The kynurenine pathway (KP) is the major metabolic pathway of the essential amino acid tryptophan (TRP). Stimulation by inflammatory molecules, such as interferon-γ (IFN-γ), is the trigger for ...induction of the KP, driving a complex cascade of production of both neuroprotective and neurotoxic metabolites, and in turn, regulation of the immune response and responses of brain cells to the KP metabolites. Consequently, substantial evidence has accumulated over the past couple of decades that dysregulation of the KP and the production of neurotoxic metabolites are associated with many neuroinflammatory and neurodegenerative diseases, including Parkinson's disease, AIDS-related dementia, motor neurone disease, schizophrenia, Huntington's disease, and brain cancers. In the past decade, evidence of the link between the KP and multiple sclerosis (MS) has rapidly grown and has implicated the KP in MS pathogenesis. KP enzymes, indoleamine 2,3-dioxygenase (IDO-1) and tryptophan dioxygenase (highest expression in hepatic cells), are the principal enzymes triggering activation of the KP to produce kynurenine from TRP. This is in preference to other routes such as serotonin and melatonin production. In neurological disease, degradation of the blood-brain barrier, even if transient, allows the entry of blood monocytes into the brain parenchyma. Similar to microglia and macrophages, these cells are highly responsive to IFN-γ, which upregulates the expression of enzymes, including IDO-1, producing neurotoxic KP metabolites such as quinolinic acid. These metabolites circulate systemically or are released locally in the brain and can contribute to the excitotoxic death of oligodendrocytes and neurons in neurological disease principally by virtue of their agonist activity at N-methyl-d-aspartic acid receptors. The latest evidence is presented and discussed. The enzymes that control the checkpoints in the KP represent an attractive therapeutic target, and consequently several KP inhibitors are currently in clinical trials for other neurological diseases, and hence may make suitable candidates for MS patients. Underpinning these drug discovery endeavors, in recent years, several advances have been made in how KP metabolites are assayed in various biological fluids, and tremendous advancements have been made in how specimens are imaged to determine disease progression and involvement of various cell types and molecules in MS.
Next-generation vaccines for tropical infectious diseases Allen, Tammy; Castellanos, Maria Eugenia; Giacomin, Paul ...
International journal of infectious diseases,
June 2024, 2024-Jun, 2024-06-00, 20240601, 2024-06-01, Volume:
143
Journal Article
Peer reviewed
Open access
•TAK-003 a recent candidate is a significant advancement to Dengvaxia.•Combination vaccination could have an extraordinary impact on schistosomiasis control.•New concepts on how to rationally design ...hookworm subunit vaccines.•Typhoid conjugate vaccines will reduce the global burden of typhoid fever.
Tropical infectious diseases inflict an unacceptable burden of disease on humans living in developing countries. Although anti-pathogenic drugs have been widely used, they carry a constant threat of selecting for resistance. Vaccines offer a promising means by which to enhance the global control of tropical infectious diseases; however, these have been difficult to develop, mostly because of the complex nature of the pathogen lifecycles. Here, we present recently developed vaccine candidates for five tropical infectious diseases in the form of a catalog that have either entered clinical trials or have been licensed for use. We deliberate on recently licensed dengue vaccines, provide evidence why combination vaccination could have a synergistic impact on schistosomiasis, critically appraise the value of typhoid conjugate vaccines, and discuss the potential of vaccines in the efforts to eliminate vivax malaria and hookworms.
