Search Results (490)

Messenger RNA (mRNA) entered clinical medicine through vaccines, where the innate immune reactivity that complicates protein therapeutics acts as a built-in adjuvant. The success of the coronavirus disease 2019 (COVID-19) mRNA vaccines inspired an expansive vision of an mRNA 2.0 era extending the modality to rare and common diseases, with delivery framed as the principal challenge. This review accepts much of that vision but argues it rests on an unstated assumption: that all protein therapeutics form a single pharmacological class. They do not. We propose a taxonomy, the Dose–Response Architecture Classification, separating two classes. Exposure-controlled therapeutics require a specific quantity of active protein on a defined regimen, as outcomes depend on reproducible exposure; examples include insulin, erythropoietin, growth hormone, coagulation factors, and narrow-therapeutic-index biologics. Threshold-response therapeutics depend on surpassing a functional threshold rather than maintaining a precise concentration; these include vaccines, many enzyme-replacement therapies, genome editing, receptor-saturating antibodies, and immune-cell reprogramming. Because an mRNA drug is dosed as an instruction, and a single message is translated into a variable number of proteins through a multiplicative, stochastic intracellular chain, the dose-to-effect relationship is inherently variable. Our central, deliberately falsifiable proposition is that mRNA is suitable for threshold-response therapeutics but unsuitable for exposure-controlled therapeutics unless a construct or delivery system demonstrates validated post-delivery output control within predefined pharmacokinetic and pharmacodynamic limits. This is a pharmacological boundary, not a delivery obstacle. We conclude that the greatest advances in mRNA 2.0 will come not from delivery alone but from disciplined indication triage by class. Full article

We report the first documented case of extreme, intact parathyroid hormone (PTH)-independent hypercalcemia mediated by a rare non-osteoclastic bone remodeling mechanism in a 65-year-old Puerto Rican woman, detected within 24 h of the second dose of the Moderna mRNA-1273 COVID-19 vaccine and leading to the diagnosis of high-risk biclonal IgA plasma cell myeloma (R-ISS Stage III). Peak serum calcium reached 17.4 mg/dL with concurrent hyperphosphatemia, normal lactate dehydrogenase (LDH), and without marrow osteoclasts or osteolytic lesions, findings inconsistent with classical cancer-associated hypercalcemia. Hypercalcemia resolved within eight days with supportive treatment alone, remaining durably normal nine months later. The temporal proximity to vaccination, together with the biochemical–histopathological profile, generates the hypothesis, without implying causation, that a vaccine-induced innate immune response triggered a rare inflammatory osteocytic perilacunar/canalicular remodeling. The biclonal gammopathy, Clone-1 (normal karyotype, CD33⁺, OCT-2⁺, MYC⁻, CD19⁺, PAX5⁻) and Clone-2 (complex high-risk karyotype, OCT-2⁻, MYC⁺low, CD19⁻), suggests epigenetic rather than genomic drivers in the predominant clone. This case proposes a novel mechanistic hypothesis for vaccine-associated hypercalcemia and generates testable questions that warrant prospective investigation. Full article

Coronavirus disease 2019 (COVID-19) and influenza share key pathogenic mechanisms, including viral invasion, dysregulated innate immune activation, and the development of severe systemic complications. A central mediator of disease progression in both infections is the hyperactivation of the NLRP3 inflammasome, which drives excessive production of pro-inflammatory cytokines, immunothrombosis, multiorgan injury, and increased mortality. Colchicine possesses a unique pharmacokinetic property of preferential accumulation within myeloid cells, where sufficiently high intracellular concentrations inhibit NLRP3 inflammasome activation. This mechanism provides a biological rationale for preventing the cytokine storm and its downstream consequences when colchicine is administered early during infection. Available pharmacokinetic, toxicological, and clinical evidence suggests that loading doses of colchicine up to approximately 0.05 mg/kg body weight can be administered safely in appropriately selected patients, provided that clinically significant drug–drug interactions and hepatic or renal impairment are carefully excluded. The widely accepted belief that total doses of 7–7.5 mg are inherently lethal appears to reflect historical cases complicated by drug interactions and/or hepatic or renal impairment, rather than toxicity attributable to colchicine dose alone. These observations support reconsideration of current guideline recommendations regarding colchicine dosing. In particular, cumulative doses below 0.1 mg/kg appear to be consistently safe, whereas doses between 0.1 and 0.2 mg/kg are associated with only a low risk of toxicity and rarely with severe intoxication. Reassessment of colchicine dosing strategies may therefore be warranted to optimize NLRP3 inflammasome inhibition and improve outcomes in patients with COVID-19 and influenza. Full article

