Adaptive immune responses are defined as antigen-sensitization-dependent and antigen-specific responses leading to establishment of long-lived immunological memory. While natural killer (NK) cells have traditionally been considered cells of the innate immune system, mounting evidence in mice and non-human primates warrants reconsideration of the existing paradigm that B and T cells are the sole mediators of adaptive immunity. However, it is currently unknown whether human NK cells can exhibit adaptive immune responses. We therefore tested whether human NK cells mediate adaptive immunity to virally encoded antigens using humanized mice and human volunteers. We found that human NK cells displayed vaccination-dependent, antigen-specific recall responses in vitro, when isolated from livers of humanized mice previously vaccinated with human immunodeficiency virus (HIV)-encoded envelope protein. Furthermore, we discovered that large numbers of cytotoxic NK cells with a tissue-resident phenotype were recruited to sites of varicella-zoster virus (VZV) skin test antigen challenge in VZV-experienced human volunteers. These NK-mediated recall responses in humans occurred decades after initial VZV exposure, demonstrating that NK memory in humans is long-lived. Our data demonstrates that human NK cells exhibit adaptive immune responses upon vaccination or infection. The existence of human memory NK cells may allow for the development of vaccination-based approaches capable of establishing potent NK-mediated memory functions contributing to host protection.
Macrophages are the primary host cells for Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), during its intracellular survival in humans. The pathogen has a remarkable capacity to survive within the hostile environment of macrophages. However, primary infection does not result in active TB disease in most individuals. The majority of individuals remain latently infected, wherein the bacteria are held in check by the host immune response. Nevertheless, such individuals can develop active TB later upon the decline in their immune status. In contrast, in a small fraction of infected individuals, the host immune response fails to control the growth of M. tuberculosis bacilli, and granulomatous TB develops progressively. Elucidating the molecular and phenotypic events that govern the outcome of the infection within macrophages is fundamental to understanding the key features of these cells that could be equally critical in infection control. The molecular details of the M. tuberculosis‐macrophage interaction continue to be discerned, and emerging evidence suggests that macrophage population that participate in infection is heterogeneous. While the local environment and developmental origin could influence the phenotypic heterogeneity and functional plasticity of macrophages, M. tuberculosis has also been demonstrated to modulate the polarization of macrophages. In this review, we draw on work investigating specialized macrophage populations and their interactions with M. tuberculosis with respect to pathogenesis and specific immune responses. Understanding the mechanisms that control the repertoire of macrophage phenotypes and behaviors during infection may provide prospects for novel TB control strategies through modulation of immunobiological functions of macrophages.
Background: Biosynthesis and functions of Mycobacterium marinum lipooligosaccharides (LOSs) remain elusive. Results: M. marinum mutants expressing various LOS profiles were generated and used to infect macrophages and amoebae. Conclusion: Deep LOS mutants are more efficiently phagocytosed than those lacking only LOS-IV. Significance: Three novel biosynthetic genes and the effect of the LOS content in modulating uptake by phagocytes are reported.
Mycobacterium tuberculosis (Mtb) is responsible for approximately 1.5 million deaths each year. Though 10% of patients develop tuberculosis (TB) after infection, 90% of these infections are latent. Further, mice are nearly uniformly susceptible to Mtb but their M1-polarized macrophages (M1-MΦs) can inhibit Mtb in vitro, suggesting that M1-MΦs may be able to regulate anti-TB immunity. We sought to determine whether human MΦ heterogeneity contributes to TB immunity. Here we show that IFN-γ-programmed M1-MΦs degrade Mtb through increased expression of innate immunity regulatory genes (Inregs). In contrast, IL-4-programmed M2-polarized MΦs (M2-MΦs) are permissive for Mtb proliferation and exhibit reduced Inregs expression. M1-MΦs and M2-MΦs express pro- and anti-inflammatory cytokine-chemokines, respectively, and M1-MΦs show nitric oxide and autophagy-dependent degradation of Mtb, leading to increased antigen presentation to T cells through an ATG-RAB7-cathepsin pathway. Despite Mtb infection, M1-MΦs show increased histone acetylation at the ATG5 promoter and pro-autophagy phenotypes, while increased histone deacetylases lead to decreased autophagy in M2-MΦs. Finally, Mtb-infected neonatal macaques express human Inregs in their lymph nodes and macrophages, suggesting that M1 and M2 phenotypes can mediate immunity to TB in both humans and macaques. We conclude that human MФ subsets show unique patterns of gene expression that enable differential control of TB after infection. These genes could serve as targets for diagnosis and immunotherapy of TB.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has now become a serious global threat after inflicting more than 8 million infections and 425,000 deaths in less than 6 months. Currently, no definitive treatment or prevention therapy exists for COVID-19. The unprecedented rise of this pandemic has rapidly fueled research efforts to discover and develop new vaccines and treatment strategies against this novel coronavirus. While hundreds of vaccines/therapeutics are still in the preclinical or early stage of clinical development, a few of them have shown promising results in controlling the infection. Here, in this review, we discuss the promising vaccines and treatment options for COVID-19, their challenges, and potential alternative strategies.
