Nature Of Immune Response Research Articles

SARS-CoV-2 spike protein diversity at an intra-host level, among SARS-CoV-2 infected individuals in South Africa, 2020 to 2022.

Intra-host diversity studies are used to characterise the mutational heterogeneity of SARS-CoV-2 infections in order to understand the impact of virus-host adaptations. This study investigated the frequency and diversity of the spike (S) protein mutations within SARS-CoV-2 infected South African individuals. The study included SARS-CoV-2 respiratory samples, from individuals of all ages, received at the National Health Laboratory Service at Charlotte Maxeke Johannesburg Academic hospital, Gauteng, South Africa, from June 2020 to May 2022. Single nucleotide polymorphism (SNP) assays and whole genome sequencing were performed on a random selection of SARS-CoV-2 positive samples. The allele frequency (AF) was determined using TaqMan Genotyper software for SNP PCR analysis and galaxy.eu for analysis of FASTQ reads from sequencing. The SNP assays identified 5.3% (50/948) of Delta cases with heterogeneity at delY144 (4%; 2/50), E484Q (6%; 3/50), N501Y (2%; 1/50) and P681H (88%; 44/50), however only heterogeneity for E484Q and delY144 were confirmed by sequencing. From sequencing we identified 9% (210/2381) of cases with Beta, Delta, Omicron BA.1, BA.2.15, and BA.4 lineages that had heterogeneity in the S protein. Heterogeneity was primarily identified at positions 19 (1.4%) with T19IR (AF 0.2-0.7), 371 (92.3%) with S371FP (AF 0.1-1.0), and 484 (1.9%) with E484AK (0.2-0.7), E484AQ (AF 0.4-0.5) and E484KQ (AF 0.1-0.4). Mutations at heterozygous amino acid positions 19, 371 and 484 are known antibody escape mutations, however the impact of the combination of multiple substitutions identified at the same position is unknown. Therefore, we hypothesise that intra-host SARS-CoV-2 quasispecies with heterogeneity in the S protein facilitate competitive advantage of variants that can completely/partially evade host's natural and vaccine-induced immune responses.

A scientific perspective of how and why Omicron is less severe than SARS-CoV-2

Abstract Omicron is currently the dominant variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the coronavirus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Omicron is associated with mild symptoms, although it can cause harmful effects in high-risk patient populations. Omicron and COVID-19 affect multiple organ systems, including the respiratory system, gastrointestinal tract, cardiovascular system, central nervous system, ophthalmic system, genitourinary tract, and musculoskeletal system. COVID-19 infects additional organ systems, including the hematological system, hepatobiliary system, renal system, and dermatologic system. The viral-induced complications were compared to discuss the effects of Omicron versus the authentic SARS-CoV-2 virus, revealing less detrimental outcomes for Omicron. Moreover, COVID-19 is more likely to infect older adults, males, and obesity with mild to severe symptoms. Omicron causes mild symptoms in younger populations and overweight females. Data were acquired using PubMed, Centers for Disease Prevention and Control, and the World Health Organization. COVID-19 and Omicron mechanisms causing organ system-related complications are likely because of the natural immune response to the active infection, the uncontrollable release of cytokines causing cytokine release syndrome, and direct viral damage through angiotensin-converting enzyme 2/transmembrane serine protease 2 receptor binding and entrance to the host cell for infection.

Anti-bacterial activity of Cymbopogon citratus nanoparticles against Vibrio species infecting aquatic organisms

The presence of Vibrio parahaemolyticus, Vibrio alginolyticus, and Vibrio harveyi in aquatic organisms causes vibriosis, leading to their significant mortality. The efficacy of antibiotic treatment is reduced due to increasing antibiotic resistance. As a result, novel therapeutic agents are increasingly needed to treat outbreak of such diseases in aquatic organisms and humans. This study focuses on utilizing the bioactive compounds of Cymbopogon citratus as they are rich in a variety of secondary metabolites which promotes growth, natural immune response and disease resistance against pathogenic bacteria in various ecosystems. In silico studies were performed to evaluate the binding potential of the bioactive compounds against targeted protein beta – lactamase in Vibrio parahaemolyticus and metallo – beta – lactamase in V. alginolyticus via molecular docking. Cymbopogon citratus nanoparticles (CcNps) were synthesized, characterized and toxicity studies were performed by using Vigna radiata, and Artemia nauplii at different concentrations of Cymbopogon citratus nanoparticles. The results revealed that the synthesized nanoparticles were non-ecotoxic and act as potential growth promoters in plants. The antibacterial activity of synthesized Cymbopogon citratus was evaluated using agar well diffusion method. MIC, MBC, and biofilm assays performed by using different concentrations of synthesized nanoparticles. Thus, it was proved that Cymbopogon citratus nanoparticles showed better antibacterial activity against Vibrio species.

