Current Opinion in Immunology最新文献

Granulocytes are innate immune effector cells with essential functions in host resistance to bacterial infections. I will discuss emerging evidence that during Mycobacterium tuberculosis infection, counter-intuitively, eosinophils are host-protective while neutrophils are host detrimental. Additionally, I will propose a ‘tipping-point’ model in which neutrophils are an integral part of a feedforward loop driving tuberculosis disease exacerbation.

Increasing global concerns of pandemic respiratory viruses highlight the importance of developing optimal vaccination strategies that encompass vaccine platform, delivery route, and regimens. The decades-long effort to develop vaccines to combat respiratory infections such as influenza, respiratory syncytial virus, and tuberculosis has met with challenges, including the inability of systemically administered vaccines to induce respiratory mucosal (RM) immunity. In this regard, ample preclinical and available clinical studies have demonstrated the superiority of RM vaccination to induce RM immunity over parenteral route of vaccination. A great stride has been made in developing vaccines for RM delivery against respiratory pathogens, including M. tuberculosis and SARS-CoV-2. In particular, inhaled aerosol delivery of adenoviral-vectored vaccines has shown significant promise.

Delivery of vaccines via the mucosal route is regarded as the most effective mode of immunization to counteract infectious diseases that enter via mucosal tissues, including oral, nasal, pulmonary, intestinal, and urogenital surfaces. Mucosal vaccines not only induce local immune effector elements, such as secretory Immunoglobulin A (IgA) reaching the luminal site of the mucosa, but also systemic immunity. Moreover, mucosal vaccines may trigger immunity in distant mucosal tissues because of the homing of primed antigen-specific immune cells toward local and distant mucosal tissue via the common mucosal immune system.

While most licensed intramuscular vaccines induce only systemic immunity, next-generation mucosal vaccines may outperform parenteral vaccination strategies by also eliciting protective mucosal immune responses that block infection and/or transmission. Especially the nasal route of vaccination, targeting the nasal-associated lymphoid tissue, is attractive for local and distant mucosal immunization. In numerous studies, bacterial outer membrane vesicles (OMVs) have proved attractive as vaccine platform for homologous bacterial strains, but also as antigen delivery platform for heterologous antigens of nonbacterial diseases, including viruses, parasites, and cancer. Their application has also been extended to mucosal delivery. Here, we will summarize the characteristics and clinical potential of (engineered) OMVs as vaccine platform for mucosal, especially intranasal delivery.

Oral vaccines have a distinctive advantage of stimulating immune responses in the mucosa, where numerous pathogens gain entry and cause disease. Although various efforts have been attempted to create recombinant mucosal vaccines that provoke strong immunogenicity, the outcomes in clinical trials have been weak or inconsistent. Therefore, next-generation mucosal vaccines are needed that are more immunogenic. Here, we discuss oral vaccines with an emphasis on a next-generation mucosal vaccine that utilizes a nonreplicating human recombinant adenovirus type-5 (rAd5) vector. Numerous positive clinical results investigating oral rAd5 vaccines are reviewed, with a summary of the immunogenicity and efficacy results for specific vaccine indications of influenza, norovirus, and SARS-CoV-2. The determination of correlates of protection for oral vaccination and the potential impact this novel vaccine formulation may have on disease transmission are also discussed. In summary, successful oral vaccination can be accomplished and would have major public health benefits if approved.

The eradication of polio during the latter half of the 20th century can be considered one of the greatest medical triumphs in history. This achievement can be attributed to the development of vaccines that received the public's almost unwavering acceptance of them, especially by parents who had been waiting/hoping for a medical breakthrough that would ensure that their children would not succumb to the devastating effects of infantile paralysis. Sixty years later, the worldwide population was now confronted with an equally devastating disease — Covid-19 — which by the 2020–2021 time period had reached pandemic levels not seen since the flu outbreak of 1918. Unlike polio, however, several vaccines against Covid-19 were rapidly developed and deployed due to advances in microbiologic and immunologic technology. But also, unlike the polio vaccine experience, there was not universal acceptance of the Covid-19 vaccines and this has led to continuation of the pandemic into 2023 (albeit at a reduced level). In addition, acceptance of the Covid-19 vaccines has been confronted with the uncertainty that they do not apparently prevent transmission in asymptomatic people, and the mutation rate of the virus requires periodic re-evaluation and possible upgrading of the vaccines. This review will focus on the various factors that have led to these contrasting attitudes toward these two different vaccines and how resistance and hesitancy to vaccine use can be overcome by implementing various measures, after introducing the key roles that the sciences of microbiology and immunology have played in vaccine development over the past 250+ years.

