Functional Response Research Articles

The aryl hydrocarbon receptor shapes monocyte transcriptional responses to interleukin-4 by prolonging STAT6 binding to promoters.

Cytokines induce functional and metabolic adaptations in immune cells, typically through transcriptional responses that can be influenced by other extracellular signals and by intracellular factors. The binding of the cytokine interleukin-4 (IL-4) to its receptor induces the phosphorylation and activation of the transcription factor STAT6. The aryl hydrocarbon receptor (AhR), a transcription factor activated by various endogenous and microbe-derived metabolites, modulates the responses of immune cells to danger signals or inflammatory mediators such as cytokines. Here, we investigated cross-talk between the AhR and signaling stimulated by IL-4 in human and mouse monocytes. AhR activation was required for a subset of IL-4-induced transcriptional responses and inhibited the IL-4-induced metabolic switch to fatty acid β-oxidation. The promoters of the genes that were induced by IL-4 in an AhR-dependent manner lacked canonical AhR binding sites, implying a nongenomic mechanism of AhR action. Mechanistically, AhR activation reduced the activity of SHP-1, a phosphatase that targets and inhibits STAT6, and prolonged STAT6 phosphorylation and binding to specific target loci, thus extending the duration of STAT6 activity. Our results identify AhR as a key player in the molecular control of responses to IL-4 in monocytes and suggest a nongenomic mechanism through which AhR ligands may influence the functional responses of cells to IL-4.

Global Dynamics and Integrability of a Leslie-Gower Predator–Prey Model with Linear Functional Response and Generalist Predator

We deal with a Leslie-Gower predator–prey model with a generalist or alternating food for predator and linear functional response. Using a topological equivalent polynomial system we prove that the system is not Liouvillian (hence also not Darboux) integrable. In order to study the global dynamics of this model, we use the Poincaré compactification of R2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\\mathbb {R}}^2$$\\end{document} to characterize all phase portraits in the Poincaré disc, obtaining two different topological phase portraits.

Effects of High-Temperature Stress on Biological Characteristics of Coccophagus japonicus Compere.

The parasitoid, Coccophagus japonicus Compere (Hymenoptera: Aphelinidae) is a dominant natural enemy of Parasaissetia nigra Nietner (Hemiptera: Coccidae), an important pest of rubber trees. Much of Chinese rubber is cultivated in hotter regions such as Yunnan and Hainan, exposing applied parasitoids to non-optimal temperatures. Therefore, C. japonicus must adapt to avoid temperature-related impacts on survival and population expansion. In this study, we monitored the survival rate, developmental duration, parasitism rate, and fecundity of C. japonicus during short-term exposures to 36 °C, 38 °C, and 40 °C for 2, 4, and 6 h, as well as continuous exposures to 32 °C and 34 °C for 3 days. The results show that short-term exposure to high-temperature stress leads to decreased survival rate of C. japonicus larvae and pupae, with survival rates declining as temperature and duration increase. High-temperature stress also delayed insect development, reduced mature egg production, shortened the body length of newly emerged females, and decreased female lifespans. Moreover, continuous high-temperature stress was found to significantly impact the development and reproduction of C. japonicus. Compared with the CK (27 °C), 3 d of continuous exposure to 34 °C prolonged developmental duration, shortened the body length and lifespan of newly emerged females, reduced survival rate and single female fecundity, and significantly decreased offspring numbers and parasitism rates. Temperatures of 36 °C, 38 °C, and 40 °C decreased the mortality time of adult females to 28.78, 16.04, and 7.91 h, respectively. Adverse temperatures also affected the insects' functional response, with 8 h of stress at 36 °C, 38 °C, and 40 °C causing the control efficiency of C. japonicus on P. nigra. This level of stress in the parasitoids was found to reduce the immediate attack rate and search effect, prolong processing time, and attenuate interference between small prey. Parasitoid efficiency was lowest following exposure to 40 °C. In this study, we determined the range of high temperatures that C. japonicus populations can tolerate under short- or long-term stress, providing guidance for future field applications.

Functional Response of Four Phytoseiid Mites to Eggs and First-Instar Larvae of Western Flower Thrips, Frankliniella occidentalis.

