International review of cell and molecular biology最新文献

The last several years have revealed increasing evidence of the immunomodulatory role of radiation therapy. Radiotherapy reshapes the tumoral microenvironment can shift the balance toward a more immunostimulatory or immunosuppressive microenvironment. The immune response to radiation therapy appears to depend on the irradiation configuration (dose, particle, fractionation) and delivery modes (dose rate, spatial distributions). Although an optimal irradiation configuration (dose, temporal fractionation, spatial dose distribution, etc.) has not yet been determined, temporal schemes employing high doses per fraction appear to favor radiation-induced immune response through immunogenic cell death. Through the release of damage-associated molecular patterns and the sensing of double-stranded DNA and RNA breaks, immunogenic cell death activates the innate and adaptive immune response, leading to tumor infiltration by effector T cells and the abscopal effect. Novel radiotherapy approaches such as FLASH and spatially fractionated radiotherapies (SFRT) strongly modulate the dose delivery method. FLASH-RT and SFRT have the potential to trigger the immune system effectively while preserving healthy surrounding tissues. This manuscript reviews the current state of knowledge on the immunomodulation effects of these two new radiotherapy techniques in the tumor, healthy immune cells and non-targeted regions, as well as their therapeutic potential in combination with immunotherapy.

Chagas disease (CD), caused by the protozoan parasite Trypanosoma cruzi, is the third largest parasitic disease burden globally. Currently, more than 6 million people are infected, mainly in Latin America, but international migration has turned CD into an emerging health problem in many nonendemic countries. Despite intense research, a vaccine is still not available. A complex parasite life cycle, together with numerous immune system manipulation strategies, may account for the lack of a prophylactic or therapeutic vaccine. There is substantial experimental evidence supporting that T. cruzi acute infection generates a strong immunosuppression state that involves numerous immune populations with regulatory/suppressive capacity. Myeloid-derived suppressor cells (MDSCs), Foxp3+ regulatory T cells (Tregs), regulatory dendritic cells and B regulatory cells are some of the regulatory populations that have been involved in the acute immune response elicited by the parasite. The fact that, during acute infection, MDSCs increase notably in several organs, such as spleen, liver and heart, together with the observation that depletion of those cells can decrease mouse survival to 0%, strongly suggests that MDSCs play a major role during acute T. cruzi infection. Accumulating evidence gained in different settings supports the capacity of MDSCs to interact with cells from both the effector and the regulatory arms of the immune system, shaping the outcome of the response in a very wide range of scenarios that include pathological and physiological processes. In this sense, the aim of the present review is to describe the main knowledge about MDSCs acquired so far, including several crosstalk with other immune populations, which could be useful to gain insight into their role during T. cruzi infection.

Antibiotics are one of the greatest discoveries of medicine of the past century. Despite their invaluable contribution to infectious disease, their administration could lead to side effects that in some cases are serious. The toxicity of some antibiotics is in part due to their interaction with mitochondria: these organelles derive from a bacterial ancestor and possess specific translation machinery that shares similarities with the bacterial counterpart. In other cases, the antibiotics could interfere with mitochondrial functions even if their main bacterial targets are not shared with the eukaryotic cells. The purpose of this review is to summarize the effects of antibiotics administration on mitochondrial homeostasis and the opportunity that some of these molecules could represent in cancer treatment. The importance of antimicrobial therapy is unquestionable, but the identification of interaction with eukaryotic cells and in particular with mitochondria is crucial to reduce the toxicity of these drugs and to explore other useful medical applications.

Gene therapy has seen major progress in recent years. Viral vectors have made a significant contribution through efficient engineering for improved delivery and safety. A large variety of indications such as cancer, cardiovascular, metabolic, hematological, neurological, muscular, ophthalmological, infectious diseases, and immunodeficiency have been targeted. Viral vectors based on adenoviruses, adeno-associated viruses, herpes simplex viruses, retroviruses including lentiviruses, alphaviruses, flaviviruses, measles viruses, rhabdoviruses, Newcastle disease virus, poxviruses, picornaviruses, reoviruses, and polyomaviruses have been used. Proof-of-concept has been demonstrated for different indications in animal models. Therapeutic efficacy has also been achieved in clinical trials. Several viral vector-based drugs have been approved for the treatment of cancer, and hematological, metabolic, and neurological diseases. Moreover, viral vector-based vaccines have been approved against COVID-19 and Ebola virus disease.

Alphaviruses have frequently been engineered for cancer therapy, cancer immunotherapy, and cancer vaccine development. As members of self-replicating RNA viruses, alphaviruses provide high levels of transgene expression through efficient self-amplifying of their RNA genome in host cells. Alphavirus vectors can be used as recombinant viral particles or oncolytic viruses. Alternatively, either naked or nanoparticle-encapsulated RNA and DNA replicons can be utilized. In the context of cancer prevention and treatment, antitumor, cytotoxic and suicide genes have been expressed from alphavirus vectors to provide tumor regression and tumor eradication. Moreover, immunostimulatory genes such as cytokines and chemokines have been used for cancer immunotherapy approaches. Expression of tumor antigens has been applied for cancer vaccine development. Alphavirus vectors has demonstrated tumor regression and even cure in various preclinical animal models. Immunization has elicited strong immune responses and showed protection against challenges with tumor cells in animal models. Several clinical trials have confirmed good safety and tolerability of alphaviruses in cancer patients although therapeutic efficacy will still require optimization.

