Chromosome aberrations and autoimmunity: Immune-mediated diseases associated with 18p deletion and other chromosomal aberrations.

Recent advances in genomic methodologies have significantly enhanced our understanding of immune-mediated rheumatic diseases. Specific structural variants (SVs), such as substantial DNA deletions or insertions, including chromosomal aberrations, have been implicated in diseases of immune dysregulation. Regrettably, SVs are frequently overlooked in next-generation sequencing (NGS) targeted-gene panels, whole exome sequencing (WES) and whole genome sequencing (WGS). In view of a case of chromosome 18p deletion syndrome, characterized by hypogammaglobulinemia and an autoinflammatory phenotype, we provide a comprehensive review on chromosome aberrations associated with multiple immune-mediated conditions, highlighting the clinical aspects of the various chromosome aberrations associated with immune-mediated diseases. Further investigations and development of functional tests should contribute to elucidate the mechanistic connection between chromosome aberrations and Primary Immune Regulatory Disorders (PIRD), bringing novel perspectives in the field of autoinflammatory and autoimmune diseases.

Leptin, NK cells, and the weight of immunity: Insights into obesity.

Obesity is a chronic inflammatory disease that affects more than 1 billion people worldwide and is associated with various metabolic and physiological dysfunctions, directly impacting the dynamics of the immune response, partly due to elevated leptin levels. Leptin is an important peptide hormone that regulates neuroendocrine function and energy homeostasis, with its blood levels reflecting energy reserves, fat mass, or energy deprivation. This hormone also plays a fundamental role in regulating immune function, including the activity of NK cells, which are essential components in antiviral and antitumor activity. In obese individuals, leptin resistance is commonly established, however, NK cells and other immune components remain responsive to this hormone. So far, leptin has demonstrated paradoxical activities of these cells, often associated with a dysfunctional profile when associated with obesity. The excessive fat is usually related to metabolic remodeling in NK cells, resulting in compromised antitumor responses due to reduced cytotoxic capacity and decreased expression of cytokines important for these defense mechanisms, such as IFN-γ. Therefore, this review approaches a better understanding of the immunoendocrine interactions between leptin and NK cells in the context of obesity.

Therapeutic BCG vaccine protects against long COVID: The BATTLE randomized clinical trial.

BACKGROUND: Bacillus Calmette-Guérin (BCG) injected during the COVID-19 convalescence period was safe and enhanced recovery from anosmia and dysgeusia in the acute phase. OBJECTIVES: To report the long-term results of the BATTLE trial, BCG vaccine in adults with mild COVID-19. METHODS: Design: Double-blind, placebo-controlled, randomized (1:1) clinical trial. INTERVENTION: BCG intradermal vaccine and placebo. PATIENTS: A total of 157 BCG and 142 placebo recipients participated in the 6-month follow-up, and 97 BCG and 95 placebo recipients participated in the 12-month follow-up. MEASUREMENTS: Long COVID symptoms and mechanistic analyses. RESULTS: BCG reduced hearing problems at 6 months (odds ratio [OR] = 0.26) and sleeping, concentration, memory, and vision problems at 12 months (OR = 0.45, 0.36, 0.38, and 0.36, respectively). Sensitivity analyses confirmed that long COVID-19 symptoms were reduced at the 6- and 12-month follow-ups (p = 0.010 and 0.031, respectively). BCG's crossover interaction paradoxically increased hair loss in women and decreased it in men at 6 months (p = 0.032). BCG immunomodulation is likely mediated through inhibition of Fas ligand expression in the blood and increased induction of IL6, IL10, interferon-induced transmembrane protein 3, and angiotensin-converting enzyme 2 in cultured human macrophages. CONCLUSION: Long-term follow-up of the BATTLE trial participants revealed that BCG protects against long COVID development if administered within the COVID-19 convalescence period. The response to BCG was subject-specific, including a paradoxical crossover interaction based on sex. LIMITATIONS: Not tested for previous mycobacterial exposure; loss to follow-up, particularly at 12 months.

Mitochondrial ß-Cyanoalanine Synthase Participates in flg22-Induced Stomatal Immunity.

