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Introduction Research has shown that exposure to traffic-related air pollution (TRAP) can damage the respiratory mucosa by decreasing epithelial barrier function, exaggerating inflammatory responses at the mucosal surface, and impairing [...]

I was a keen first-year medical student in Kuala Lumpur, standing in a pediatric bay. 'Isles of white in a sea of red,' my consultant said while inspecting the child's [...]

Cutaneous leishmaniasis caused by Leishmania parasites exhibits a wide range of clinical manifestations. Although parasites influence disease severity, cytolytic [CD8.sup.+] T cell responses mediate disease. Although these responses originate in the lymph node, we found that expression of the cytolytic effector molecule granzyme B was restricted to lesional [CD8.sup.+] T cells in Leishmania-infected mice, suggesting that local cues within inflamed skin induced cytolytic function. Expression of Blimp-1 (Prdml), a transcription factor necessary for cytolytic [CD8.sup.+] T cell differentiation, was driven by hypoxia within the inflamed skin. Hypoxia was further enhanced by the recruitment of neutrophils that consumed oxygen to produce ROS and ultimately increased the hypoxic state and granzyme B expression in [CD8.sup.+] T cells. Importantly, lesions from patients with cutaneous leishmaniasis exhibited hypoxia transcription signatures that correlated with the presence of neutrophils. Thus, targeting hypoxia- driven signals that support local differentiation of cytolytic [CD8.sup.+] T cells may improve the prognosis for patients with cutaneous leishmaniasis, as well as for other inflammatory skin diseases in which cytolytic [CD8.sup.+] T cells contribute to pathogenesis., Introduction Cutaneous leishmaniasis is caused by Leishmania parasites and exhibits a wide range of clinical manifestations, from self-healing lesions to chronic, debilitating infections (1). No vaccines exist for leishmaniasis, and [...]

Rat-bite fever (RBF) is a rare disease that typically manifests with fever, rash, and arthritis (1). Possible complications are abscess formation, endocarditis, and death if left untreated (1,2). Streptobacillus moniliformis [...]

Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer primarily induced by Merkel cell polyomavirus, which is driven by the expression of the oncogenic T antigens (T-Ags). Blockade of the programmed cell death protein-1 (PD- 1) pathway has shown remarkable response rates, but evidence for therapy-associated T-Ag-specific immune response and therapeutic strategies for the nonresponding fraction are both limited. We tracked T-Ag-reactive [CD8.sup.+] T cells in peripheral blood of 26 MCC patients under anti-PD1 therapy, using DNA-barcoded pMHC multimers, displaying all peptides from the predicted HLA ligandome of the oncoproteins, covering 33 class I haplotypes. We observed a broad T cell recognition of T-Ags, including identification of 20 T-Ag-derived epitopes we believe to be novel. Broadening of the T-Ag recognition profile and increased T cell frequencies during therapy were strongly associated with clinical response and prolonged progression-free survival. T-Ag-specific T cells could be further boosted and expanded directly from peripheral blood using artificial antigen-presenting scaffolds, even in patients with no detectable T-Ag-specific T cells. These T cells provided strong tumor-rejection capacity while retaining a favorable phenotype for adoptive cell transfer. These findings demonstrate that T-Ag-specific T cells are associated with the clinical outcome to PD-1 blockade and that Ag-presenting scaffolds can be used to boost such responses., Introduction Immunotherapy based on blockade of the programmed cell death protein-1/programmed cell death ligand 1 (PD-1/PD-L1) pathway has demonstrated pronounced efficacy in restoring antitumor activity in some patients with solid [...]

Infection results when a pathogen produces host tissue damage and elicits an immune response. Critically ill patients experience immune activation secondary to both sterile and infectious insults, with overlapping clinical phenotypes and underlying immunological mechanisms. Patients also undergo a shift in microbiota with the emergence of pathogen-dominant microbiomes. Whilst the combination of inflammation and microbial shift has long challenged intensivists in the identification of true infection, the advent of highly sensitive molecular diagnostics has further confounded the diagnostic dilemma as the number of microbial detections increases. Given the key role of the host immune response in the development and definition of infection, profiling the host response offers the potential to help unravel the conundrum of distinguishing colonisation and sterile inflammation from true infection. This narrative review provides an overview of current approaches to distinguishing colonisation from infection using routinely available techniques and proposes matrices to support decision-making in this setting. In searching for new tools to better discriminate these states, the review turns to the understanding of the underlying pathobiology of the host response to infection. It then reviews the techniques available to assess this response in a clinically applicable context. It will cover techniques including profiling of transcriptome, protein expression, and immune functional assays, detailing the current state of knowledge in diagnostics along with the challenges and opportunities. The ultimate infection diagnostic tool will likely combine an assessment of both host immune response and sensitive pathogen detection to improve patient management and facilitate antimicrobial stewardship., Author(s): Mark Jeffrey [sup.1] [sup.2], Kerina J. Denny [sup.3] [sup.4], Jeffrey Lipman [sup.5] [sup.6] [sup.7], Andrew Conway Morris [sup.1] [sup.2] [sup.8] Author Affiliations: (1) grid.24029.3d, 0000 0004 0383 8386, John [...]