A mathematical model and simulation scenarios for T and B cells immune response to severe acute respiratory syndrome-coronavirus-2

Severe acute respiratory syndrome coronavirus is a type 2 highly contagious, and transmissible among humans; the natural human immune response to severe acute respiratory syndrome-coronavirus-2 combines cell-mediated immunity (lymphocyte) and antibody production. In the present study, we analyzed the dynamic effects of adaptive immune system cell activation in the human host. The methodology consisted of modeling using a system of ordinary differential equations; for this model, the equilibrium free of viral infection was obtained, and its local stability was determined. Analysis of the model revealed that lymphocyte activation leads to total pathogen elimination by specific recognition of viral antigens; the model dynamics are driven by the interaction between respiratory epithelial cells, viral infection, and activation of helper T, cytotoxic T, and B lymphocytes. Numerical simulations showed that the model solutions match the dynamics involved in the role of lymphocytes in preventing new infections and stopping the viral spread; these results reinforce the understanding of the cellular immune mechanisms and processes of the organism against severe acute respiratory syndrome-coronavirus-2 infection, allowing the understanding of biophysical processes that occur in living systems, dealing with the exchange of information at the cellular level.

Clinical value of Toll-like receptor 2 protein expression in natural immune response of human traumatic pulp tissue.

Clinical value of Toll-like receptor 2 protein expression in natural immune response of human traumatic pulp tissue.

Prior infection exposure alters the immune response at homeostasis and following SARS-CoV-2 vaccination and experimental infection in laboratory mice.

Abstract Variable translatability represents a major criticism of the use of mouse models for preclinical research. Lack of exposure to most endogenous murine pathogens results in natural immune responses of specific pathogen free (SPF) lab mice to more closely resemble that of newborns rather than adult humans. Recently, the effects of prior infection exposure (PIE) on immune maturation and responses have been increasingly explored in mice. Here, we employed a PIE model where BALB/c mice underwent sequential subclinical infection with four pathogens at two-week intervals: 1) MHV-68, a gammaherpesvirus, 2) MCMV, a betaherpesvirus, 3) influenza virus, and 4) Heligmosomoides polygyrus, a murine intestinal nematode. Four-to-12 weeks following H. polygyrus infection, mice were sacrificed, spleens were collected for flow cytometric analysis, and lungs were collected for histological evaluation. Compared to SPF mice, PIE spleens demonstrated increased proportions of CD4+ and CD8+ T effector memory cells. In the lungs, PIE induced the formation of bronchus-associated lymphoid tissue and increased infiltration of CD4+ and CD8+ T cells. Following vaccination against SARS-CoV-2 with either a protein subunit-based (S2P) or inactivated (iCoV2) vaccine, iCoV2-, but not S2P-, vaccinated PIE mice demonstrated significantly reduced serum neutralizing antibodies compared to SPF mice. Following infection with SARS-CoV-2-MA10, PIE mice showed a mild reduction in mortality, weight loss, and lung titers, and a significant increase in lung T cell infiltration compared to SPF mice. These data indicate that PIE results in adaptive immune maturation but has a variable effect on SARS-CoV-2-specific vaccine responses and clinical outcomes in mice. This work was supported by the NIH (K01OD026529, T32AI007151, U19AI100625, U19AI09680), an AAI Careers in Immunology Fellowship Award, an UNC School of Medicine Junior Investigator Development Award, and a NCTraCS and Emerging Challenges in Biomedical Research COVID Pilot Award.

Tyrosine kinase inhibitor cabozantinib impacts dendritic and natural killer cells immune response in C38 syngeneic tumor model.

