone demethylase KDM8 in hepatocellular carcinoma (HCC), aiming to uncover insights and promising diagnostics biomarkers.Materials & methods: Leveraging TCGA-LIHC multi-omics data, we employed R/Bioconductor libraries and Cytoscape to analyze and construct a gene correlation network, and LASSO regression to develop an HCC-predictive model.Results: In HCC, KDM8 downregulation is correlated with CpGs hypermethylation. Differential gene correlation analysis unveiled a liver carcinoma-associated network marked by increased cell division and compromised liver-specific functions. The LASSO regression identified a highly accurate HCC prediction signature, prominently featuring CpG methylation at cg02871891.Conclusion: Our study uncovers CpG hypermethylation at cg02871891, possibly influencing KDM8 downregulation in HCC, suggesting these as promising biomarkers and targets.

Changes in gene function can play a role in causing cancer. In this study, we looked at how a specific gene called KDM8 behaves in liver cancer. By analyzing a large set of liver cancer samples, we investigated how gene interactions are different in this disease and if they can help predict liver cancer risk. Our results show that the KDM8 gene is less active, and its DNA gets chemically modified more often in liver cancer. We also found a group of genes and DNA changes, which are linked to the disease. Using this information, we identified 16 important markers and built a computer model that can accurately predict liver cancer. We found that DNA methylation at a specific spot called cg02871891 is especially important for predicting liver cancer. Overall, our study suggests that high levels of DNA methylation may lead to reduced KDM8 activity in liver cancer, which could be important for future research and better diagnostic tools.

Numerically analysis of Marangoni convective flow of hybrid nanofluid over an infinite disk with thermophoresis particle deposition.

This study discusses the flow of hybrid nanofluid over an infinite disk in a Darcy-Forchheimer permeable medium with variable thermal conductivity and viscosity. The objective of the current theoretical investigation is to identify the thermal energy characteristics of the nanomaterial flow resulting from thermo-solutal Marangoni convection on a disc surface. By including the impacts of activation energy, heat source, thermophoretic particle deposition and microorganisms the proposed mathematical model becomes more novel. The Cattaneo-Christov mass and heat flux law is taken into account when examining the features of mass and heat transmission rather than the traditional Fourier and Fick heat and mass flux law. MoS2 and Ag nanoparticles are dispersed in the base fluid water to synthesize the hybrid nanofluid. PDEs are transformed to ODEs by using similarity transformations. The RKF-45th order shooting method is used to solve the equations. With the use of appropriate graphs, the effects of a number of non-dimensional parameters on velocity, concentration, microorganism, and temperature fields are addressed. The local Nusselt number, density of motile microorganisms and Sherwood number are calculated numerically and graphically to derive correlations in terms of the relevant key parameters. The findings show that as we increase the Marangoni convection parameter, skin friction, local density of motile microorganisms, Sherwood number, velocity, temperature and microorganisms profiles increase, whereas Nusselt number and concentration profile exhibit an opposite behavior. The fluid velocity is reduced as a result of enhancing the Forchheimer parameter and Darcy parameter.

Heat and mass transfer analysis for magnetized flow of [Formula: see text] nanolubricant with variable properties: an application of Cattaneo-Christov model.

The current study scrutinizes heat and mass transfer features of magnetized flow of [Formula: see text] nanolubricant over Riga plate in a Darcy Forchheimer medium. The effects of variable viscosity, thermal radiation, variable thermal conductivity, viscous dissipation and uniform heat source/sink are examined in this study. The diffusion model presented by Cattaneo-Christov is incorporated in this study to enclose heat and mass transport phenomenon. Additionally, the mass transfer rate is inspected subjected to the effects of variable solutal diffusivity and higher order chemical reaction. Heat and mass transfer phenomena have significant applications in the disciplines of science and technology that can be seen everywhere in nature. This simultaneous transportation phenomenon indicates a variety of applications in manufacturing processes, aerodynamics, cooling systems, environmental sciences, oceanography, food industries, biological disciplines, and energy transport systems etc. The modeled system of PDEs is metamorphosed to nonlinear ODEs with the introduction of appropriate transformations. An eminent bvp4c method in MATLAB has been incorporated to execute the resulting system of ODEs numerically. The outcomes of velocity, temperature and concentration profiles corresponding to various emerging parameters have been exposed graphically. The motion of [Formula: see text] nanolubricant tends to enhance significantly with larger modified Hartmann number, whereas converse behavior is reported by increasing porosity parameter and variable viscosity parameter. The greater heat transfer rate is observed for variable thermal conductivity parameter. The rates of heat and mass transfer slow down for thermal and solutal time relaxation parameters respectively. The concentration profile gets enriched by growing the order of the chemical reaction and variable mass diffusivity parameter. It is concluded that by increasing solid volume fraction up to [Formula: see text], the viscosity of the nanolubricant enhances up to [Formula: see text] which consequently slows down motion of the nanolubricant but increases temperature and concentration profiles.