The predation capacity and functional responses of adult females of the phytoseiid mites Amblyseius largoensis (Muma), Proprioseiopsis lenis (Corpuz and Rimando), Paraphytoseius cracentis (Corpuz and Rimando), and Amblyseius swirskii (Athias-Henriot) were studied on eggs and first instars of the western flower thrips, Frankliniella occidentalis (Pergande), in the laboratory at 25 °C and 30 °C. At both temperatures, the functional response of all four phytoseiid mites was type II to first instars of the thrips. In contrast, when offered thrips eggs, the functional response was type III. At both temperatures tested, A. swirskii had the highest mean daily consumption of first-instar F. occidentalis, followed by A. largoensis, P. cracentis, and P. lenis. Amblyseius largoensis had the shortest handling time and the highest maximum attack rate when first-instar thrips were the prey. When fed on thrips eggs, A. largoensis had the highest mean daily consumption, followed by A. swirskii, P. cracentis, and P. lenis. On thrips eggs, A. swirskii showed the shortest handling time and highest maximum attack rate. Our findings indicate that all four phytoseiids had a better ability to prey on first-instar larvae of F. occidentalis compared to thrips eggs. At 25 and 30 °C, A. largoensis was the better predator on thrips larvae, whereas A. swirskii was superior in consuming eggs of F. occidentalis. Proprioseiopsis lenis was the inferior predator on both thrips larvae and eggs compared to the other phytoseiids tested.

The relationship between ON-OFF function and OCT structural and angiographic parameters in early diabetic retinal disease.

This study measured associations between ON and OFF functional indicators and structural optical coherence tomography (OCT) and OCT angiography (OCTA) markers in diabetic retinal disease. Fifty-four participants with type 1 or type 2 diabetes (mean age = 34.1 years; range 18-60) and 48 age-matched controls (mean age = 35.4 years, range 18-59) underwent visual psychophysical testing, OCT and OCTA retinal imaging. Psychophysical tasks measuring (A) contrast increment and decrement sensitivity and (B) response times to increment and decrement targets were assessed as surrogate measures of ON and OFF retinal ganglion cell function. The group with diabetes had worse foveal contrast increment and decrement thresholds (p = 0.04) and were slower to search for increment and decrement targets relative to controls (p = 0.009). Individuals with diabetes had a less circular foveal avascular zone (FAZ) (p < 0.001) but did not differ from controls in foveal vessel density and FAZ area. Functional and structural outcome measures related to the peripheral retina were also comparable between those with and without diabetes. Functional responses to increments and decrements were not significantly correlated with FAZ circularity or vessel density in individuals with diabetes. Diabetic retinal disease results in impaired performance on measures of inferred ON and OFF pathway function in addition to vascular deficits measurable with OCTA. Future longitudinal studies may determine the temporal relationship between these deficits, and whether they predict future diabetic retinopathy.

Comparing the ecological consequences of globally invasive fishes versus their F1 hybrids in recreational fisheries

Recreational angling is a major introduction pathway for non-native fish into freshwaters, where multiple non-native fishes are often released into waterbodies to diversify the angling opportunities. When these non-native fishes are taxonomically similar, then there is concern that their hybridisation will result in F1 generations comprising of novel phenotypes that outperform their parental species, resulting in the impacts of these ecological engineering species being accelerated. Across two water temperatures (18 °C, 26 °C), comparative functional response analyses (CFR) quantified the consumption patterns of the globally invasive freshwater fish common carp Cyprinus carpio and goldfish Carassius auratus, plus their F1 hybrids, before testing differences in their specific growth rates (SGRs). In CFRs, carp consumed significantly more prey at 18 °C than the other fishes, and with no differences between any of the fishes at 26 °C. SGRs also did not differ substantially between the fishes at either temperature. These results suggest that hybridisation between the high impacting parental species did not produce novel phenotypes of high ecological performance that could accelerate their ecological impacts in invaded ecosystems. Accordingly, the ecological risks of their use in recreational angling remain an issue that is primarily associated with the parent populations, and this can be reflected in their invasion management.

Teaching delay tolerance to a child with Smith‐Magenis syndrome in a classroom using a simplified approach

AbstractDelay tolerance training is used to teach children to accept delayed access to a requested item or event without exhibiting challenging behaviors. It is used during schedule thinning following acquisition of a functional communication response (FCR) or trained on its own in a skills‐based treatment package. Typically, delay tolerance training occurs in a clinic or hospital, and rarely in a school classroom. Most often delay tolerance training has been used with children with autism spectrum disorder (ASD). This study integrated findings from previous research on delay tolerance training to evaluate training in a classroom, with a child with Smith‐Magenis syndrome, using a simplified protocol. The training resulted in acquisition of delay tolerance for 5 min from a baseline of 32 s (average). The participant's teachers were then trained to use similar strategies throughout the school day and quickly acquired and applied the procedure with reported benefits.