Plants regulate gas exchange with the environment and modulate transpirational water flow through guard cells, which set the aperture of the stomatal pores. External and internal stimuli are detected by guard cells and integrated into a signalling network that modulate turgor pressure and, hence, pore size. Pathogen-associated molecular patterns are among the stimuli that induce stomatal closure, to prevent pathogen entry through the pores, and this response, also referred to as stomatal immunity, is one of the hallmarks of PAMP-triggered immunity. While reactive oxygen species (ROS)-mediated signalling plays a key role in stomatal immunity, also the gasotransmitter hydrogen sulphide (H2S) interacts with key components of the guard cell signalling network to induce stomatal closure. While the role of H2S, produced by the main cytosolic source L-cysteine desulfhydrase 1, has been already investigated, there are additional enzymatic sources that synthesize H2S in different subcellular compartments. Their function has remained enigmatic, however. In this work, we elucidate the involvement of the mitochondrial H2S source, ß-cyanoalanine synthase CAS-C1, on stomatal immunity induced by the bacterial PAMP flagellin (flg22). We show that cas-c1 plants are impaired to induce flg22-triggered stomatal closure and apoplastic ROS production, while they are more susceptible to bacterial surface inoculation. Moreover, mitochondrial H2S donor AP39 induced stomatal closure in an RBOHD-dependent manner, while depletion of endogenous H2S, impaired RBOHD-mediated apoplastic ROS production. In addition, pharmacological disruption of mitochondrial electron transport chain activity, affected stomatal closure produced by flg22, indicating its participation in the stomatal immunity response. Our findings add evidence to the emerging realization that intracellular organelles play a decisive role in orchestrating stomatal signalling and immune responses and suggest that mitochondrial-derived H2S is an important player of the stomatal immunity signalling network.

Acute low temperature and lipopolysaccharide differentially modulated the innate immune and antioxidant responses in a subtropical fish, the pacu (Piaractus mesopotamicus).

Exogenous factors such as low water temperature can be stressful and elicit negative immune system effects, especially for fish, which are ectothermic. Stress and immune responses require energy overload, which can affect the cellular redox balance, causing oxidative damage. These overall responses impair the animal's health and negatively affect fish farming. To evaluate indicators of stress, immune and antioxidant systems, and oxidative stress responses in fish during thermal challenge, the present study reduced the water temperature from 29.5 °C to 16 °C and then inoculated pacu (Piaractus mesopotamicus) with lipopolysaccharide (LPS) from Escherichia coli. Our results revealed that acute exposure to low water temperature itself increased blood glucose, impaired the serum lysozyme concentration and increased GSH-Px activity. There was an interaction effect between low temperature and LPS inoculation. After LPS inoculation, leukocytes were initially activated (3 h); glucose levels increased (3 h); GST activity initially decreased (3 h) but then increased (6 h); SOD, CAT and GSH-Px activities decreased; and lysozyme activity remained depressed in fish subjected to cold shock. The results showed that thermal and immunological challenges impaired the maintenance of leucocyte activation and compromised the pacu oxidant response. The overall response of pacu to thermal challenge indicates that the species proved to be acutely sensitive to a drop in water temperature, reducing its ability to maintain homeostasis, especially when subjected to immunological challenge.

[Necrotizing pneumonia in a patient with selective IgA deficiency]. / Neumonía necrosante en un paciente con deficiencia selectiva de IgA.

BACKGROUND: Inborn errors of immunity originate from monogenic mutations that should be considered in the suggestive diagnosis of patients with recurrent or severe infections, allergies, autoimmunity, autoinflammatory diseases, bone marrow failure and malignancy. CASE REPORT: Pediatric patient, male, 4 years old, treated in the medical service for fever of 39°C, difficult to control. The simple chest x-ray reported left pulmonary consolidation. The infectious condition evolved into necrotizing pneumonia of the left upper lobe, so it was decided to perform a lobectomy. The diagnosis of some inborn error of immunity was suspected. The determination of serum immunoglobulins reported IgA below the reference values. At 4 years he continued to have decreased serum IgA (5.5 mg/dL). CONCLUSIONS: The diagnosis of selective IgA deficiency is established after 4 years of life; However, due to the patient's severe infection, addressing some inborn error of immunity had to be implemented.