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Durability of neutralizing RSV antibodies following nirsevimab administration and elicitation of the natural immune response to RSV infection in infants

Nirsevimab is an extended half-life monoclonal antibody specific for the prefusion conformation of the respiratory syncytial virus (RSV) F protein, which has been studied in preterm and full-term infants in the phase 2b and phase 3 MELODY trials. We analyzed serum samples collected from 2,143 infants during these studies to characterize baseline levels of RSV-specific immunoglobulin G antibodies and neutralizing antibodies (NAbs), duration of RSV NAb levels following nirsevimab administration, the risk of RSV exposure during the first year of life and the infant’s adaptive immune response to RSV following nirsevimab administration. Baseline RSV antibody levels varied widely; consistent with reports that maternal antibodies are transferred late in the third trimester, preterm infants had lower baseline RSV antibody levels than full-term infants. Nirsevimab recipients had RSV NAb levels >140-fold higher than baseline at day 31 and remained >50-fold higher at day 151 and >7-fold higher at day 361. Similar seroresponse rates to the postfusion form of RSV F protein in nirsevimab recipients (68–69%) compared with placebo recipients (63–70%; not statistically significant) suggest that while nirsevimab protects from RSV disease, it still allows an active immune response. In summary, nirsevimab provided sustained, high levels of NAb throughout an infant’s first RSV season and prevented RSV disease while allowing the development of an immune response to RSV.

Syngeneic mouse model of human HER2+ metastatic breast cancer for the evaluation of trastuzumab emtansine combined with oncolytic rhabdovirus.

Established mouse models of HER2+ cancer are based on the over-expression of rodent Neu/Erbb2 homologues, which are incompatible with human HER2 (huHER2) targeted therapeutics. Additionally, the use of immune-deficient xenograft or transgenic models precludes assessment of native anti-tumour immune responses. These hurdles have been a challenge for our understanding of the immune mechanisms behind huHER2-targeting immunotherapies. To assess the immune impacts of our huHER2-targeted combination strategy, we generated a syngeneic mouse model of huHER2+ breast cancer, using a truncated form of huHER2, HER2T. Following validation of this model, we next treated tumour-bearing with our immunotherapy strategy: oncolytic vesicular stomatitis virus (VSVΔ51) with clinically approved antibody-drug conjugate targeting huHER2, trastuzumab emtansine (T-DM1). We assessed efficacy through tumour control, survival, and immune analyses. The generated truncated HER2T construct was non-immunogenic in wildtype BALB/c mice upon expression in murine mammary carcinoma 4T1.2 cells. Treatment of 4T1.2-HER2T tumours with VSVΔ51+T-DM1 yielded robust curative efficacy compared to controls, and broad immunologic memory. Interrogation of anti-tumour immunity revealed tumour infiltration by CD4+ T cells, and activation of B, NK, and dendritic cell responses, as well as tumour-reactive serum IgG. The 4T1.2-HER2T model was used to evaluate the anti-tumour immune responses following our complex pharmacoviral treatment strategy. These data demonstrate utility of the syngeneic HER2T model for assessment of huHER2-targeted therapies in an immune-competent in vivo setting. We further demonstrated that HER2T can be implemented in multiple other syngeneic tumour models, including but not limited to colorectal and ovarian models. These data also suggest that the HER2T platform may be used to assess a range of surface-HER2T targeting approaches, such as CAR-T, T-cell engagers, antibodies, or even retargeted oncolytic viruses.

Abstract 1806: Modulation of natural killer cell immune response to tumor with novel synthetic tumor -immune cell agonist, NK-TICA(r)

Abstract The tumor specific activation of natural killer (NK) cells with Bicycles is an area of active investigation in immune oncology. NK cells are highly responsive immune cells that can detect and eliminate tumor cells and bridge innate to adaptive immune responses. Bicycles are small (ca.1.5kDa), chemically synthetic, structurally constrained peptides discovered via phage display and optimized using structure-driven design and medicinal chemistry approaches. We have applied the Bicycle platform technology to discover and evaluate a new class of fully synthetic molecules termed NK tumor immune cell agonists (NK-TICA®). The NK-TICA® consists of chemically coupled Bicycles® that bind specifically to the key activating receptor, NKp46, and to tumor antigens, that results in highly potent, antigen-dependent receptor activation and NK cell activation. We demonstrate potent, selective binding of our Bicycles to receptor-expressing cells and the capability of the bifunctional molecule to induce NK cell function in vitro. With Bicycle’s novel NK-TICA® compound, we demonstrate the engagement of NK cells, the specific activation and function of NK cells, and enhanced tumor cytotoxicity in a tumor target- and dose-dependent manner. In conclusion, NK-TICAs drive NK cell-mediated tumor cell killing and cytokine production in vitro and as such have the potential to catalyze the development of durable anti-tumor immunity in tumor types not well served by current therapies. We hypothesize that utilization of Bicycle NK-TICA® as a multifunctional immune cell engager will promote the modulation of NK cells, as well as the infiltration and anti-tumor activity of NK cells in solid tumors. Citation Format: Fay Dufort, Christopher J. Leitheiser, Kathleen Ho, Tucker Ezell, Alexandra Rezvaya, Peter Brown, Liuhong Chen, Philip Brandish, Kevin McDonnell, Michael Skynner, Nicholas Keen. Modulation of natural killer cell immune response to tumor with novel synthetic tumor -immune cell agonist, NK-TICA(r) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1806.