Fetal Liver-like Organoids Recapitulate Blood-Liver Niche Development and Multipotent Hematopoiesis from Human Pluripotent Stem Cells.

The fetal liver is a hematopoietic organ, hosting a diverse and evolving progenitor population. While human liver organoids derived from pluripotent stem cells (PSCs) mimic aspects of embryonic and fetal development, they typically lack the complex hematopoietic niche and the interaction between hepatic and hematopoietic development. We describe the generation of human Fetal Liver-like Organoids (FLOs), that model human hepato-hematopoietic interactions previously characterized in mouse models. Developing FLOs first integrate a yolk sac-like hemogenic endothelium into hepatic endoderm and mesoderm specification. As the hepatic and hematopoietic lineages differentiate, the FLO culture model establishes an autonomous niche capable of driving subsequent progenitor differentiation without exogenous factors. Consistent with yolk sac-derived waves, hematopoietic progenitor cells (HPCs) within FLOs exhibit multipotency with a preference for myeloid lineage commitment, while retaining fetal B and T cell differentiation potential. We reconstruct in FLOs the embryonic monocyte-to-macrophage and granulocyte immune trajectories within the FLO microenvironment and assess their functional responses in the liver niche. In vivo, FLOs demonstrate a liver engraftment bias of hematopoietic cells, recapitulating a key phenomenon of human hematopoietic ontogeny. Our findings highlight the intrinsic capacity of liver organoids to support hematopoietic development, establishing FLOs as a platform for modeling and manipulating human blood-liver niche interactions during critical stages of development and disease.

Revealing the Response of Cucumber Soil Microbial Community Composition and Function to Nitrogen Addition in Northern Chinese Greenhouses

At present, the soil of Chinese greenhouses is experiencing severe nitrogen input in the form of fertilizer, which will cause damage to the soil environment and restrict crop growth in the long run. The response of potential functions of microorganisms as drivers of nutrient cycling and material transformation to nitrogen enrichment has rarely been reported in northern vegetable planting systems. Therefore, we set up four cucumber pot experiments with different nitrogen addition rates (0, 258, 516, and 1032 kg N ha−1 yr−1) in the greenhouse. Bacterial and fungal communities were detected by 16S and ITS rRNA gene sequencing, and bacterial and fungal functional groups were predicted using the FAPROTAX and FUNGuild databases. The findings showed that nitrogen addition induced soil acidification (a decrease of 0.25–1.63 units) significantly reduced microbial diversity and changed the community composition of bacteria and fungi. The relative abundance of bacterial functional groups associated with the nitrogen cycle increased significantly when medium and high levels of nitrogen were added. Conversely, the bacterial functional groups involved in the carbon cycle exhibited the opposite pattern. In this study, NO3− and soil pH were the main factors affecting the soil microbial community and its functional groups. Our results highlight that hydrocarbon degradation and saprophytic fungi may play key roles in yield formation during cucumber cultivation in northern solar greenhouses. In general, adopting a fertilization strategy that ensures low-medium nitrogen availability can contribute to the sustainable progress of facility agriculture.

Differential expression of components of the CGRP-receptor family in human coronary and human middle meningeal arteries: functional implications

BackgroundDifferent responses in human coronary arteries (HCA) and human middle meningeal arteries (HMMA) were observed for some of the novel CGRP receptor antagonists, the gepants, for inhibiting CGRP-induced relaxation. These differences could be explained by the presence of different receptor populations in the two vascular beds. Here, we aim to elucidate which receptors are involved in the relaxation to calcitonin gene-related peptide (CGRP), adrenomedullin (AM) and adrenomedullin 2 (AM2) in HCA and HMMA.MethodsRNA was isolated from homogenized human arteries (23 HCAs; 12 F, 11 M, age 50 ± 3 years and 26 HMMAs; 14 F, 12 M, age 51 ± 3 years) and qPCR was performed for different receptor subunits. Additionally, relaxation responses to CGRP, AM or AM2 of the human arteries were quantified using a Mulvany myograph system, in the presence or absence of the adrenomedullin 1 receptor antagonist AM22-52 and/or olcegepant.ResultsCalcitonin-like receptor (CLR) mRNA was expressed equally in both vascular beds, while calcitonin receptor (CTR) and receptor activity-modifying protein 3 (RAMP3) expression was low and could not be detected in all samples. RAMP1 expression was similar in HCA and HMMA, while RAMP2 expression was higher in HMMA. Moreover, receptor component protein (RCP) expression was higher in HMMA than in HCA. Functional experiments showed that olcegepant inhibits relaxation to all three agonists in both vascular beds. In HCA, antagonist AM22-52 did not inhibit relaxation to any of the agonists, while a trend for blocking relaxation to AM and AM2 could be observed in HMMA.ConclusionBased on the combined results from receptor subunit mRNA expression and the functional responses in both vascular tissues, relaxation of HCA is mainly mediated via the canonical CGRP receptor (CLR-RAMP1), while relaxation of HMMA can be mediated via both the canonical CGRP receptor and the adrenomedullin 1 receptor (CLR-RAMP2). Future research should investigate whether RAMP2 predominance over RAMP1 in the meningeal vasculature results in altered migraine susceptibility or in a different response to anti-migraine medication in these patients. Moreover, the exact role of RCP in CGRP receptor signalling should be elucidated in future research.