The Middle East respiratory syndrome coronavirus (MERS-CoV) is a betacoronavirus that is of special interest for public health. Dromedary camels have been identified as natural animal reservoirs, with >90% MERS-CoV [...]

Decapod iridescent virus 1 (DIV1). also known as shrimp hemocyte iridescent virus or Cherax quadricarinatus iridovirus, has received extensive attention in recent years due to its highly contagious and lethal properties in crustaceans. In 2019, the Executive Committee of the International Committee on Taxonomy of Viruses approved DIV1 as a new species of the new genus Decapodiridovirus in the family Iridoviridae. To gain a more comprehensive understanding of DIV1, this review summarizes recent advances in DIV1 research, including classification, detection techniques, clinical symptoms, infection mechanisms, and host immune responses. A deeper understanding of the interaction between DIV1 and the host has potentially important implications for developing effective antiDIVl strategies. KEY WORDS: Decapod iridescent virus 1, detection method, transcriptome, symptom, latent infection, INTRODUCTION According to the FAO and 'China Aquaculture Yearbook' data (FAO 2022), with the rapid development of technology, aquaculture output also shows a rapid growth trend in the world. Although [...]

BACKGROUND. The tumor immune microenvironment can provide prognostic and therapeutic information. We aimed to develop noninvasive imaging biomarkers from computed tomography (CT) for comprehensive evaluation of immune context and investigate their associations with prognosis and immunotherapy response in gastric cancer (GC). METHODS. This study involved 2,600 patients with GC from 9 independent cohorts. We developed and validated 2 CT imaging biomarkers (lymphoid radiomics score [LRS] and myeloid radiomics score [MRS]) for evaluating the IHC-derived lymphoid and myeloid immune context respectively, and integrated them into a combined imaging biomarker [LRS/MRS: low(-) or high(+)] with 4 radiomics immune subtypes: 1 (-/-), 2 (+/-), 3 (-/+), and 4 (+/+). We further evaluated the imaging biomarkers' predictive values on prognosis and immunotherapy response. RESULTS. The developed imaging biomarkers (LRS and MRS) had a high accuracy in predicting lymphoid (AUC range: 0.765-0.773) and myeloid (AUC range: 0.736-0.750) immune context. Further, similar to the IHC-derived immune context, 2 imaging biomarkers (HR range: 0.240-0.761 for LRS; 1.301-4.012 for MRS) and the combined biomarker were independent predictors for disease-free and overall survival in the training and all validation cohorts (all P < 0.05). Additionally, patients with high LRS or low MRS may benefit more from immunotherapy (P < 0.001). Further, a highly heterogeneous outcome on objective response rate was observed in 4 imaging subtypes: 1 (-/-) with 27.3%, 2 (+/-) with 53.3%, 3 (-/+) with 10.2%, and 4 (+/+) with 30.0% (P < 0.0001). CONCLUSION. The noninvasive imaging biomarkers could accurately evaluate the immune context and provide information regarding prognosis and immunotherapy for GC., Introduction Recently, the tumor immune microenvironment (TIME) has attracted increasing research attention (1). A growing body of literature highlights its crucial role in cancer progression and therapeutic responses (1-3). In [...]

In the relentless battle against the COVID-19 pandemic, the deployment of mRNA vaccines has stood out as a beacon of hope. The successes of Pfizer-BioNTech NT162b2 and Moderna mRNA-1273 vaccines have been remarkable, marking a revolutionary advancement in the field of vaccinology. Despite their rapid development and impressive efficacy, challenges have emerged, particularly concerning the waning immune response over time and the evolving landscape of SARS-CoV-2 variants. The study published in this issue of JCI by Fazli et al. introduces an approach to potentially enhancing the immune responses generated by COVID-19 mRNA vaccines. The study meticulously examines the outcomes of nearly 1,000 participants who received one or two booster doses with the Pfizer-BioNTech NT162b2 vaccine either ipsilaterally or contralaterally in relation to the initial vaccine dose. Intriguingly, those who received the booster contralaterally exhibited a heightened antibody response that was particularly noteworthy in the later time points after boost., mRNA COVID-19 vaccination successes and limitations The advent of mRNA technology in vaccine development has been transformative, allowing scientists to respond rapidly to the urgent global need for effective COVID-19 [...]