Abstract 4166: Effects of cyproheptadine in eliciting natural killer cell-mediated immune response in bladder cancer

Abstract Bladder cancer is one of the most common occurring cancers in urothelial carcinoma. The previous study suggested that cancer cells undergo immunoevasion due to epigenetic silencing of NKG2DL, in which NKG2D-NKG2DL interaction induced natural killer (NK) cell-mediated cytotoxicity. We hypothesized that NK-mediated cytotoxicity can be reactivated by restoring the expression of NKG2DL on tumor cells. Our previous studies demonstrated that cyproheptadine (CPH) is a novel HDAC inhibitor exhibiting antitumor activity by cell cycle arrest and apoptosis. To understand the mechanism behind, RNA-seq showed an upregulation of ULBP2, a NKG2DL, in bladder cancer cells treated with CPH. Interestingly, upregulation of ULBP2, was accompanied with the enrichment of H3K27Ac and H3K4me3 at ULBP2 promoter, was observed in cells treated with CPH. Increased NK-specific lysis was observed in CPH-treated cells co-cultured with NK-92 cells. More importantly, treatment of CPH enhanced the efficacy of immune checkpoint inhibitor in a syngeneic mice bladder cancer model. In conclusion, our results suggested that CPH may be a novel HDAC inhibitor which may elicit immune response in NK-cell dependent manner. Citation Format: Himani Kumari, Guan-Ling Lin, Chih-Chieh Yeh, Ciao-Ni Chen, Yu-Ming Chuang, Wan-Hong Huang, Wen-Long Huang, Steven Lin, Michael W. Chan. Effects of cyproheptadine in eliciting natural killer cell-mediated immune response in bladder cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4166.

Abstract 693: A novel multi-subset dendritic cell vaccine derived from hematopoietic progenitor cells

Abstract Owing to their molecular features, tissue localization and antigen processing and presentation capacity, dendritic cells (DCs) induce and regulate T cell immunity including licensing T cells to kill target cells. However, tumors often suppress DC differentiation and function leaving cancer patients with DC populations that are quantitatively and qualitatively deficient. This limits both the native immune responses to tumors as well as response to cancer therapy including immunotherapy. Thus, provision of healthy and functionally intact DCs to replace and correct the in vivo function offers an interesting therapeutic opportunity. DCs are composed of multiple subsets which specialize in activation of different immune effectors. Thus, a combination of DC subsets could generate a broad and diverse immunity targeted at cancer. To date, several attempts have been made to generate functional human DCs ex vivo for injection to patients, but the DC subtypes most effective in generation of anti-tumor responses—cDC1 and cDC2s—have proven difficult to make ex vivo using clinically compliant protocols. Here we show that cDC1s and cDC2s can be generated at high yield from hematopoietic progenitor cells (HPCs) from three different HPCs sources (including adult bone marrow) using clinically compliant protocols. We characterize the phenotype and functionality of these cells showing that both cDC1s and cDC2s efficiently process antigens, stimulate, and expand T cells specific for those antigens, and that those T cell populations display targeted killing of tumor cells in vitro. The ability to produce these subtypes using clinically compliant protocols is a major step towards developing effective autologous DC therapy for cancer patients. Citation Format: Chun Yu, Richard L. Barrett, Ananya Zutshi, Karolina Palucka. A novel multi-subset dendritic cell vaccine derived from hematopoietic progenitor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 693.

Potent NTD-Targeting Neutralizing Antibodies against SARS-CoV-2 Selected from a Synthetic Immune System.