An innovative strategy harnessing self-activating CAR-NK cells to mitigate TGF-β1-driven immune suppression

The dysfunction of natural killer (NK) cells, mediated by transforming growth factor β1 (TGFβ1) within the tumor microenvironment, impedes antitumor therapy and contributes to poor clinical outcomes. Our study introduces self-activating chimeric antigen receptor (CAR)-NK cells that block TGFβ1 signaling by releasing a specifically designed peptide, P6, which targets mesothelin in pancreatic tumors. P6 originates from the interaction sites between TGFβ1 and TGFβ receptor 1 and effectively disrupts TGFβ1's inhibitory signaling in NK cells. Our analysis demonstrates that P6 treatment interrupts the SMAD2/3 pathway in NK cells, mitigating TGFβ1-mediated suppression of NK cell activity, thereby enhancing their metabolic function and cytotoxic response against pancreatic tumors. These CAR-NK cells exhibit potent antitumor capabilities, as evidenced in spheroid cultures with cancer-associated fibroblasts and in vivo mouse models. Our approach marks a substantial advancement in overcoming TGFβ1-mediated immune evasion, offering a promising avenue for revolutionizing cancer immunotherapy.

Seasonal influence on miRNA expression dynamics of extracellular vesicles in equine follicular fluid.

Ovarian follicular fluid (FF) is a dynamic environment that changes with the seasons, affecting follicle development, ovulation, and oocyte quality. Cells in the follicles release tiny particles called extracellular vesicles (EVs) containing vital regulatory molecules, such as microRNAs (miRNAs). These miRNAs are pivotal in facilitating communication within the follicles through diverse signaling and information transfer forms. EV-coupled miRNA signaling is implicated to be associated with ovarian function, follicle and oocyte growth and response to various environmental insults. Herein, we investigated how seasonal variations directly influence the ovulatory and anovulatory states of ovarian follicles and how are they associated with follicular fluid EV-coupled miRNA dynamics in horses. Ultrasonographic monitoring and follicular fluid aspiration of preovulatory follicles in horses during the anovulatory (spring: non-breeding) and ovulatory (spring, summer, and fall: breeding) seasons and subsequent EV isolation and miRNA profiling identified significant variation in EV-miRNA cargo content. We identified 97 miRNAs with differential expression among the groups and specific clusters of miRNAs involved in the spring transition (miR-149, -200b, -206, -221, -328, and -615) and peak breeding period (including miR-143, -192, -451, -302b, -100, and let-7c). Bioinformatic analyses showed enrichments in various biological functions, e.g., transcription factor activity, transcription and transcription regulation, nucleic acid binding, sequence-specific DNA binding, p53 signaling, and post-translational modifications. Cluster analyses revealed distinct sets of significantly up- and down-regulated miRNAs associated with spring anovulatory (Cluster 1) and summer ovulation-the peak breeding season (Clusters 4 and 6). The findings from the current study shed light on the dynamics of FF-EV-coupled miRNAs in relation to equine ovulatory and anovulatory seasons, and their roles in understanding the mechanisms involved in seasonal shifts and ovulation during the breeding season warrant further investigation.