ANTECEDENTES: Los errores innatos de la inmunidad se originan por mutaciones monogénicas que deben considerarse en el diagnóstico sugerente de pacientes con infecciones recurrentes o graves, alergias, autoinmunidad, enfermedades autoinflamatorias, insuficiencia de médula ósea y malignidad. REPORTE DE CASO: Paciente pediátrico de 4 años de edad, género masculino, quien a los dos años tuvo fiebre de 39°C, de difícil control. La radiografía simple de tórax reportó consolidación pulmonar izquierda. El cuadro infeccioso evolucionó a neumonía necrosante del lóbulo superior izquierdo, por lo que se decidió practicar lobectomía. Se sospechó el diagnóstico de algún error innato de la inmunidad. La determinación de inmunoglobulinas séricas informó IgA por debajo de los valores de referencia. A los 4 años continúo con IgA sérica disminuida (5.5 mg/dL). CONCLUSIONES: El diagnóstico de deficiencia selectiva de IgA se establece a partir de los 4 años de vida; sin embargo, debido a la infección grave del paciente aquí reportado, tuvo que implementarse el abordaje diagnóstico en búsqueda de algún error innato de la inmunidad.

Potential protective role of interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) in COVID-19.

The COVID-19 pandemic has prompted a quest to understand why certain individuals remain uninfected or asymptomatic despite repetitive exposure to SARS-CoV-2. Here, we focused on six exposed females residing with their symptomatic and reinfected SARS-CoV-2 PCR-positive COVID-19 partners. Peripheral blood mononuclear cell samples from couples were analysed for poly (I:C)-induced mRNA expression of type I/III interferons and interferon-stimulated genes (ISGs). Remarkably, we found a significant upregulation of the ISG interferon-inducible protein with tetrapeptide repeats 3 (IFIT3) gene exclusively in exposed uninfected or asymptomatic females, suggesting a potential role in protective immunity against symptomatic COVID-19.

Selective IgM deficiency: evaluation of 75 patients according to different diagnostic criteria.

Selective IgM deficiency (SIgMD) has recently been included in the inborn errors of immunity classification. SIgMD has conflicting diagnostic criteria and diverse clinical and immunological findings. We aimed to assess the clinical and laboratory profiles of patients with SIgMD and to compare the data of patients diagnosed using two inclusion criteria. This was a descriptive, retrospective, observational, collaborative study. Patients were included according to the following definitions: Group 1, IgM levels < 0.20 g/L in children and < 0.30 g/L in adults, and Group 2, serum IgM levels below 2SD and, for both, absence of associated immunological diseases or secondary causes. The protocol was approved by the Ethics Committee, and patients provided consent. In total, 75 patients were included: 37 (16 M:21F; mean age, 52.92) and 38 (13 M:25F; mean age, 53.47) in Groups 1 and 2, respectively. The most frequent clinical manifestations were allergic rhinitis (G1, 45.9%; G2, 36.8%), asthma (G1, 37.8%; G2, 28.9%), and pulmonary infections (G1, 27.03%; G2, 21.05%). Chromosomopathies (16.22%) and neoplasia (13.51%) were more frequent in G1, whereas URTI (23.68%) and skin infections (23.68%) were more common in G2. There was no difference in sex or mean age at symptom onset between both groups of patients. Regarding the clinical picture, 90.7% of the lesions were benign (68/75). Chromosomopathies may be associated with SIgMD, suggesting the need to quantify serum IgM levels in these cases. Considering the possibility of developing autoimmunity, neoplasia, and common variable immunodeficiency, it is advisable to follow up patients with SIgMD.

Fasciola hepatica Soluble Antigen (FhAg)-Induced NETs Under Hypoxic Conditions Exert Cytotoxic Effects on Hepatic Cells In Vitro.