The majority of neutralizing antibodies (NAbs) against SARS-CoV-2 recognize the receptor-binding domain (RBD) of the spike (S) protein. As an escaping strategy, the RBD of the virus is highly variable, evolving mutations to thwart a natural immune response or vaccination. Targeting non-RBD regions of the S protein thus provides a viable alternative to generating potential, robust NAbs. Using a pre-pandemic combinatorial antibody library of 1011, through an alternate negative and positive screening strategy, 11 non-RBD-targeting antibodies are identified. Amongst one NAb that binds specifically to the N-terminal domain of the S protein, SA3, shows mutually non-exclusive binding of the angiotensin-converting enzyme 2 receptor with the S protein. SA3 appears to be insensitive to the conformational change and to interact with both the "open" and "closed" configurations of the trimeric S protein. SA3 shows compatible neutralization as S-E6, an RBD-targeting NAb, against the wild type and variant of concern (VOC) B.1.351 (Beta) of the SARS-CoV-2 pseudo virus. More importantly, the combination of SA3 with S-E6 is synergistic and recovers from the 10-fold loss in neutralization efficacy against the VOC B.1.351 pseudo virus.

Dietary 1,3-β-Glucans Affect Growth, Breast Muscle Composition, Antioxidant Activity, Inflammatory Response, and Economic Efficiency in Broiler Chickens.

Recently, researchers have been intensively looking for novel, safe antibiotic alternatives because of the prevalence of many clinical and subclinical diseases affecting bird flocks and the risks of using antibiotics in subtherapeutic doses as feed additives. The present study intended to evaluate the potential use of 1,3-β-glucans (GLC) as antibiotic alternative growth promotors and assessed the effect of their dietary inclusion on the growth performance, carcass traits, chemical composition of breast muscles, economic efficiency, blood biochemical parameters, liver histopathology, antioxidant activity, and the proinflammatory response of broiler chickens. This study used 200 three-day-old ROSS broiler chickens (50 chicks/group, 10 chicks/replicate, with an average body weight of 98.71 ± 0.17 g/chick). They were assigned to four experimental groups with four dietary levels of GLC, namely 0, 50, 100, and 150 mg kg-1, for a 35-day feeding period. Birds fed diets containing GLC showed an identical different growth rate to the control group. However, the total feed intake (TFI) increased quadratically in the GLC50 and GLC100 groups as compared to that in the control group. GLC addition had no significant effect on the weights of internal and immune organs, except for a decrease in bursal weight in the GLC150 group (p = 0.01). Dietary GLC addition increased the feed cost and total cost at 50 and 100 mg kg-1 doses. The percentages of n-3 and n-6 PUFA in the breast muscle of broiler chickens fed GLC-supplemented diets increased linearly in a dose-dependent manner (p < 0.01). The serum alanine aminotransferase (ALT) level and the uric acid level were quadratically increased in the GLC150 group. The serum levels of total antioxidant capacity, catalase, superoxide dismutase, interleukin-1β, and interferon-gamma linearly increased, while the MDA level decreased in the GLC-fed groups in a dose-dependent manner. Normal histological characterization of different liver structures in the different groups with moderate round cells was noted as a natural immune response around the hepatic portal area. The different experimental groups showed an average percentage of positive immunostaining to the proinflammatory marker transforming growth factor-beta with an increase in the dose of GLC addition. The results suggest that GLC up to 100 mg kg-1 concentration can be used as a feed additive in the diets of broiler chickens and shows no adverse effects on their growth, dressing percentage, and internal organs. GLC addition in diets improves the antioxidant activity and immune response in birds. GLC help enrich the breast muscle with n-3 and n-6 polyunsaturated fatty acids.

PPARβ/δ Ligands Regulate Oxidative Status and Inflammatory Response in Inflamed Corpus Luteum-An In Vitro Study.