Global dynamics of a prey–predator model with component Allee effect for predator reproduction and Crowley–Martin-type functional response: the role of strong Allee effect

Global dynamics of a prey–predator model with component Allee effect for predator reproduction and Crowley–Martin-type functional response: the role of strong Allee effect

Dynamic analysis of a modified fast-slow Leslie–Gower aquatic ecosystem with weak Allee effect and piecewise-smooth functional response

Dynamic analysis of a modified fast-slow Leslie–Gower aquatic ecosystem with weak Allee effect and piecewise-smooth functional response

Decoupled fungal and bacterial functional responses to biochar amendment drive rhizosphere priming effect on soil organic carbon mineralization

The application of biochar to soil is widely recognized as a promising strategy for enhancing the accumulation and stability of soil organic carbon (SOC), which is crucial in mitigating climate change. However, the influence of interactions between plants and biochar on soil microbial communities and their involvement in SOC mineralization and stability remains unclear. This understanding is essential for optimizing carbon (C) sequestration in systems involving plants, soil, and biochar. In this study, employing a 13C natural abundance approach, we investigated the effect of biochar on the maize rhizosphere priming effect (RPE) in paddy soil. We also examined alterations in microbial communities and functional genes related to C degradation and fixation. Over the 99 days of maize growth, biochar application increased RPE and total SOC while decreasing dissolved organic C. It also elevated soil pH, resulting in shifts in fungal and bacterial community structure, favoring oligotrophic species. Fungal and bacterial assemblies were dominated by deterministic and stochastic processes, respectively. While the abundance of fungal guilds varied irregularly, bacterial guilds were uniformly enriched under biochar-plant interactions. Functional traits such as ecoenzymatic activities, bacterial guilds, and functional genes predominantly affected RPE under biochar application. Bacterial functional genes associated with C degradation and fixation were concurrently enhanced with biochar application. Our results indicate that interactions between plants and biochar can enhance native SOC mineralization and accumulation in a short timeframe by modulating functional traits of soil microorganisms, particularly the bacterial community involved in C degradation and fixation.Graphical

Zero‐Hopf bifurcation in a family of tritrophic food chain model with Holling III–III functional response

Zero‐Hopf bifurcation in a family of tritrophic food chain model with Holling III–III functional response

Deciphering Peripheral Taste Neuron Diversity: Using Genetic Identity to Bridge Taste Bud Innervation Patterns and Functional Responses.

Peripheral taste neurons exhibit functional, genetic, and morphological diversity, yet understanding how or if these attributes combine into taste neuron types remains unclear. In this study, we used male and female mice to relate taste bud innervation patterns to the function of a subset of proenkephalin-expressing (Penk+) taste neurons. We found that taste arbors (the portion of the axon within the taste bud) stemming from Penk+ neurons displayed diverse branching patterns and lacked stereotypical endings. The range in complexity observed for individual taste arbors from Penk+ neurons mirrored the entire population, suggesting that taste arbor morphologies are not primarily regulated by neuron type. Notably, the distinguishing feature of arbors from Penk+ neurons was their propensity to come within 110 nm (in apposition with) different types of taste-transducing cells within the taste bud. This finding is contrary to the expectation of genetically defined taste neuron types that functionally represent a single stimulus. Consistently, further investigation of Penk+ neuron function revealed that they are more likely to respond to innately aversive stimuli -sour, bitter and high salt concentrations - as compared to the full taste population. Penk+ neurons are less likely to respond to non-aversive stimuli -sucrose, umami, and low salt- compared to the full population. Our data support the presence of a genetically defined neuron type in the geniculate ganglion that is responsive to innately aversive stimuli. This implies that genetic expression might categorize peripheral taste neurons into hedonic groups, rather than simply identifying neurons that respond to a single stimulus.Significance Statement Peripheral taste neuron coding has been heavily debated. Our study delves into this issue by leveraging genetic expression in a specific neuron subset to relate peripheral innervation patterns to functional taste responses. We examined a taste neuron type that appears to be in apposition with multiple taste-transducing cell types and responds to innately aversive concentrations of sour, bitter, and high NaCl stimuli. These collective observations suggest that genetic markers can delineate groups of neurons sharing similar hedonic responses rather than categorizing neurons solely based on individual taste qualities.

Functional plasticity shapes neutrophil response to Leishmania major infection in susceptible and resistant strains of mice.