Fasciola hepatica is a parasitic trematode that causes fasciolosis in sheep, provoking a decrease in their reproductive capacity, weight gain, meat and milk production, and wool quality. In the pathogenesis of F. hepatica, the penetration and migration of parasitic stages through the liver provoke intense inflammatory immune responses and tissue damage. The aim of this study was to investigate the cytotoxic effects of Fascila hepatica-induced ovine NETs in exposed hepatocytes in vitro, and to analyze whether F. hepatica antigens (FhAg) trigger the release of ovine NETs under hypoxic conditions as well as the roles of matrix metalloproteinase-9 (MMP-9) and CD11b in this cellular process in vitro. Here, isolated ovine PMNs were co-cultured with FhAg under hypoxia (5% O2) and NETs were visualized via immunofluorescence analyses, confirming their classical characteristics. The quantification of NETs in response to FhAg in hypoxic conditions significantly enhanced the formation of anchored and cell-free NETs (p < 0.01), and NADPH oxidase (NOX) inhibitor diphenylene iodonium (DPI) significantly reduced their production (p < 0.05). Furthermore, the cytotoxic effect of NETs on hepatic cells was determined by using a live/dead-staining with Sytox Orange, thereby demonstrating that FhAg-induced NETs are cytotoxic for hepatic cells (p = 0.001). We additionally analyzed PMN supernatants to determine the enzymatic activity of MMP-9, observing that FhAg exposure enhances MMP-9 release in ovine PMNs (p < 0.05) but not in bovine PMNs. Interestingly, by using flow cytometric analysis, we determined that the exposure of PMNs to FhAg does not increase the CD11b surface expression of ovine PMNs. This could be an effect of the activation of other surface receptors or transcription factors involved in F. hepatica-induced NETosis. Consequently, we hypothesize that F. hepatica-induced NETs play a role in the pathogenesis of fasciolosis, contributing to liver tissue damage if released in an uncontrolled manner.

Appeasing Substance Administration at Feedlot Entry Impacted Temperament, Pen Behavior, Immunocompetence, and Meat Quality of Beef Heifers.

This experiment evaluated the effects of bovine appeasing substance (BAS) administration at feedlot entry on growth, temperament, inflammation, response to vaccination, behavior, carcass characteristics, and meat quality of beef heifers. Thirty heifers were weaned and assigned to (d 0): (1) BAS (n = 15; SecureCattle; IRSEA Group) or (2) Saline (n = 15). On d 0, heifers were also vaccinated against respiratory diseases and slaughtered on d 150. Administering BAS increased (p = 0.05) average daily gain from d 6 to 45, reduced (p ≤ 0.03) plasma ceruloplasmin and serum cortisol concentrations on d 15 and 45 and increased (p = 0.03) the response to vaccination. Additionally, BAS reduced (p < 0.01) the entry scores on d 6, 15, and 45 and reduced (p = 0.05) exit scores on d 2, 6, and 15. The BAS increased (p ≤ 0.04) walking, drinking, and eating time, and tended (p ≤ 0.10) to increase lying and ruminating time. Lastly, BAS tended (p ≤ 0.10) to increase the myofibrillar fragmentation index and reduce the thiobarbituric acid reactive substance concentration in meat. Thus, BAS administration increased growth, reduced stress, and inflammation, and improved immune responses, behavior, and meat quality of heifers.

[Measles and Rubella IgG Seropositivity in the Post-elimination Era, Costa Rica, 2012-2023Soropositividade de IgG para os vírus do sarampo e da rubéola na era pós-eliminação, Costa Rica, 2012-2023]. / Seropositividad de IgG para los virus del sarampión y de la rubéola en la era poseliminación, Costa Rica, 2012-2023.

Objective: To determine measles and rubella IgG seropositivity in the post-elimination era, based on data generated by the Costa Rican National Reference Center for Virology laboratory at Inciensa from 2012 to 2023. Methods: Cross-sectional, descriptive, observational study analyzing the frequency of measles IgG and rubella IgG reactivity by enzyme-linked immunofluorescence (ELISA) in 877 subjects. Results: The average age of the studied individuals was 36 years; 51.8% were women. Measles and rubella IgG seropositivity was slightly higher in females. The average seropositivity over the study period was 74.8% for measles IgG antibodies and 84.5% for rubella. The age group 50 years and older exhibited the highest positivity for the both measles and rubella IgG, while the 20-to-39 age group had the lowest protective humoral response. Conclusions: Descriptive studies of measles and rubella IgG seropositivity can identify age groups susceptible to these infections, which in turn can guide health authorities in directing supplementary immunization campaigns to strengthen the immune response of the population and prevent outbreaks of both diseases.

