Current topics in microbiology and immunology最新文献

A number of different experimental models using both non-selective and selective PI3K inhibitors have shown that many pathogenic steps of respiratory disorders, such as bronchial asthma, Chronic Obstructive Pulmonary Disease (COPD), Idiopathic Pulmonary Fibrosis (IPF), Acute Respiratory Distress Syndrome (ARDS) and Lung Cancer (LC) are, at least in part, regulated by the PI3K signaling pathway, suggesting that the inhibition of PI3K could represent an ideal therapeutic target for the treatment of respiratory diseases. This chapter summarizes the current state of the therapeutic strategies aimed to exploit the inhibition of PI3K in this context. In animal models of asthma, selective δ and γ inhibitors have shown to be effective, and when administered by inhalation, reasonably safe. Nevertheless, very few clinical trials have been performed so far. The efficacy of current traditional therapies for allergic bronchial asthma has likely diminished the need for new alternative treatments. Surprisingly, in COPD, where instead there is an urgent need for new and more effective therapeutic approaches, the number of clinical studies is still low and not capable yet, with the exception for an acceptable safety profile, to show a significant improvement of clinical outcomes. In IPF, a disease with a disappointing prognosis, PI3K inhibitors have been bound to a FAP ligand with the aim to selectively target myofibroblasts, showing to significantly reduce collagen production and the development of lung fibrosis in an animal model of lung fibrosis. Due to its role in cell activation and cell replication, the PI3K pathway is obviously largely involved in lung cancer. Several studies, currently ongoing, are testing the effect of PI3K inhibitors mainly in NSCLC. Some evidence in the treatment of cancer patients suggests the possibility that PI3K inhibitors may enhance the response to conventional treatment. The involvement of PI3Kδ in the modulation of airway neutrophil recruitment and bronchial epithelial functional alterations also suggest a potential role in the treatment of ARDS, but at the current state the ongoing trials are aimed to the treatment of ARDS in COVID-19 patients. In general, few clinical trials investigating PI3K inhibitors in respiratory disorders have been performed so far. This relatively new approach of treatment is just at its beginning and certainly needs further efforts and additional studies.

Chikungunya virus (CHIKV) was discovered more than six decades ago, but has remained poorly investigated. However, after a recent outbreak of CHIK fever in both hemispheres and viral adaptation to new species of mosquitoes, it has attracted a lot of attention. The currently available experimental data suggest that molecular mechanisms of CHIKV replication in vertebrate and mosquito cells are similar to those of other New and Old World alphaviruses. However, this virus exhibits a number of unique characteristics that distinguish it from the other, better studied members of the alphavirus genus. This review is an attempt to summarize the data accumulated thus far regarding the molecular mechanisms of alphavirus RNA replication and interaction with host cells. Emphasis was placed on demonstrating the distinct features of CHIKV in utilizing host factors to build replication complexes and modify the intracellular environment for efficient viral replication and inhibition of the innate immune response. The available data suggest that our knowledge about alphavirus replication contains numerous gaps that potentially hamper the development of new therapeutic means against CHIKV and other pathogenic alphaviruses.

CD8⁺ T cells are an essential part of the immune system and play a vital role in defending against tumors and infections. The phosphoinositide-3-kinase (PI3K), especially class I, is involved in numerous interrelated signaling pathways which control CD8⁺ T cell development, maturation, migration, activation, and differentiation. While CD8⁺ T lymphocytes express all class I PI3K isoforms (PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ), isoform-specific functions, especially for PI3Kα and PI3Kβ have not been fully elucidated. A few studies suggest the important role of p110δ and p110γ in CD8⁺ T cell activation, signaling, chemotaxis and function and several clinical trials are currently testing the effect of isoform-specific inhibitors in various types of cancers, including Indolent Non-Hodgkin Lymphoma, Peripheral T cell Lymphoma, Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, non-small cell lung carcinoma (NSCLC), head & neck cancer, and breast cancer. This chapter summarizes current knowledge of the roles of various PI3K isoforms and downstream signaling pathways in regulating CD8⁺ T cell fate, including cell proliferation, migration, and memory generation. We also discuss certain clinical trials employing PI3K inhibitors for cancer therapy, their limitations, and future perspectives.

Self-amplifying mRNAs derived from the genomes of positive-strand RNA viruses have recently come into focus as a promising technology platform for vaccine development. Non-virally delivered self-amplifying mRNA vaccines have the potential to be highly versatile, potent, streamlined, scalable, and inexpensive. By amplifying their genome and the antigen encoding mRNA in the host cell, the self-amplifying mRNA mimics a viral infection, resulting in sustained levels of the target protein combined with self-adjuvanting innate immune responses, ultimately leading to potent and long-lasting antigen-specific humoral and cellular immune responses. Moreover, in principle, any eukaryotic sequence could be encoded by self-amplifying mRNA without the need to change the manufacturing process, thereby enabling a much faster and flexible research and development timeline than the current vaccines and hence a quicker response to emerging infectious diseases. This chapter highlights the rapid progress made in using non-virally delivered self-amplifying mRNA-based vaccines against infectious diseases in animal models. We provide an overview of the unique attributes of this vaccine approach, summarize the growing body of work defining its mechanism of action, discuss the current challenges and latest advances, and highlight perspectives about the future of this promising technology.