Since emerging in late 2019, SARS-CoV-2 has caused over 7 million deaths globally and remains a public health concern. Understanding SARS-CoV-2 pathogenesis is vital, especially as factors like environmental exposures are still poorly understood. Polycyclic aromatic hydrocarbons (PAHs), like benzo[a]pyrene (BP), found in pollutants like cigarette smoke, diesel exhaust, and charcoal-broiled steaks, are known to injure the lungs. We aimed to evaluate if BP exacerbates SARS-CoV-2 pathogenesis in a mouse model of disease. One day following intranasal administration of BP (20 mg/kg) or vehicle control, we infected male and female K18-hACE2 mice with ancestral SARS-CoV-2 and assessed lung viral load, weight change, clinical scores, immune cell recruitment, and survival in the presence and absence of BP exposure. We found that BP-exposed mice had decreased survival compared to mock-exposed mice. Additionally, BP did not alter innate or adaptive immune cell populations in the lungs of SARS-CoV-2-infected mice. These findings suggest that PAH exposure exacerbates severe COVID-19 outcomes by unknown mechanisms, highlighting the need to further explore environmental impacts on SARS-CoV-2 infection. Full article

Background: Prior to the COVID-19 pandemic, the etiology of postural orthostatic tachycardia syndrome (POTS) remained elusive. Since the pandemic, a newly recognized disorder, termed Long COVID, has emerged with a significant subset of patients developing dysautonomia and a multitude of comorbidities consistent with POTS. Aim: The aim of this study was to determine if pre-pandemic POTS and Long COVID POTS share a common inflammatory-associated biomarker profile. Methods: Volunteers were recruited for four study groups; patients diagnosed with POTS prior to the pandemic, Long COVID-associated POTS, SARS-CoV-2-recovered controls, and naïve controls. All participants completed a COMPASS-31 survey and a medical history questionnaire. Plasma biomarkers of the innate and adaptive immune system were quantified using a custom multiplex bead assay and ELISAs. Results: Both POTS cohorts demonstrated indistinguishable and significant elevations in 14 of the 15 measured biomarkers including markers of the NLRP3 axis (Caspase-1p20, interleukins IL-1β, IL-18), regulatory cytokine IL-10, and immune activation markers (sCD40L, sCD40, sCD30) compared to controls. Multivariate PERMANOVA analysis revealed no significant difference in global cytokine profiles between the two POTS cohorts. Random Forest classification accurately distinguished POTS from controls, with IL-18 emerging as the most important feature. Conclusions: These associative findings suggest that pre-pandemic POTS and Long COVID-associated POTS share a distinct inflammatory profile among measured cytokines. The identification of IL-18 as a key biomarker, alongside Caspase-1p20 and other inflammatory cytokines, are compatible with inflammasome-related signaling. Further investigation is necessary to characterize the role of the inflammasome, platelet activation, and immune dysregulation in POTS and Long COVID. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen of coronavirus disease 2019 (COVID-19). Toll-like receptor 8 (TLR8), which is located on the X chromosome, plays as a key mediator of the innate immune response. Genetic variation in the form of single-nucleotide polymorphisms (SNPs) within TLR8 has been linked to changes in the transcriptional activity of this gene. Thus, we aimed to identify TLR8 SNPs in the proximal promoter region and investigate whether these SNPs are associated with COVID-19 case status in a Korean population. We performed amplicon sequencing to investigate the genotypes and allele frequencies of regulatory SNPs in COVID-19 patients (n = 191) and the control group (n = 173). Four polymorphic sites, rs5741883, rs186566524, rs3764879, and rs3764880, were identified within the TLR8 proximal promoter. Given the X-linked nature of this locus, allele and genotype frequencies were computed independently by sex. Notably, the minor C allele at rs3764879 occurred at a markedly reduced rate among male patients (10%) relative to male controls (24%), corresponding to an OR of 0.35 (95% CI 0.15–0.8; p = 0.018; q = 0.036). A parallel pattern emerged for rs3764880, where the minor A allele was likewise underrepresented in male patients (9%) versus male controls (24%), yielding an OR of 0.3 (95% CI 0.12–0.7; p = 0.01; q = 0.036). By contrast, neither genotype nor allele distributions differed significantly between female patients and female controls for any of the four variants. These results indicate that the TLR8 polymorphisms rs3764879 and rs3764880 may be associated with COVID-19 case status among Korean males, although further validation in larger, independent cohorts is required. Full article