Objetivo: Determinar a soropositividade de IgG para sarampo e rubéola na era pós-eliminação, com base em dados gerados pelo laboratório do Centro Nacional de Referência em Virologia, Inciensa, entre 2012­2023. Metodologia: Estudo observacional descritivo transversal analisando as frequências dos resultados dos testes ELISA IgG contra sarampo e rubéola em 877 indivíduos. Resultados: A idade média dos indivíduos estudados era 36 anos; 51,8% eram mulheres. A soropositividade de IgG para sarampo e rubéola é ligeiramente maior em mulheres. A soropositividade média durante os anos do estudo foi de 74,8% para anticorpos IgG contra sarampo e 84,5% para rubéola. A faixa etária de 50 anos ou mais apresentou a maior positividade para IgG contra sarampo e IgG contra rubéola, e a faixa com a menor resposta humoral protetora foi a de 20 a 39 anos. Conclusões: Os estudos descritivos de soropositividade de anticorpos IgG contra sarampo e rubéola podem identificar faixas etárias suscetíveis a essas doenças, o que pode ajudar as autoridades de saúde a direcionar campanhas de vacinação de seguimento para aumentar a resposta imunológica da população a fim de evitar surtos de ambas as doenças.

Molecular and Clinical Characterization of a Founder Mutation Causing G6PC3 Deficiency.

G6PC3 deficiency is a monogenic immunometabolic disorder that causes severe congenital neutropenia type 4. Patients display heterogeneous extra-hematological manifestations, contributing to delayed diagnosis. Here, we investigated the origin and functional consequence of the G6PC3 c.210delC variant found in patients of Mexican descent. Based on the shared haplotypes amongst mutation carriers, we estimated that this variant originated from a founder effect in a common ancestor. Furthermore, by ancestry analysis, we concluded that it appeared in the indigenous Mexican population. At the protein level, we showed that this frameshift mutation leads to an aberrant protein expression in overexpression and patient-derived Epstein-Barr Virus-immortalized B (EBV-B) cells. The neutropenia observed in G6PC3-deficient patients is driven by the intracellular accumulation of the metabolite 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) that inhibits glycolysis. We characterized how the c.210delC variant impacts glycolysis by performing extracellular flux assays on patient-derived EBV-B cells. When treated with 1,5-anhydroglucitol (1,5-AG), the precursor to 1,5-AG6P, patient cells exhibited markedly reduced engagement of glycolysis. Finally, we compared the clinical presentation of patients with the mutation c.210delC and all other G6PC3-deficient patients reported in the literature, and we found that the c.210delC carriers display all prominent clinical features observed in prior patients. In conclusion, G6PC3 c.210delC is a loss-of-function mutation that arose from a founder effect in the indigenous Mexican population. These findings may facilitate the diagnosis of additional patients in this geographical area. Moreover, the in vitro 1,5-AG-dependent functional assay used in our study could be employed to assess the pathogenicity of additional G6PC3 variants.

Preclinical study of TLR stimulation combined PD-1 antibody enhance the therapeutic effect of microwave ablation on NSCLC.

PURPOSE: The purpose of this study was to investigate the therapeutic efficacy of the combination of microwave ablation (MWA) with immune checkpoints blockade and TLR9 stimulation in the treatment of non-small cell lung cancer (NSCLC) using the C57BL/6 tumor-bearing mice model. MATERIALS AND METHODS: Tumor-bearing mice were treated with MWA, programmed cell death protein1 blockade (PD-1) plus MWA (MWA + P), TLR9 agonist CpG ODNs and MWA (MWA + C), PD-1 blockade and CpG ODNs (P + C), MWA plus PD-1 blockade and CpG ODNs (MWA + P + C), or untreated. Survival time was evaluated with the Kaplan-Meyer method comparing survival curves by log-rank test. On day 15 after MWA, ten mice from the combination therapy group received tumor rechallenge with LLC cells and the volumes of rechallenge tumor were calculated every 5 days. Immune cells were identified by immunohistochemistry and flow cytometry, and the concentrations of IFN-γ、TNF-α and TGF-ß were identified by enzyme-linked immunosorbent assay (ELISA). RESULTS: The MWA + P + C combination therapy significantly prolonged tumor-bearing mice survival and reduced tumor size compared to untreated group, MWA group, MWA + P group, M + C group, P + C group. The combination therapy also protected most surviving mice from LLC tumor rechallenge. CD8 + T-cell in tumor and spleen were remarkably induced by MWA + P + C and Treg cell further diminished by combination therapy. Both tumor necrosis factor-alpha (TNF-α) and interferon-gama (IFN-γ) concentrations in plasma were significantly elevated in the combination therapy group compared to other groups, while transforming growth factor Beta (TGF-ß) was reduced. CONCLUSION: MWA combined with immune checkpoints blockade and TLR stimulation could significantly enhance antitumor efficacy with augmented specific immune responses, and the combination therapy is a promising approach to treat non-small cell lung cancer (NSCLC).