Polycyclic aromatic hydrocarbons (PAHs) are compounds with two or more fused benzene rings produced by incomplete combustion of organic substances involved in natural and anthropogenic processes. Children are exposed to these compounds through inhalation, dietary ingestion, and, also, soil at the playground. It has been well established that PAHs have carcinogenic, mutagenic, and teratogenic effects. Considering possible health risks due to PAHs exposure among children, the present study was carried out in collaboration with the Pediatrics Department, King George's Medical University (KGMU), Lucknow, to determine its exposure in children by estimating blood PAHs levels. Due to the variable composition of PAHs mixtures emitted from different environmental sources, any single compound or metabolite may not be representative of all exposure conditions. For these reasons, the measurement of blood PAHs levels as a possible biomarker, especially of the EPA (Environmental Protection Agency, USA) priority list, has been proposed. Acenaphthylene, anthracene, phenanthrene, fluoranthene, naphthalene, pyrene, benzo(b)fluoranthene, benzo(k)fluoranthene, and benzo(a)pyrene were determined by HPLC-FD/UV. On the basis of the individual compound, the median (50th percentile) of naphthalene (19 ppb) was highest, however, benzo(a)pyrene (4.0 ppb) level was found to be lowest among all detected PAHs. The median level of total noncarcinogenic PAHs (113.55 ppb) was higher than the total carcinogenic PAHs (32.35 ppb) in blood samples of children. A significant correlation was found between period of time spent in the surrounding breathing zone of the cooking place and total noncarcinogenic PAHs (p < 0.05), while the blood carcinogenic PAHs level in children was found to be associated with lower status of their families (p < 0.05). It is speculated that there may be chances of health hazards through exposure to PAHs, those not yet declared hazardous and present at higher concentrations in the Indian environment. Further study with a larger sample size and accompanying environmental data is desired to validate the findings of this pilot study and strengthen the database of PAHs exposure in India.
Summary Although the BCG vaccine offers partial protection, tuberculosis remains a leading cause of infectious disease death, killing ∼1.5 million people annually. We developed mucosal vaccines expressing the autophagy-inducing peptide C5 and mycobacterial Ag85B-p25 epitope using replication-defective human adenovirus (HAdv 85C5 ) and bovine adenovirus (BAdv 85C5 ) vectors. BAdv 85C5 -infected dendritic cells (DCs) expressed a robust transcriptome of genes regulating antigen processing compared to HAdv 85C5 -infected DCs. BAdv 85C5 -infected DCs showed enhanced galectin-3/8 and autophagy-dependent in vitro Ag85B-p25 epitope presentation to CD4 T cells. BCG-vaccinated mice were intranasally boosted using HAdv 85C5 or BAdv 85C5 followed by infection using aerosolized Mycobacterium tuberculosis (Mtb). BAdv 85C5 protected mice against tuberculosis both as a booster after BCG vaccine (>1.4-log 10 reduction in Mtb lung burden) and as a single intranasal dose (>0.5-log 10 reduction). Protection was associated with robust CD4 and CD8 effector (T EM ), central memory (T CM ), and CD103 + /CD69 + lung-resident memory (T RM ) T cell expansion, revealing BAdv 85C5 as a promising mucosal vaccine for tuberculosis.
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