Viral vaccine development requires both mechanistic understanding of protective immunity and translational study designs that connect preclinical data with human outcomes. Animal models remain important for early assessment of safety, immunogenicity and protective efficacy, but their predictive value depends on the question being asked, the pathophysiology of infection, the immune mechanisms expected to mediate protection, and the biomarkers chosen to bridge animal and human data. This review focuses on viral vaccines and examines innate and adaptive mechanisms of vaccine-induced protection, including B cell and antibody responses, Fc-mediated functions, Fc glycosylation, T cell memory and CD8+ cytotoxic responses. We discuss common reasons for clinical failure and show how preclinical endpoints can be classified as human-counterpart, surrogate or comparative/mechanistic readouts. Influenza and COVID-19 examples illustrate how different models can be combined across discovery, challenge, transmission and late-stage bridging studies. Emerging tools such as systems serology, omics, AI/ML and new approach methods can improve candidate prioritization, but their value depends on assay standardization, biological validation and cautious interpretation. A mechanism-driven model cascade, paired with human-relevant immunological readouts, can improve preclinical interpretation and reduce the risk of advancing candidates that are unlikely to succeed in clinical trials. Full article

The complement system is a key link between innate and adaptive immunity, contributing to pathogen elimination, immune regulation, and tissue homeostasis. Its activation is not only crucial in infections, such as COVID-19, but also plays a major role in the pathomechanism of several non-infectious respiratory diseases, such as asthma, COPD, sarcoidosis and lung cancer. Complement components can modulate the quality of the adaptive immune responses, including through the regulation of T2 immunity and eosinophilic inflammation, thereby linking natural defense to complex immune processes. In recent years, it has become increasingly clear that dysregulated complement activity contributes to inflammation, thrombosis and tissue damage in a wide range of respiratory diseases. The study of the various components of this cascade system may therefore be promising from both a diagnostic and therapeutic point of view. Some of its components may serve as biomarkers for distinguishing between different phenotypes of certain lung diseases, while their targeted inhibition or modulation may open the way towards new treatment options. A better understanding of the complement system’s integrative and regulatory role not only allows for a deeper insight into immunological interactions but may also bring us closer to phenotype-oriented, immunology-based pulmonology, which may have real clinical benefits in the future. Full article

Background/Objectives: The induction of anti-SARS-CoV-2 antibodies by COVID-19 vaccination reduces morbidity and mortality, but immune responses may be compromised in people living with HIV (PLWH). The aims of the current study were to determine whether viral suppression (VS) or immune reconstitution (IR) in PLWH directly affected their ability to produce effective levels of anti-SARS-CoV-2 antibodies in mucosal secretions or blood induced by vaccination. Methods: Anti-SARS-CoV-2 spike IgG, IgA and secretory IgA (SIgA) antibodies and their avidities were measured by ELISA in HIV-negative healthy controls (HC; n = 49) and PLWH (n = 94) using stimulated oral fluid (SOF) and serum. Frequencies of CD4/CD8 T cells and their expression of exhaustion/senescence were determined by flow cytometry. Cytokine levels were measured by cytokine bead arrays. Results: We showed that higher HIV burden negatively impacted the levels of systemic and mucosal anti-SARS-CoV-2 spike IgG antibodies produced. This differential IgG antibody production was unaffected by IR status, antiretroviral therapy duration or T cell exhaustion/senescence. PLWH elicited higher anti-SARS-CoV-2 spike IgA antibodies both in peripheral blood and oral mucosa and highr secretory IgA (SIgA) antibodies in the oral mucosa. PLWH with higher HIV RNA copies elicited lower IgG avidity but the IgA avidity indices remained unaffected. PLWH expressed higher levels of innate immunity cytokines in the oral mucosa, irrespective of the HIV RNA copies. Conclusions: Significantly fewer breakthrough infections in PLWH compared with HC, along with high IgA/SIgA antibodies and increased innate immunity cytokines in the SOF, suggest a potential role for mucosal immunity in the immunopathogenesis of COVID-19. Full article