[Association between alterations in the expanded lymphoid profileby flow cytometry and inborn errors of immunity]. / Asociación entre alteraciones del perfil linfoide ampliado por citometría de flujo y errores innatos de la inmunidad.

OBJECTIVE: To evaluate the association between the expanded lymphoid profile and inborn errors of immunity using flow cytometry. METHODS: Observational and cross-sectional, case-control study, carried out in patients with a diagnosis or clinical suspicion of inborn errors of immunity, treated at the Santísima Trinidad Children's Hospital in Córdoba, Argentina, from August 2021 to November 2022. Clinical data were collected, and peripheral blood samples were obtained for flow cytometry analysis, using the PIDOT tube, to identify lymphocyte subpopulations. For statistical analysis, Fisher's exact test, odds ratio and binary logistic regression model were used. RESULTS: 40 cases and 20 controls were analyzed. The most frequently altered lymphocyte subpopulations were: CD4+ n (63%), Mem c/s (60%) and Mem s/s (55%). A statistically significant association was found between several lymphocyte subpopulations and health-disease status. Binary logistic regression reported Mem s/s and CD4+n as altered lymphocyte subpopulations with a greater probability to have inborn errors of immunity. CONCLUSIONS: This study contributes to improving the understanding of inborn errors of immunity and demonstrates a strong association with altered lymphocyte subpopulation profiles. Mem s/s and CD4+n emerge as relevant biomarkers for diagnosis. Heterogeneity in different diseases and in flow cytometry underlines the importance of evaluating each patient individually, to improve diagnosis and treatment.

OBJETIVO: Evaluar la asociación entre el perfil linfoide ampliado y los errores innatos de la inmunidad mediante citometría de flujo. MÉTODOS: Estudio observacional y transversal, de casos y controles, llevado a cabo en pacientes con diagnóstico o sospecha clínica de errores innatos de la inmunidad, atendidos en el Hospital de Niños de la Santísima Trinidad de Córdoba, Argentina, de agosto de 2021 a noviembre de 2022. Se recolectaron los datos clínicos y se obtuvieron muestras de sangre periférica para el análisis por citometría de flujo, mediante el tubo PIDOT, para identificar subpoblaciones de linfocitos alteradas. Para el análisis estadístico se utilizó la prueba exacta de Fisher, razón de momios y modelo de regresión logística binaria. RESULTADOS: Se analizaron 40 casos y 20 controles. Las subpoblaciones de linfocitos más frecuentemente alteradas fueron: CD4+ n (63%), Mem c/s (60%) y Mem s/s (55%). Se encontró asociación estadísticamente significativa entre varias subpoblaciones de linfocitos y el estado de salud-enfermedad. La regresión logística binaria reportó Mem s/s y CD4+n como las subpoblaciones de linfocitos alteradas con mayor probabilidad de padecer errores innatos de la inmunidad. CONCLUSIONES: Este estudio contribuye a mejorar la comprensión de los errores innatos de la inmunidad, y demuestra una sólida asociación con los perfiles de subpoblaciones de linfocitos alteradas. Los Mem s/s y CD4+n emergen como biomarcadores relevantes para su diagnóstico. La heterogeneidad en diferentes enfermedades y en la citometría de flujo subraya la importancia de evaluar a cada paciente individualmente, para mejorar el diagnóstico y tratamiento.

Longitudinal analysis of SARS-CoV-2 IgG antibody durability in Puerto Rico.