BACKGROUND. Systemic administration of adeno-associated virus (AAV) can trigger life-threatening inflammatory responses, including thrombotic microangiopathy (TMA), acute kidney injury due to atypical hemolytic uremic syndrome- like complement activation, immune-mediated myocardial inflammation, and hepatic toxicity. METHODS. We describe the kinetics of immune activation following systemic AAV serotype 9 (AAV9) administration in 38 individuals following 2 distinct prophylactic immunomodulation regimens. Group 1 received corticosteroids and Group 2 received rituximab plus sirolimus in addition to steroids to prevent anti-AAV antibody formation. RESULTS. Group 1 participants had a rapid increase in immunoglobulin M (IgM) and IgG. Increase in D-dimer, decline in platelet count, and complement activation are indicative of TMA. All Group 1 participants demonstrated activation of both classical and alternative complement pathways, as indicated by depleted C4 and elevated soluble C5b-9, Ba, and Bb antigens. Group 2 patients did not have a significant change in IgM or IgG and had minimal complement activation. CONCLUSIONS. This study demonstrates that TMA in the setting of AAV gene therapy is antibody dependent (classical pathway) and amplified by the alternative complement pathway. Critical time points and interventions are identified to allow for management of immune-mediated events that impact the safety and efficacy of systemic gene therapy., Introduction Adeno-associated virus-mediated (AAV-mediated) gene therapy has emerged as a promising treatment approach for a spectrum of monogenic genetic disorders (1-4). With the approval of the first recombinant AAV vector-based [...]

Intranasal vaccines are anticipated to be powerful tools for combating many infectious diseases, including SARS- CoV-2, because they induce not only systemic immunity but also mucosal immunity at the site of initial infection. However, they are generally inefficient in inducing an antigen-specific immune response without adjuvants. Here, we developed an adjuvant-free intranasal vaccine platform that utilizes the preexisting immunity induced by previous infection or vaccination to enhance vaccine effectiveness. We made RBD-HA, a fusion of the receptor- binding domain (RBD) of spike derived from SARS-CoV-2 as a vaccine target with HA derived from influenza A virus (IAV) as a carrier protein. Intranasal immunization of previously IAV- infected mice with RBD-HA without an adjuvant elicited robust production of RBD-specific systemic IgG and mucosal IgA by utilizing both HA-specific preexisting IgG and [CD4.sup.+] T cells. Consequently, the mice were efficiently protected from SARS-CoV-2 infection. Additionally, we demonstrated the high versatility of this intranasal vaccine platform by assessing various vaccine antigens and preexisting immunity associated with a variety of infectious diseases. The results of this study suggest the promising potential of this intranasal vaccine platform to address problems associated with intranasal vaccines., Introduction The SARS-CoV-2 pandemic has accelerated vaccine development at an unprecedented rate. Several types of COVID-19 vaccines, including mRNA and adenovirus-vector vaccines expressing the SARS-CoV-2 spike glycoprotein, provide highly effective [...]

Prostate cancer is generally considered an immunologically 'cold' tumor type that is insensitive to immunotherapy. Targeting surface antigens on tumors through cellulartherapy can induce a potent antitumor immune response to 'heat up' the tumor microenvironment. However, many antigens expressed on prostate tumor cells are also found on normal tissues, potentially causing on-target, off-tumortoxicities and a suboptimal therapeutic index. Our studies revealed that six-transmembrane epithelial antigen of prostate-2 (STEAP2) was a prevalent prostate cancer antigen that displayed high, homogeneous cell surface expression across all stages of disease with limited distal normal tissue expression, making it ideal for therapeutic targeting. A multifaceted lead generation approach enabled development of an armored STEAP2 chimeric antigen receptor T cell (CAR-T) therapeutic candidate, AZD0754. This CAR-T product was armored with a dominant-negative TGF-[beta] type II receptor, bolstering its activity in the TGF-[beta]-rich immunosuppressive environment of prostate cancer. AZD0754 demonstrated potent and specific cytotoxicity against antigen-expressing cells in vitro despite TGF-[beta]-rich conditions. Further, AZD0754 enforced robust, dose-dependent in vivo efficacy in STEAP2- expressing cancer cell line-derived and patient-derived xenograft mouse models, and exhibited encouraging preclinical safety. Together, these data underscore the therapeutic tractability of STEAP2 in prostate cancer as well as build confidence in the specificity, potency, and tolerability of this potentially first-in-class CAR-T therapy., Introduction Prostate cancer is the most common non-skin cancer diagnosed in men and has the second-highest mortality rate of any cancer (1). Despite advancements in biomarkers and therapeutic approaches, the [...]