This review aims to examine the immunological, anti-inflammatory, antiviral, and antibacterial activities of key whey and milk proteins, specifically lactoferrin, glycomacropeptide, β-lactoglobulin, α-lactalbumin and their derived peptides, particularly lactoferricin and lactoferrampin, highlighting their potential as preventive or therapeutic agents. Whey and dairy products represent complex biological matrices that, beyond their high nutritional value, serve as reservoirs of bioactive proteins and peptides with documented health-promoting properties. It has been reported that certain whey proteins (WPs) and whey-derived peptides may contribute to improvements in both innate and adaptive immunity, exert direct antiviral and antibacterial effects while also modulating host defenses through immunoregulatory, antioxidant, and anti-inflammatory activities. These mechanisms contribute not only to enhanced resistance against viral pathogens but also to maintaining intestinal homeostasis and microbiota balance, both of which are critical during infection. In recent years, particularly in the context of the COVID-19 pandemic, natural bioactive compounds derived from whey, and, more broadly, milk, have attracted increasing attention as potential adjuncts or alternatives to conventional antivirals, with reported activity not only against SARS-CoV-2, influenza but also other viral and microbial infections. Despite encouraging in vitro and in vivo evidence, clinical validation remains limited, and the antiviral and immunomodulatory effects of WPs still require deeper mechanistic clarification. Future research should focus on identifying molecular targets, as well as characterizing the pharmacokinetics and safety profiles of WPs and WP peptides across diverse clinical settings. At the same time, attention should be given to optimizing their application as nutraceuticals or functional dairy ingredients. Full article

Mucormycosis, triggered by fungi of the order Mucorales, represents a potentially fatal invasive mycosis, with death rates over 50% despite intensive therapy. The COVID-19 pandemic brought a sharp increase in cases, especially in individuals with diabetes mellitus and those undergoing immunosuppressive treatment, emphasizing significant gaps in our comprehension of disease pathogenesis. Emerging molecular studies have highlighted key virulence factors, such as the CotH family of invasins that facilitate endothelial invasion via interaction with glucose-regulated protein 78 (GRP78), complex iron acquisition systems necessary for fungal growth, and the release of mucoricin, a ricin-like toxin that impairs vascular integrity. Host defense depends mainly on innate immunity, with neutrophils and macrophages working as critical effector cells, while adaptive Th1 and Th17 responses aid in the fungal removal. Mucorales use a variety of immune evasion techniques, such as pathogen-associated molecular pattern (PAMP) masking via cell wall transformations, resistance to phagocytic death, and metabolic utilization of host factors including hyperglycemia and increased free iron in diabetic ketoacidosis (DKA). This review summarizes current evidence of the molecular processes underlying mucormycosis pathogenesis, underscoring host–pathogen interactions at the cellular and molecular levels, immune evasion tactics, and translational potential for new diagnostic and therapeutic approaches. Comprehending these molecular processes is crucial for creating efficient therapies against mucormycosis in an era of growing immunocompromised patients and expanding infectious disease synergies. Full article

Most infectious pathogens enter the host through mucosal surfaces, yet conventional injectable vaccines primarily induce systemic immunity without eliciting robust secretory immunoglobulin A (SIgA) responses at mucosal sites. The COVID-19 pandemic highlighted this limitation, as intramuscular mRNA vaccines failed to establish durable mucosal immunity in the upper respiratory tract. This review covers recent progress in mucosal vaccine development. We first discuss the organization of the mucosal immune system, focusing on SIgA induction, tissue-resident memory T (${\mathrm{T}}_{\mathrm{RM}}$) cells, and resident memory B (${\mathrm{B}}_{\mathrm{RM}}$) cells. We then examine mucosal adjuvants, from cholera toxin and heat-labile enterotoxin derivatives to stimulator of interferon gene (STING) agonists and a strategy to enhance alum adjuvanticity through neutrophil elastase inhibition. Delivery routes including intranasal, oral, and sublingual administration are reviewed alongside viral vectors, nanoparticles, mRNA-lipid nanoparticles, virus-like particles, and engineered bacterial platforms. The roles of innate immune cells, T helper cell subsets, and the microbiota in shaping vaccine responses are discussed. Finally, we survey licensed mucosal vaccines and the COVID-19 mucosal vaccine pipeline, analyze persistent barriers to clinical translation including the absence of validated mucosal correlates of protection, and outline future directions for thermostable formulations and systems biology-driven vaccine design. Full article