Understanding the dynamics of antibody responses following vaccination and SARS-CoV-2 infection is important for informing effective vaccination strategies and other public health interventions. This study investigates SARS-CoV-2 antibody dynamics in a Puerto Rican cohort, analyzing how IgG levels vary by vaccination status and previous infection. We assess waning immunity and the distribution of hybrid immunity with the aim to inform public health strategies and vaccination programs in Puerto Rico and similar settings. We conducted a prospective, longitudinal cohort study to identify SARS-CoV-2 infections and related outcomes in Ponce, Puerto Rico, from June 2020-August 2022. Participants provided self-collected nasal swabs every week and serum every six months for RT-PCR and IgG testing, respectively. IgG reactivity against nucleocapsid (N) antigens, which generally indicate previous infection, and spike (S1) and receptor-binding domain (RBD) antigens, which indicate history of either infection or vaccination, was assessed using the Luminex Corporation xMAP® SARS-CoV-2 Multi-Antigen IgG Assay. Prior infection was defined by positive RT-PCRs, categorized by the predominant circulating SARS-CoV-2 variant at the event time. Demographic information, medical history, and COVID-19 vaccination history were collected through standardized questionnaires. Of 882 participants included in our analysis, 34.0% experienced at least one SARS-CoV-2 infection, with most (78.7%) occurring during the Omicron wave (December 2021 onwards). SARS-CoV-2 antibody prevalence increased over time, reaching 98.4% by the final serum collection, 67.0% attributable to vaccination alone, 1.6% from infection alone, and 31.4% from both. Regardless of prior infection status, RBD and S1 IgG levels gradually declined following two vaccine doses. A third dose boosted these antibody levels and showed a slower decline over time. N-antibody levels peaked during the Omicron surge and waned over time. Vaccination in individuals with prior SARS-CoV-2 infection elicited the highest and most durable antibody responses. N or S1 seropositivity was associated with lower odds of a subsequent positive PCR test during the Omicron period, with N antibodies showing a stronger association. By elucidating the differential decay of RBD and S1 antibodies following vaccination and the complexities of N-antibody response following infection, this study in a Puerto Rican cohort strengthens the foundation for developing targeted interventions and public health strategies.

Genomic analysis of Salmonella isolated from surface water and animal sources in Chile reveals new T6SS effector protein candidates.

Type VI Secretion Systems (T6SS), widely distributed in Gram-negative bacteria, contribute to interbacterial competition and pathogenesis through the translocation of effector proteins to target cells. Salmonella harbor 5 pathogenicity islands encoding T6SS (SPI-6, SPI-19, SPI-20, SPI-21 and SPI-22), in which a limited number of effector proteins have been identified. Previous analyses by our group focused on the identification of candidate T6SS effectors and cognate immunity proteins in Salmonella genomes deposited in public databases. In this study, the analysis was centered on Salmonella isolates obtained from environmental sources in Chile. To this end, bioinformatics and comparative genomics analyses were performed using 695 genomes of Salmonella isolates representing 44 serotypes obtained from surface water and animal sources in Chile to identify new T6SS effector proteins. First, T6SS gene clusters were identified using the SecreT6 server. This analysis revealed that most isolates carry the SPI-6 T6SS gene cluster, whereas the SPI-19 and SPI-21 T6SS gene clusters were detected in isolates from a limited number of serotypes. In contrast, the SPI-20 and SPI-22 T6SS gene clusters were not detected. Subsequently, each ORF in the T6SS gene clusters identified was analyzed using bioinformatics tools for effector prediction, identification of immunity proteins and functional biochemical prediction. This analysis detected 20 of the 37 T6SS effector proteins previously reported in Salmonella. In addition, 4 new effector proteins with potential antibacterial activity were identified in SPI-6: 2 Rhs effectors with potential DNase activity (PAAR-RhsA-NucA_B and PAAR-RhsA-GH-E) and 2 effectors with potential RNase activity (PAAR-RhsA-CdiA and RhsA-CdiA). Interestingly, the repertoire of SPI-6 T6SS effectors varies among isolates of the same serotype. In SPI-19, no new effector protein was detected. Of note, some Rhs effectors of SPI-19 and SPI-6 present C-terminal ends with unknown function. The presence of cognate immunity proteins carrying domains present in bona fide immunity proteins suggests that these effectors have antibacterial activity. Finally, two new effectors were identified in SPI-21: one with potential peptidoglycan hydrolase activity and another with potential membrane pore-forming activity. Altogether, our work broadens the repertoire of Salmonella T6SS effector proteins and provides evidence that SPI-6, SPI-19 and SPI-21 T6SS gene clusters harbor a vast array of antibacterial effectors.

Pan-cancer analysis reveals the prognostic and immunomodulatory potential of super-enhancer-induced ANGPT2 and experimental validation in colorectal cancer.