Secondary lung infection by inhaled Staphylococcus aureus (SA) is a common and lethal event for individuals infected with influenza A virus (IAV). How IAV disrupts host defense to promote SA infection in lung alveoli, where fatal lung injury occurs, is not known. We addressed this issue using real-time determinations of alveolar responses to IAV in live, intact, perfusedlungs. Our findings show that IAV infection blocked defensive alveolar wall liquid (AWL) secretion and induced airspace liquid absorption, thereby reversing normal alveolar liquid dynamics and inhibiting alveolar clearance of inhaled SA. Loss of AWL secretion resulted from inhibition of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel in the alveolar epithelium, and airspace liquid absorption was caused by stimulation of the alveolar epithelial [Na.sup.+] channel (ENaC). Loss of AWL secretion promoted alveolar stabilization of inhaled SA, but rescue of AWL secretion protected against alveolar SA stabilization and fatal SA-induced lung injury in IAV-infected mice. These findings reveal a central role for AWL secretion in alveolar defense against inhaled SA and identify AWL inhibition as a critical mechanism of IAV lung pathogenesis. AWL rescue may represent a new therapeutic approach for IAV-SA coinfection., Introduction Lung infection is the fourth leading cause of global mortality (1), and the majority of severe lung infections are caused by respiratory viruses (2, 3). Among virus-infected individuals, the [...]

Antibody-drug conjugates (ADCs) have emerged as a revolutionary therapeutic class, combining the precise targeting ability of monoclonal antibodies with the potent cytotoxic effects of chemotherapeutics. Notably, ADCs have rapidly advanced in the field of breast cancer treatment. This innovative approach holds promise for strengthening the immune system through antibody-mediated cellular toxicity, tumor-specific immunity, and adaptive immune responses. However, the development of upfront and acquired resistance poses substantial challenges in maximizing the effectiveness of these therapeutics, necessitating a deeper understanding of the underlying mechanisms. These mechanisms of resistance include antigen loss, derangements in ADC internalization and recycling, drug clearance, and alterations in signaling pathways and the payload target. To overcome resistance, ongoing research and development efforts are focused on urgently identifying biomarkers, integrating immune therapy approaches, and designing novel cytotoxic payloads. This Review provides an overview of the mechanisms and clinical effectiveness of ADCs, and explores their unique immune-boosting function, while also highlighting the complex resistance mechanisms and safety challenges that must be addressed. A continued focus on how ADCs impact the tumor microenvironment will help to identify new payloads that can improve patient outcomes., Introduction Antibody-drug conjugates (ADCs) are a class of therapeutics that have been developed to increase the specificity of cytotoxic therapy by linking cytotoxic molecules to a targeted protein carrier. A [...]

In recent years, there has been an explosion of interest in how fibroblasts initiate, sustain, and resolve inflammation across disease states. Fibroblasts contain heterogeneous subsets with diverse functionality. The phenotypes of these populations vary depending on their spatial distribution within the tissue and the immunopathologic cues contributing to disease progression. In addition to their roles in structurally supporting organs and remodeling tissue, fibroblasts mediate critical interactions with diverse immune cells. These interactions have important implications for defining mechanisms of disease and identifying potential therapeutic targets. Fibroblasts in the respiratory tract, in particular, determine the severity and outcome of numerous acute and chronic lung diseases, including asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, and idiopathic pulmonary fibrosis. Here, we review recent studies defining the spatiotemporal identity of the lung-derived fibroblasts and the mechanisms by which these subsets regulate immune responses to insult exposures and highlight past, current, and future therapeutic targets with relevance to fibroblast biology in the context of acute and chronic human respiratory diseases. This perspective highlights the importance of tissue context in defining fibroblast-immune crosstalk and paves the way for identifying therapeutic approaches to benefit patients with acute and chronic pulmonary disorders., Frameworks for defining lung fibroblast heterogeneity Phenotypic heterogeneity of lung fibroblasts. Fibroblasts in the respiratory tract represent a diverse group of cells with a high degree of plasticity. Their plasticity [...]