During experimental cerebral malaria (ECM) mice develop a lethal neuropathological syndrome associated with microcirculatory dysfunction and intravascular leukocyte sequestration. The precise ...spatio-temporal context in which the intravascular immune response unfolds is incompletely understood. We developed a 2-photon intravital microscopy (2P-IVM)-based brain-imaging model to monitor the real-time behaviour of leukocytes directly within the brain vasculature during ECM. Ly6C(hi) monocytes, but not neutrophils, started to accumulate in the blood vessels of Plasmodium berghei ANKA (PbA)-infected MacGreen mice, in which myeloid cells express GFP, one to two days prior to the onset of the neurological signs (NS). A decrease in the rolling speed of monocytes, a measure of endothelial cell activation, was associated with progressive worsening of clinical symptoms. Adoptive transfer experiments with defined immune cell subsets in recombinase activating gene (RAG)-1-deficient mice showed that these changes were mediated by Plasmodium-specific CD8(+) T lymphocytes. A critical number of CD8(+) T effectors was required to induce disease and monocyte adherence to the vasculature. Depletion of monocytes at the onset of disease symptoms resulted in decreased lymphocyte accumulation, suggesting reciprocal effects of monocytes and T cells on their recruitment within the brain. Together, our studies define the real-time kinetics of leukocyte behaviour in the central nervous system during ECM, and reveal a significant role for Plasmodium-specific CD8(+) T lymphocytes in regulating vascular pathology in this disease.
Toxoplasmic encephalitis is an AIDS-defining condition. The decline of IFN-γ-producing CD4
T cells in AIDS is a major contributing factor in reactivation of quiescent Toxoplasma gondii to an actively ...replicating stage of infection. Hence, it is important to characterize CD4-independent mechanisms that constrain acute T. gondii infection. We investigated the in vivo regulation of IFN-γ production by CD8
T cells, DN T cells and NK cells in response to acute T. gondii infection. Our data show that processing of IFN-γ by these non-CD4 cells is dependent on both IL-12 and IL-18 and the secretion of bioactive IL-18 in response to T. gondii requires the sensing of viable parasites by multiple redundant inflammasome sensors in multiple hematopoietic cell types. Importantly, our results show that expansion of CD8
T cells, DN T cells and NK cell by S4B6 IL-2 complex pre-treatment increases survival rates of mice infected with T. gondii and this is dependent on IL-12, IL-18 and IFN-γ. Increased survival is accompanied by reduced pathology but is independent of expansion of T
cells or parasite burden. This provides evidence for a protective role of IL2C-mediated expansion of non-CD4 cells and may represent a promising lead to adjunct therapy for acute toxoplasmosis.
The global prevalence of respiratory infectious and inflammatory diseases remains a major public health concern. Prevention and management strategies have not kept pace with the increasing incidence ...of these diseases. The airway mucosa is the most common portal of entry for infectious and inflammatory agents. Therefore, significant benefits would be derived from a detailed understanding of how immune responses regulate the filigree of the airways. Here, the role of different antigen‐presenting cells (APC) in the lower airways and the mechanisms used by pathogens to modulate APC function during infectious disease is reviewed. Features of APC that are unique to the airways and the influence they have on uptake and presentation of antigen to T cells directly in the airways are discussed. Current information on the crucial role that airway APC play in regulating respiratory infection is summarised. We examine the clinical implications of APC dysregulation in the airways on asthma and tuberculosis, two chronic diseases that are the major cause of illness and death in the developed and developing world. A brief overview of emerging therapies that specifically target APC function in the airways is provided.
We review the role of different antigen‐presenting cells (APC) in the lower airways and the mechanisms used by pathogens to modulate APC function during infectious disease. We discuss features of APC that are unique to the airways and their influence on uptake and presentation of antigen to T cells directly in situ in the airways. We summarize current information on the crucial role that airway APC play in regulating respiratory infection.
Tuberculosis (TB) is a major global public health problem causing significant mortality and morbidity. In addition to ~10.4 million cases of active TB annually, it is estimated that about two billion ...people are latently infected with
(
), the causative agent of TB. Reactivation of latent
infection is the leading cause of death in patients with immunodeficiency virus (HIV) infection. The low efficiency of the only licensed anti-TB vaccine, Bacille Calmette-Guérin (BCG) to reduce pulmonary TB in adults contributes to this problem. Here we investigated if vaccination with conventional BCG or the genetically modified experimental BCGΔBCG1419c strain can prevent reactivation of latent lymphatic TB in a mouse model of induced reactivation, following the depletion of CD4
T cells, as it occurs in HIV
individuals. Vaccination with conventional BCG or BCGΔBCG1419c prevented reactivation of
from the infected lymph node and the systemic spread of
to spleen and lung. Prevention of reactivation was independent of vaccination route and was accompanied by reduced levels of circulating inflammatory cytokines and the absence of lung pathology. Our results demonstrate that vaccine-induced CD4
T cells are not essential to prevent reactivation of latent lymphatic murine TB, and highlight the need to better understand how non-CD4
immune cell populations participate in protective immune responses to control latent TB.