BACKGROUND: ANGPT2 plays important roles in cancer development. However, there is still no systematic analysis of ANGPT2 in pan-cancer. METHODS: In this paper, we conducted a pan-cancer analysis to investigate the characteristics of ANGPT2. Furthermore, we investigated the impact of genetic and epigenetic factors on ANGPT2 expression by bioinformatics and assays. RESULTS: By several TCGA and GEO databases, we identified elevated expression of ANGPT2 in various tumor types. Besides, high expression of ANGPT2 induced poor prognosis of patients in multiple tumors. Through enrichment analysis, we found that ANGPT2 participated in various biological processes, including angiogenesis and immunity. Various immune analyses indicated that high expression of ANGPT2 might suggest a propensity towards a hot tumor microenvironment, but its impact on immunotherapy was negative. Bioinformatics analysis and experiments confirmed that genetic and epigenetic factors explained part of the mechanism behind ANGPT2 abnormal expression. Finally, we screened candidate drugs targeting the ANGPT2 protein by molecular docking and molecular dynamics simulation. CONCLUSION: ANGPT2 has diagnostic and prognostic values in multiple tumor types. Though with a hot tumor microenvironment, ANGPT2 high expression patients are not suitable for immunotherapy because of its proangiogenic function, contributing to selecting the exact patients for immunotherapy. Both genetic and epigenetic factors influenced ANGPT2 expression, with the influence of super-enhancer being more pronounced. This paper for the first time did the systematic analysis of ANGPT2 and showed its characteristic in pan-cancer. We summarized the biomarker role of ANGPT2 on tumor diagnosis and prognosis, as well as its target role on tumor immunotherapy.

What immunology has to say about pesticide safety.

The use of pesticides has enabled the development of contemporary industrial agriculture and significantly increased crop yields. However, they are also considered a source of environmental pollution and a potential hazard to human health. Despite national agencies and the scientific community analyzing pesticide safety, immunotoxicity assays are often not required, poorly designed, or underestimated. Epidemiological evidence indicates that pesticide exposure increases the risk of developing cancer. Therefore, pesticides may not only act as carcinogens per se but also as immunosuppressive agents that create a permissive context for tumor development. Given recent evidence demonstrating the critical role of the immune response in cancer progression, we will highlight the necessity of assessing the potential impacts of pesticides on the immune response, particularly on tumor immunosurveillance. In this Perspective article, we will focus on the need to critically review fundamental aspects of toxicological studies conducted on pesticides to provide a clearer understanding of the risks associated with exposure to these compounds to human health.

Screening and computational characterization of novel antimicrobial cathelicidins from amphibian transcriptomic data.

As cold-blooded organisms living in damp and dark environments, amphibians have evolved robust defense mechanisms to protect themselves from predators and infections. Among the wide repertoire of bioactive compounds they produce are antimicrobial peptides (AMPs), which are required as part of innate immunity. One important class of AMPs is cathelicidins, known for their broad-spectrum activity against pathogens and their immunoregulatory roles. However, despite their promising biomedical potential and the increasing availability of omics data, few cathelicidins have been studied in amphibians, mostly through conventional experimental techniques. Here, we present 210 novel cathelicidin sequences from amphibian transcriptomes, identified through a comprehensive computational pipeline, which employed HMMER and BLAST tools to screen cathelicidin domains. These sequences reveal a typical tripartite domain architecture that was confirmed by SignalP and InterProScan analysis. Phylogenetic inference with IQ-TREE classified the sequences into six categories based on evolutionary relationships. Compared to cathelicidins from other vertebrates, amphibian mature peptides exhibit longer average lengths (around 50 amino acids), fewer aromatic and hydrophobic residues, and reduced thermal stability. Furthermore, these amphibian cathelicidins were characterized for their physicochemical and biological properties, revealing significant antimicrobial potential with lower hemolytic capability, especially in anurans, which suggests a balance between their antimicrobial and hemolytic activities predicted through AMPlify, ampir, AmpGram, and HemoPI. Secondary structure estimations, including three-dimensional modeling using AlphaFold2, indicate that amphibian cathelicidins predominantly feature α-helices and coils. Some representative models also display a high α-helix composition with amphipathic topology, facilitating interactions with simulated bacterial membranes as assessed by the PPM approach. Thus, these findings highlight the functional role of cathelicidins in amphibian immunity and their promising biomedical applicability, emphasizing the importance of applying computational methods to expand the scope and reveal the diverse landscape of cathelicidins across vertebrates.