Neutrophils rapidly infiltrate sites of infection and possess several microbicidal strategies, such as neutrophil extracellular traps release and phagocytosis. Enhanced neutrophil infiltration is associated with higher susceptibility to Leishmania infection, but neutrophil effector response contribution to this phenotype is uncertain. Here, we show that neutrophils from susceptible BALB/c mice (B/c) produce more NETs in response to Leishmania major than those from resistant C57BL/6 mice (B6), which are more phagocytic. The absence of neutrophil elastase contributes to phagocytosis regulation. Microarray analysis shows enrichment of genes involved in NET formation (mpo, pi3kcg, il1b) in B/c, while B6 shows upregulation of genes involved in phagocytosis and cell death (Arhgap12, casp9, mlkl, FasL). scRNA-seq in L. major-infected B6 showed heterogeneity in the pool of intralesional neutrophils, and we identified the N1 subset as the putative subpopulation involved with phagocytosis. In vivo, imaging validates NET formation in infected B/c ears where NETing neutrophils were mainly uninfected cells. NET digestion in vivo augmented parasite lymphatic drainage. Hence, a balance between NET formation and phagocytosis in neutrophils may contribute to the divergent phenotype observed in these mice.

Effects of normal saline versus lactated Ringer’s solution on organ function and inflammatory responses to heatstroke in rats

BackgroundHeatstroke is a life-threatening condition characterized by severe hyperthermia and multiple organ dysfunction. Both normal saline (NS) and lactated Ringer’s solution (LR) are commonly used for cooling and volume resuscitation in heatstroke patients; however, their specific impacts on patient outcomes during heatstroke management are poorly understood. Given that the systemic inflammatory response and multiple-organ damage caused by heat toxicity are the main pathophysiological features of heatstroke, the aim of this study was to evaluate the effects of NS and LR on the production of inflammatory cytokines and the functional and structural integrity of renal and cardiac tissues in a rat model of heatstroke.MethodsFifty-five male Sprague‒Dawley rats were randomly divided into four groups: cold NS or LR infusion postheatstroke (4 ℃, 4 ml/100 g, over 10 min) and NS or LR infusion without heatstroke induction (control groups). Vital signs, arterial blood gases, inflammatory cytokines, and renal and cardiac function indicators, such as serum creatinine and cTnI, were monitored after treatment. Tissue samples were analysed via HE staining, electron microscopy, and fluorescence staining for apoptosis markers, and protein lysates were used for Western blotting of pyroptosis-related proteins.ResultsCompared with LR-treated heatstroke rats, NS-treated heatstroke rats presented lower mean arterial pressures, worsened metabolic acidosis, and higher levels of IL-6 and TNF-α in both the serum and tissue. These rats also presented increased serum creatinine, troponin, catecholamines, and NGAL and reduced renal clearance. Histological and ultrastructural analyses revealed more severe tissue damage in NS-treated rats, with increased apoptosis and increased expression of NLRP3/caspase-1/GSDMD signalling molecules. Similar differences were not observed between the control groups receiving either NS or LR infusion. One NS-treated heatstroke rat died within 24 h, whereas all the LR-treated and control rats survived.ConclusionsNS resuscitation in heat-exposed rats significantly promotes metabolic acidosis and the inflammatory response, leading to greater functional and structural organ damage than does LR. These findings underscore the necessity of selecting appropriate resuscitation fluids for heatstroke management to minimize organ damage and improve outcomes.

Preclinical immunogenicity and safety of hemagglutinin-encoding modRNA influenza vaccines

Seasonal epidemics of influenza viruses are responsible for a significant global public health burden. Vaccination remains the most effective way to prevent infection; however, due to the persistence of antigenic drift, vaccines must be updated annually. The selection of vaccine strains occurs months in advance of the influenza season to allow adequate time for production in eggs. RNA vaccines offer the potential to accelerate production and improve efficacy of influenza vaccines. We leveraged the nucleoside-modified RNA (modRNA) platform technology and lipid nanoparticle formulation process of the COVID-19 mRNA vaccine (BNT162b2; Comirnaty®) to create modRNA vaccines encoding hemagglutinin (HA) (modRNA-HA) for seasonal human influenza strains and evaluated their preclinical immunogenicity and toxicity. In mice, a monovalent modRNA vaccine encoding an H1 HA demonstrated robust antibody responses, HA-specific Th1-type CD4+ T cell responses, and HA-specific CD8+ T cell responses. In rhesus and cynomolgus macaques, the vaccine exhibited durable functional antibody responses and HA-specific IFN-γ+ CD4+ T cell responses. Immunization of mice with monovalent, trivalent, and quadrivalent modRNA-HA vaccines generated functional antibody responses targeting the seasonal influenza virus(es) encoded in the vaccines that were greater than, or similar to, those of a licensed quadrivalent influenza vaccine. Monovalent and quadrivalent modRNA-HA vaccines were well-tolerated by Wistar Han rats, with no evidence of systemic toxicity. These nonclinical immunogenicity and safety data support further evaluation of the modRNA-HA vaccines in clinical studies.