Recognition of pathogen-associated molecular patterns can triggerthe inositol- requiring enzyme 1[alpha] (IRE1[alpha]) arm of the endoplasmic reticulum (ER) stress response in innate immune cells. This process maintains ER homeostasis and also coordinates diverse immunomodulatory programs during bacterial and viral infections. However, the role of innate IRE1[alpha] signaling in response to fungal pathogens remains elusive. Here, we report that systemic infection with the human opportunistic fungal pathogen Candida albicans induced proinflammatory IRE1[alpha] hyperactivation in myeloid cells that led to fatal kidney immunopathology. Mechanistically, simultaneous activation of the TLR/IL-1R adaptor protein MyD88 and the C-type lectin receptor dectin-1 by C. albicans induced NADPH oxidase-driven generation of ROS, which caused ER stress and IRE1[alpha]-dependent overexpression of key inflammatory mediators such as IL-1[beta], IL-6, chemokine (C-C motif) ligand 5 (CCL5), prostaglandin E2 ([PCE.sub.2]), and TNF- [alpha]. Selective ablation of IRE1[alpha] in leukocytes, ortreatment with an IRE1[alpha] pharmacological inhibitor, mitigated kidney inflammation and prolonged the survival of mice with systemic C. albicans infection. Therefore, controlling IRE1[alpha] hyperactivation may be useful for impeding the immunopathogenic progression of disseminated candidiasis., Introduction Sensing and responding to pathogens entails massive protein synthesis, folding, modification, and trafficking in immune cells, which are processes governed by the endoplasmic reticulum (ER). The excess demand in [...]

Long-term protection against SARS-CoV-2 requires the persistence of vaccine antibodies above protective thresholds, the maintenance of immune memory cells capable of reactivation after subsequent viral exposure, or both (1). A [...]

* Context.--Moderna (mRNA-1272) and Pfizer (BNT162b2) SARS-CoV-2 vaccines demonstrate favorable safety and efficacy profiles, but direct comparison data are lacking. Objective.--To determine the vaccines' side effect profiles and expected antibody responses. These data may help personalize vaccine selection and identify individuals with a suboptimal vaccine response. Design.--One hundred forty-nine healthy, largely seronegative adults were assigned Moderna (n = 79) or Pfizer (n = 70). Following the second dose, participants completed a survey documenting their side effects. Serum was collected 0 to 4 days prior to dose 2, and 14 [+ or -] 4 days, 30 6 4 days, 90 [+ or -] 10 days, and 180 [+ or -] 20 days after dose 2. Convalescent serum specimens were collected 32 to 54 days from donors after a polymerase chain reaction-confirmed SARS-CoV-2 infection (n = 20). Anti-spike antibodies were measured using the Roche Diagnostics Elecys Anti-SARS-CoV-2 S assay on a Roche cobas e801 instrument. Results.--Participants receiving the Moderna vaccine experienced side effects with greater frequency and severity. Both vaccines elicited a robust antibody response, but median signal was higher in Moderna recipients. Symptom severity decreased with age. Antibody response in Pfizer recipients negatively correlated with age. Antibody response decreased after 6 months (84% reduction in Moderna, 79% Pfizer), but values remained greater than for convalescent donors. Antibody response did not correlate with gender or symptom severity. Conclusions.--Moderna may be preferred in individuals in need of greater immune stimulation (eg, older individuals), whereas Pfizer may be preferred in those concerned about vaccine reactions. Anti-spike antibody signal varies by vaccine, so specific reference intervals will be needed to identify individuals with a suboptimal response., Since its identification as the cause of a novel respiratory pneumonia first documented in Wuhan, China, in December 2019, SARS-CoV-2 has spread rapidly throughout the globe, causing 221 million confirmed [...]

Neutralizing antibodies (nAbs) and binding antibodies (bAbs) appear to be associated with protection against symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease (COVID-19) (1,2). Early assessments [...]

Persistence of vaccination-induced cellular and humoral immune responses is crucial to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or at least provide protection against severe coronavirus disease (COVID-19) [...]

Several respiratory viruses can circulate during the same period and can concurrently or sequentially infect the respiratory tract, leading to virus-virus interactions. At the host level, the course of infection [...]