Objectives
The immunologic events that build up to the fatal neurological stage of experimental cerebral malaria (ECM) are incompletely understood. Here, we dissect immune cell behaviour occurring in ...the central nervous system (CNS) when Plasmodium berghei ANKA (PbA)‐infected mice show only minor clinical signs.
Methods
A 2‐photon intravital microscopy (2P‐IVM) brain imaging model was used to study the spatiotemporal context of early immunological events in situ during ECM.
Results
Early in the disease course, antigen‐specific CD8+ T cells came in contact and arrested on the endothelium of post‐capillary venules. CD8+ T cells typically adhered adjacent to, or were in the near vicinity of, perivascular macrophages (PVMs) that line post‐capillary venules. Closer examination revealed that CD8+ T cells crawled along the inner vessel wall towards PVMs that lay on the abluminal side of large post‐capillary venules. ‘Activity hotspots’ in large post‐capillary venules were characterised by T‐cell localisation, activated morphology and clustering of PVM, increased abutting of post‐capillary venules by PVM and augmented monocyte accumulation. In the later stages of infection, when mice exhibited neurological signs, intravascular CD8+ T cells increased in number and changed their behaviour, actively crawling along the endothelium and displaying frequent, short‐term interactions with the inner vessel wall at hotspots.
Conclusion
Our study suggests an active interaction between PVM and CD8+ T cells occurs across the blood–brain barrier (BBB) in early ECM, which may be the initiating event in the inflammatory cascade leading to BBB alteration and neuropathology.
Our study suggests that perivascular macrophages and CD8+ T cells interact across the blood–brain barrier (BBB) in the early stages of experimental cerebral malaria, which may be the initiating event in the inflammatory cascade leading to BBB alteration and neuropathology.
Inflammation of the CNS can have devastating, long-lived, and in some cases fatal consequences for patients. The stimuli that can induce CNS inflammation are diverse, and include infectious agents, ...autoimmune responses against CNS-expressed antigens, and sterile inflammation following ischemia or traumatic injury. In these conditions, cells of the immune system play central roles in promulgation and resolution of the inflammatory response. However, the immunological mechanisms at work in these diverse responses differ according to the nature of the response. Our understanding of the actions of immune cells in the CNS has been restricted by the difficulty in visualising leukocytes as they undergo recruitment from the cerebral microvasculature and following their entry into the CNS parenchyma. However, advances in in vivo microscopy over the last 10-15 years have overcome many of these difficulties, and studies using these forms of microscopy have revealed a wealth of new information regarding the cellular and molecular mechanisms of CNS inflammation. This Research Topic brings together state of the art reviews examining the use of in vivo imaging in investigating inflammation and leukocyte behaviour in the CNS. Papers in this Research Topic describe how in vivo microscopy has increased our understanding of the actions of immune cells in the inflamed CNS, following various stimuli including autoimmunity, infection and sterile inflammation.
Abstract Nuclear factor (NF)-κB is a transcription factor family which transmits signals from the cell surface to the nucleus, resulting in transcriptional effects on genes involved in inflammation, ...cell differentiation and survival. The signaling of NF-κB and mitogen-activated protein (MAP) kinases through adapter molecules is of critical importance to survival and activation of all cells in the body, including those regulating innate and adaptive immunity. Here we review the individual and intersecting roles played by the alternate and classical NF-κB pathways in the pathogenesis of autoimmune disease. Understanding the differences in classical and alternate NF-κB function has greatly assisted the development of models of their contribution to different autoimmune diseases. To exemplify these concepts, we consider the contribution of NF-κB to rheumatoid arthritis and type 1 diabetes pathogenesis and approaches to immunotherapy.
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