Cystic fibrosis (CF) is a genetic disease characterized by mutations of cystic fibrosis transmembrane conductance regulator (CFTR) gene, which lead to a dysfunctional chloride and bicarbonate channel. Abnormal mucus viscosity, persistent infections and hyperinflammation that preferentially affect the airways, referred to the pathogenesis of CF lung disease. It has largely demonstrated that Pseudomonas aeruginosa (P. aeruginosa) represents the most important pathogen that affect CF patients, leading to worsen inflammation by stimulating pro-inflammatory mediators release and tissue destruction. The conversion to mucoid phenotype and formation of biofilms, together with the increased frequency of mutations, are only few changes that characterize the P. aeruginosa's evolution during CF lung chronic infection. Recently, mitochondria received increasing attention due to their involvement in inflammatory-related diseases, including in CF. Alteration of mitochondrial homeostasis is sufficient to stimulate immune response. Exogenous or endogenous stimuli that perturb mitochondrial activity are used by cells, which, through the mitochondrial stress, potentiate immunity programs. Studies show the relationship between mitochondria and CF, supporting the idea that mitochondrial dysfunction endorses the exacerbation of inflammatory responses in CF lung. In particular, evidences suggest that mitochondria in CF airway cells are more susceptible to P. aeruginosa infection, with consequent detrimental effects that lead to amplify the inflammatory signals. This review discusses the evolution of P. aeruginosa in relationship with the pathogenesis of CF, a fundamental step to establish chronic infection in CF lung disease. Specifically, we focus on the role of P. aeruginosa in the exacerbation of inflammatory response, by triggering mitochondria in CF.

The ability of Mycobacterium tuberculosis (M. tb) to hijack host mitochondria and control host immune signaling is the key to its successful infection. Infection of M. tb causes distinct changes in mitochondrial morphology, metabolism, disruption of innate signaling, and cell fate. The alterations in mitochondria are intricately linked to the immunometabolism of host immune cells such as macrophages, dendritic cells, and T cells. Different immune cells are tuned to diverse immunometabolic states that decide their immune response. These changes could be attributed to the several proteins targeted to host mitochondria by M. tb. Bioinformatic analyses and experimental evidence revealed the potential localization of secreted mycobacterial proteins in host mitochondria. Given the central role of mitochondria in the host metabolism, innate signaling, and cell fate, its manipulation by M. tb renders it susceptible to infection. Restoring mitochondrial health can override M. tb-mediated manipulation and thus clear infection. Several reviews are available on the role of different immune cells in tuberculosis infection and M. tb evasion of immune responses; in the present chapter, we discuss the mitochondrial functional alterations in the innate immune signaling of various immune cells driven by differential mitochondrial immunometabolism during M. tb infection and the role of M. tb proteins, which are directly targeted to the host mitochondria and compromise its innate signaling system. Further studies would help in uncovering the molecular mechanisms of M. tb-directed proteins in host mitochondria to conceptualize both host- directed and pathogen- directed interventions in TB disease management.

Fatty acid metabolic reprogramming has emerged as a major regulator of anti-tumor immune responses with large body of evidence that demonstrate its ability to impact the differentiation and function of immune cells. Therefore, depending on the metabolic cues that stem in the tumor microenvironment, the tumor fatty acid metabolism can tilt the balance of inflammatory signals to either promote or impair anti-tumor immune responses. Oxidative stressors such as reactive oxygen species generated from radiation therapy can rewire the tumor energy supply, suggesting that radiation therapy can further perturb the energy metabolism of a tumor by promoting fatty acid production. In this review, we critically discuss the network of fatty acid metabolism and how it regulates immune response especially in the context of radiation therapy.

Dendritic cells perform critical functions in bridging innate and adaptive immunity. Their ability to sense adjuvant signals in their environment, migrate on maturation, and cross-present cell-associated antigens enables these cells to carry antigen from tissue sites to lymph nodes, and thereby prime naïve T cells that cannot enter tissues. Despite being an infrequent cell type in tumors, we discuss how dendritic cells impact the immune environment of tumors and their response to cancer therapies. We review how radiation therapy of tumors can impact dendritic cells, through transfer of cell associated antigens to dendritic cells and the release of endogenous adjuvants, resulting in increased antigen presentation in the tumor-draining lymph nodes. We explore how tumor specific factors can result in negative regulation of dendritic cell function in the tumor, and the impact of direct radiation exposure to dendritic cells in the treatment field. These data suggest an important role for dendritic cell subpopulations in activating new T cell responses and boosting existing T cell responses to tumor associated antigens in tumor draining lymph nodes following radiation therapy. It further justifies a focus on the needs of the lymph node T cells to improve systemic anti-immunity following radiation therapy.