Empowered by nanotechnology, messenger RNA (mRNA) therapeutics have shown a rapid evolution post COVID-19 from a conceptual platform to a clinically validated modality, and they diversified into oncology, cardiovascular diseases, and rare disorders. As a template for in situ protein production, it offers several advantages over traditional proteins and DNA drugs. The intrinsic stability of mRNA and its sensitivity to innate immune sensing hinder its capacity for immediate cellular entry, necessitating its need for a delivery system to obtain optimal therapeutic potential. This review explores the innovations in nanocarrier engineering, design principles for lipid nanoparticles-mRNA (LNPs) platforms, and their clinical translation across the prominent indications. It also addresses their safety, immunogenicity, and scalability while addressing the key limitations and manufacturing scalability through comparative platform analysis. Although LNPs usually dominate their delivery through encapsulation and manufacturability, their limitations, like repeat dose reactogenicity and liver tropism, require next-generation designs like SORT lipids, stimuli-responsive hybrids for extrahepatic targeting. In oncology, LNP-mRNA drives the neoantigen vaccines, and rare diseases leverage the transient enzyme replacement. While the safety profiles highlight the innate immune tuning through nucleoside mods and lipid biodegradability, chronic administration risks are still persistent. While there are novel scalability options like microfluidic mixing to support the production gaps in organ selectivity and durability, their adoption is hindered. We outline the future directions to perceive mRNA’s full potential as a broader therapeutic class. Full article

Background/Objectives: SARS-CoV-2 is the causative agent of COVID-19, an infectious viral respiratory disease with human-to-human transmission. Current molecular understanding of how hosts respond to infection by respiratory viral pathogens in general and to SARS-CoV-2 in particular is still a research field under development. The activation levels of various host pathways are dependent on several variables, including the host tissue compartment. Methods: In this work, Illumina RNA sequencing was performed to assess the transcriptional host response to SARS-CoV-2 infection using COVID-19 PCR testing nasopharyngeal (NP) swab remnants from twenty infected and nine non-infected individuals. Results: Differential gene expression (DGE) analysis identified 182 overexpressed genes, with strong enrichment in innate immune and viral response genes. This included a significant induction of IFIH1/MDA5, a pattern recognition receptor (PRR) gene participating in the initial sensing of viral RNAs and subsequent cascade activation of interferon (IFN) and IFN-stimulated genes (ISGs). Interestingly, we observed different levels of concordance with previous similar studies and a significant induction of RIG1 and TLR3, two PRR genes encoding proteins that function to upregulate IFN and ISGs, but which are not normally identified as differentially expressed genes (DEGs). Finally, the overexpression of MX1, a well-characterized biomarker of viral infection; IFIT1, one of the top upregulated genes; and OAS1, OAS2 and OAS3, genes with a molecular function, 2-5-oligoadenylate synthase activity, identified as enriched in the DGE analyses, was confirmed by RT-qPCR. Conclusions: This study provides insights into upper respiratory tract responses to SARS-CoV-2 infections and identifies a set of differentially expressed genes (DEGs) with potential as candidates for further investigations as viral infection biomarkers. Full article

Human adenovirus (HAdV), a double-stranded DNA virus, targets terminally differentiated cells in the upper respiratory tract. As a key platform for gene therapy vectors, elucidating HAdV’s virulence factors is vital for optimizing therapeutic applications and mitigating risks. To achieve productive replication, HAdV strategically neutralizes host immune defenses and induces S-phase pathways essential for viral propagation. This review synthesizes the latest insights into the key pathways through which HAdVs harness these early proteins to enhance virulence, skilfully evading and counteracting host defense mechanisms while propelling viral replication. As foundational platforms for gene therapy vectors (e.g., in oncology and rare disease treatments) and vaccine backbones (e.g., COVID-19 vaccines like ChAdOx1), understanding HAdV’s immunoshadowing—the multifaceted strategies used to cloak innate and adaptive immunity—is crucial for enhancing vector safety and efficacy. Recent insights unveil how early viral proteins—including E1A, E1B-55K, E4orf1, E4orf3, E4orf6, and the E3 complex—participate in these processes. This review critically synthesizes these pathways, evaluating study limitations such as reliance on immortalized cell lines that underestimate the role of these proteins in immunological competent cells, and addresses unresolved controversies, including differential immunoshadowing efficacy across HAdV species that impacts vaccine design. Full article