Cell-autonomous immunity is the first line of defense by which cells recognize and contribute to eliminating invasive pathogens. It is composed of immune signaling networks that sense microbial pathogens, promote pathogen restriction, and stimulate their elimination, including host cell death. Ubiquitination is a pivotal orchestrator of these pathways, by changing the activity of signal transducers and effector proteins in an efficient way. In this review, we will focus on how ubiquitin connects the pathways that sense pathogens to the cellular responses to invaders and shed light on how ubiquitination impacts the microenvironment around the infected cell, stimulating the appropriate immune response. Finally, we discuss therapeutic options directed at favoring cell-autonomous immune responses to infection.

Macrophages are phagocytic cells distributed across tissues that sustain homeostasis by constantly probing their local environment. Upon perturbations, macrophages rewire their energy metabolism to execute their immune programs. Intensive research in the field of immunometabolism highlights cell-intrinsic immunometabolites such as succinate and itaconate as immunomodulatory signals. A role for cell-extrinsic stimuli now emerges with evidence for signals that shape macrophages' metabolism in a tissue-specific manner. In this review, we will cover macrophage immunometabolism in the gut, a complex metabolic and immunologically active tissue. During homeostasis, gut macrophages are constantly exposed to pro-inflammatory ligands from the microbiota, and in contrast, are balanced by microbiota-derived anti-inflammatory metabolites. Given their extensive metabolic changes during activation, spatial analyses of the tissue will allow the characterization of metabolic niches of macrophage in the gut. Identifying metabolic perturbations of macrophage subsets during chronic inflammation and infection can direct future tissue-specific metabolotherapies.

COVID-19 is an infectious and inflammatory disease caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome-Coronavirus-2) that might progress to severe illness in humans, characterized by excessive pulmonary and systemic inflammation. Exacerbated production of inflammatory cytokines and cell death contributes to disease aggravation and the inflammasomes take a central stage in this process. Activation of the NLRP3 has been demonstrated in macrophages and monocytes infected in vitro, in mouse models of infection, and in cells and lungs of severe cases of COVID-19. It is still not clear how SARS-CoV-2 activates the NLRP3 inflammasome, and recent reports suggest that the virus engages the CASP4/11 (Caspase 4/11)-mediated noncanonical activation of NLRP3. In this review, we discuss the recent data regarding the activation of NLRP3 inflammasome by SARS-CoV-2 and their participation in the development of severe cases of COVID-19.

Macrophages function as tissue-immune sentinels and mediate key antimicrobial responses against bacterial pathogens. Yet, they can also act as a cellular niche for intracellular bacteria, such as Salmonella enterica, to persist in infected tissues. Macrophages exhibit heterogeneous activation or polarization, states that are linked to differential antibacterial responses and bacteria permissiveness. Remarkably, recent studies demonstrate that Salmonella and other intracellular bacteria inject virulence effectors into the cellular cytoplasm to skew the macrophage polarization state and reprogram these immune cells into a permissive niche. Here, we review mechanisms of macrophage reprogramming by Salmonella and highlight manipulation of macrophage polarization as a shared bacterial pathogenesis strategy. In addition, we discuss how the interplay of bacterial effector mechanisms, microenvironmental signals, and ontogeny may shape macrophage cell states and functions. Finally, we propose ideas of how further research will advance our understanding of macrophage functional diversity and immunobiology.

Intracellular Toll-like receptors (TLRs) are key components of the innate immune system. Their expression in antigen-presenting cells (APCs), and in particular dendritic cells (DCs), makes them critical in the induction of the adaptive immune response. In DCs, they interact with the chaperone UNC93B1 that mediates their trafficking from the endoplasmic reticulum (ER) to endosomes where they are cleaved by proteases and activated. All these different steps are also shared by major histocompatibility complex class-II (MHCII) molecules. Here, we will discuss the tight relationship intracellular TLRs have with the antigen processing machinery in APCs for their trafficking and activation.