Chikungunya virus (CHIKV) infection in humans is rarely fatal but is often associated with chronic joint and muscle pain. Chronic CHIKV disease is highly debilitating and is associated with viral persistence. To date, there are no approved vaccines or therapeutics to prevent or treat CHIKV infections once they are established. Current palliative treatments aim to reduce joint inflammation and pain associated with acute and chronic CHIKV disease. Development of novel therapeutics that reduces viral loads should positively impact virus inflammatory disease and improve patient outcomes following CHIKV infection. Therapies that target multiple aspects of CHIKV replication cycle should be developed since the virus is capable of rapidly mutating around any single therapeutic. This review summarizes the current status of small molecule inhibitor development against CHIKV.

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that has caused both small- and large-scale epidemics of incapacitating musculoskeletal disease across the globe. A substantial proportion of infected individuals experience debilitating arthralgia and/or arthritis that can persist in relapsing or continuous forms for months to years, an occurrence that appears independent of viral strain and outbreak location. Due to the lack of CHIKV-specific vaccine or therapeutics, treatment of chronic CHIKV disease is limited to supportive care. Although the epidemiologic and molecular mechanisms that dictate resolution or chronicity of CHIKV disease remain unclear, several risk factors and immunological responses have been implicated in the development of chronic CHIKV disease. Mounting evidence from animal models and limited case studies indicates that chronic disease is likely a result of induced autoimmunity and/or viral persistence in joint-associated tissue. Due to the global spread and explosive, often unpredictable nature of CHIKV epidemics, concerted efforts to obtain a more precise understanding of the development and maintenance of chronic CHIKV disease must be at the forefront of investigative endeavors.

mRNA vaccines have become a versatile technology for the prevention of infectious diseases and the treatment of cancers. In the vaccination process, mRNA formulation and delivery strategies facilitate effective expression and presentation of antigens, and immune stimulation. mRNA vaccines have been delivered in various formats: encapsulation by delivery carriers, such as lipid nanoparticles, polymers, peptides, free mRNA in solution, and ex vivo through dendritic cells. Appropriate delivery materials and formulation methods often boost the vaccine efficacy which is also influenced by the selection of a proper administration route. Co-delivery of multiple mRNAs enables synergistic effects and further enhances immunity in some cases. In this chapter, we overview the recent progress and existing challenges in the formulation and delivery technologies of mRNA vaccines with perspectives for future development.

The phosphoinositide-3-kinase (PI3K) pathway is a highly conserved intracellular signaling pathway involving numerous key effectors which, in response to diverse extracellular stimuli, modulate the phenotype and function of most mammalian cell types in a pleiotropic manner. PI3K signaling plays a critical role in the development, activation, and differentiation of lymphocytes. In particular, the PI3Kδ and PI3Kγ isoforms have been shown to carry out essential, non-redundant roles in T cells, and therefore, tight regulation of the PI3K pathway is important to maintain the balance between immune tolerance and inflammation. Recent and ongoing efforts to manipulate the biology of T helper cell subsets in the treatment of autoimmune conditions, inflammatory disorders, as well as cancer have shown promising results, and targeting the PI3K pathway may be beneficial in these contexts. However, more insight as to the precise function of individual PI3K isoforms in pathogenic and protective immune cell subsets is still required, and how exactly PI3K signaling is regulated and integrated with classical immune pathways. This chapter provides an overview of the role of PI3K isoforms in the differentiation and function of T helper cell subsets, within the broader context of targeting this pathway to potentially alleviate immunopathology.

Platelets are unique anucleated blood cells that constantly patrol the vasculature to seal and prevent injuries in a process termed haemostasis. Thereby they rapidly adhere to the subendothelial matrix and recruit further platelets, resulting in platelet aggregates. Apart from their central role in haemostasis, they also kept some of their features inherited by their evolutionary ancestor-the haemocyte, which was also involved in immune defences. Together with leukocytes, platelets fight pathogenic invaders and guide many immune processes. In addition, they rely on several signalling pathways which are also relevant to immune cells. Among these, one of the central signalling hubs is the PI3K pathway. Signalling processes in platelets are unique as they lack a nucleus and therefore transcriptional regulation is absent. As a result, PI3K subclasses fulfil distinct roles in platelets compared to other cells. In contrast to leukocytes, the central PI3K subclass in platelet signalling is PI3K class Iβ, which underlines the uniqueness of this cell type and opens new ways for potential platelet-specific pharmacologic inhibition. An overview of platelet function and signalling with emphasis on PI3K subclasses and their respective inhibitors is given in this chapter.

Despite the therapeutic progress, relapse remains a major problem in the treatment of acute lymphoblastic leukemia (ALL). Most leukemia cells that survive chemotherapy are found in the bone marrow (BM), thus resistance to chemotherapy and other treatments may be partially attributed to pro-survival signaling to leukemic cells mediated by leukemia cell-microenvironment interactions. Adhesion of leukemia cells to BM stromal cells may lead to cell adhesion-mediated drug resistance (CAM-DR) mediating intracellular signaling changes that support survival of leukemia cells. In ALL and chronic lymphocytic leukemia (CLL), adhesion-mediated activation of the PI3K/AKT signaling pathway has been shown to be critical in CAM-DR. PI3K targeting inhibitors have been approved for CLL and have been evaluated preclinically in ALL. However, PI3K inhibition has yet to be approved for clinical use in ALL. Here, we review the role of PI3K signaling for normal hematopoietic and leukemia cells and summarize preclinical inhibitors of PI3K in ALL.