Inflammation in the female reproductive system causes serious health problems including infertility. The aim of this study was to determine the in vitro effects of peroxisome proliferator-activated receptor-beta/delta (PPARβ/δ) ligands on the transcriptomic profile of the lipopolysaccharide (LPS)-stimulated pig corpus luteum (CL) in the mid-luteal phase of the estrous cycle using RNA-seq technology. The CL slices were incubated in the presence of LPS or in combination with LPS and the PPARβ/δ agonist-GW0724 (1 μmol/L or 10 μmol/L) or the antagonist-GSK3787 (25 μmol/L). We identified 117 differentially expressed genes after treatment with LPS; 102 and 97 differentially expressed genes after treatment, respectively, with the PPARβ/δ agonist at a concentration of 1 μmol/L or 10 μmol/L, as well as 88 after the treatment with the PPARβ/δ antagonist. In addition, biochemical analyses of oxidative status were performed (total antioxidant capacity and activity of peroxidase, catalase, superoxide dismutase, and glutathione S-transferase). This study revealed that PPARβ/δ agonists regulate genes involved in the inflammatory response in a dose-dependent manner. The results indicate that the lower dose of GW0724 showed an anti-inflammatory character, while the higher dose seems to be pro-inflammatory. We propose that GW0724 should be considered for further research to alleviate chronic inflammation (at the lower dose) or to support the natural immune response against pathogens (at the higher dose) in the inflamed corpus luteum.

N6-methyladenine regulator-mediated RNA methylation modification patterns in immune microenvironment regulation of osteoarthritis.

Background: Osteoarthritis is a common chronic degenerative disease, and recently, an increasing number of studies have shown that immunity plays an important role in the progression of osteoarthritis, which is exacerbated by local inflammation. The role of N6-methyladenine (m6A) modification in immunity is being explored. However, the role of m6A modification in regulating the immune microenvironment of osteoarthritis remains unknown. In this study, we sought to discuss the association between the N6-methyladenine (m6A) modification and the immune microenvironment of osteoarthritis. Methods: First, the data and gene expression profiles of 139 samples, including 33 healthy samples and 106 osteoarthritis samples, were obtained from the Genetics osteoARthritis and Progression (GARP) study. Then the differences in m6A regulators between healthy individuals and osteoarthritis patients were analyzed. The correlation between m6A regulators and immune characteristics was also investigated by single-sample gene set enrichment analysis (ssGSEA). Principal component analysis (PCA), Gene Set Variation Analysis (GSVA) enrichment analysis, weighted gene coexpression network analysis (WGCNA), and Associated R packages were used to identify the m6A phenotype and its biological functions. Results: A total of 23 m6A regulators were involved in this study. We found a close correlation between most m6A regulators in all samples as well as in osteoarthritis samples. VIRMA and LRPPRC were the most highly correlated m6A regulators and showed a positive correlation, whereas VIRMA and RBM15B were the most negatively correlated. M6A regulators are associated with osteoarthritis immune characteristics. For example, MDSC cell abundance was strongly correlated with RBM15B and HNRNPC. Meanwhile, RBM15B and HNRNPC were important effectors of natural killer cell immune responses. IGFBP3 is an important regulator of cytolytic activity immune function. We performed an unsupervised consensus cluster analysis of the osteoarthritis samples based on the expression of 23 m6A regulators. Three different m6A subtypes of osteoarthritis were identified, including 27 samples in subtype C1, 21 samples in subtype C2, and 58 samples in subtype C3. Different m6A subtypes have unique biological pathways and play different roles in the immune microenvironment of osteoarthritis. Conclusion: The m6A modification plays a crucial role in the diversity and complexity of the immune microenvironment in osteoarthritis.

Molecular cloning and expression analysis of Myxovirus resistance gene in Yangzhou goose (Anser cygnoides domesticus)

ABSTRACT 1. Myxovirus resistance (Mx) is a protein produced by the interferon-induced natural immune response with broad spectrum antiviral function. However, the role and expression characteristics of the Mx gene in immune defence against viral infection in goose have not yet been reported. 2. This study found a 2576 bp genomic sequence and a 2112 bp mRNA sequence for Mx, encoding 703 amino acids. Multiple sequence alignments of the amino acid sequences showed that the Yangzhou goose Mx (goMx) had 86.99% similarity to the mallard duck (Anas platyrhynchos). 3. Tissue-specific expression profiling revealed that the expression of goMx was highest in the lung and spleen. Both poly (I:C) and GPV were found to elevate the expression of goMx. The upregulated expression of goMx was associated with interferon pathway-related genes IRF7, JAK1, STAT1, and STAT2. Furthermore, overexpression of goMx significantly activated the transcription of poly (I:C) induced TNF-α, IL-1β, IL-6, and IL-18. 4. The findings of this study suggest that the goMx modulation of the antiviral response is mediated by the interferon pathway.

Neutrophils in Dendritic Cell-Based Cancer Vaccination: The Potential Roles of Neutrophil Extracellular Trap Formation.

Neutrophils have conflicting roles in the context of cancers, where they have been associated with contributing to both anti-tumor and pro-tumor responses. Their functional heterogenicity is plastic and can be manipulated by environmental stimuli, which has fueled an area of research investigating therapeutic strategies targeting neutrophils. Dendritic cell (DC)-based cancer vaccination is an immunotherapy that has exhibited clinical promise but has shown limited clinical efficacy. Enhancing our understanding of the communications occurring during DC cancer vaccination can uncover opportunities for enhancing the DC vaccine platform. There have been observed communications between neutrophils and DCs during natural immune responses. However, their crosstalk has been poorly studied in the context of DC vaccination. Here, we review the dual functionality of neutrophils in the context of cancers, describe the crosstalk between neutrophils and DCs during immune responses, and discuss their implications in DC cancer vaccination. This discussion will focus on how neutrophil extracellular traps can influence immune responses in the tumor microenvironment and what roles they may play in promoting or hindering DC vaccine-induced anti-tumor efficacy.

Trypanosoma cruzi-specific CD8+ T cells and other immunological hallmarks in chronic Chagas cardiomyopathy: Two decades of research.

Trypanosoma cruzi, the causal agent of Chagas disease, has coexisted with humans for thousands of years. Therefore, the parasite has developed several mechanisms of antigenic variability that has allowed it to live inside the cells and evade the host immune response. SinceT. cruzidisplays an intracellular cycle-stage, our research team focused on providing insights into the CD8+T cells immune response in chronic Chagas cardiomyopathy. We began our work in the 2000s studying parasite antigens that induce natural immune responses such as the KMP11 protein and TcTLE, its N-terminal derived peptide. Different approaches allowed us to reveal TcTLE peptide as a promiscuous CD8+ T cell epitope, able of inducing multifunctional cellular immune responses and eliciting a humoral response capable of decreasing parasite movement and infective capacity. Next, we demonstrated that as the disease progresses, total CD8+T cells display a dysfunctional state characterized by a prolonged hyper-activation state along with an increase of inhibitory receptors (2B4, CD160, PD-1, TIM-3, CTLA-4) expression, an increase of specific terminal effector T cells (TTE), a decrease of proliferative capacity, a decrease of stem cell memory (TSCM) frequency, and a decrease of CD28 and CD3ζexpression. Thus, parasite-specific CD8+ T cells undergo clonal exhaustion, distinguished by an increase in late-differentiated cells, a mono-functional response, and enhanced expression of inhibitory receptors. Finally, it was found that anti-parasitic treatment induces an improved CD8+T cell response in asymptomatic individuals, and a mouse animal model led us to establish a correlation between the quality of the CD8+ T cell responses and the outcome of chronic infection. In the future, using OMICs strategies, the identification of the specific cellular signals involved in disease progression will provide an invaluable resource for discovering new biomarkers of progression or new vaccine and immunotherapy strategies. Also, the inclusion of the TcTLE peptide in the rational design of epitope-based vaccines, the development of immunotherapy strategies using TSCMor the blocking of inhibitory receptors, and the use of the CD8+T cell response quality to follow treatments, immunotherapies or vaccines, all are alternatives than could be explored in the fight against Chagas disease.

AIM2 sensors mediate immunity to Plasmodium infection in hepatocytes

Malaria, caused by Plasmodium parasites is a severe disease affecting millions of people around the world. Plasmodium undergoes obligatory development and replication in the hepatocytes, before initiating the life-threatening blood-stage of malaria. Although the natural immune responses impeding Plasmodium infection and development in the liver are key to controlling clinical malaria and transmission, those remain relatively unknown. Here we demonstrate that the DNA of Plasmodium parasites is sensed by cytosolic AIM2 (absent in melanoma 2) receptors in the infected hepatocytes, resulting in Caspase-1 activation. Remarkably, Caspase-1 was observed to undergo unconventional proteolytic processing in hepatocytes, resulting in the activation of the membrane pore-forming protein, Gasdermin D, but not inflammasome-associated proinflammatory cytokines. Nevertheless, this resulted in the elimination of Plasmodium-infected hepatocytes and the control of malaria infection in the liver. Our study uncovers a pathway of natural immunity critical for the control of malaria in the liver.