Antigenic Variation Research Articles

The Role of Skunks in the Epidemiology of Rabies in the State of Yucatan from 2000 to 2022: Current Perspectives and Future Research Directions

In 2019, the World Health Organization (WHO) and the Pan American Health Organization (PAHO) bestowed upon Mexico the status of a country free from canine-transmitted human rabies; however, the lingering public health challenge in the nation continues to be the sylvatic cycle of rabies. In Mexico, skunks play a significant role as reservoirs for four antigenic variants of the rabies virus. Nonetheless, up to this point, the specific skunk species involved in this cycle had not been accurately established. This study (2002–2022) aims to identify the taxonomy of skunk specimens diagnosed as rabies-positive in the state of Yucatan, in order to determine the species that serves as the reservoir for the Yucatan sylvatic lineage of rabies. This was achieved through the sequencing of an approximately 680 bp fragment of the mitochondrial gene cytochrome B. All samples belong to the species Spilogale angustifrons yucatanensis. This discovery offers valuable information for understanding and managing the wildlife rabies cycle in Mexico. It also contributes to an improved understanding of the taxonomy within the genus Spilogale.

Genetic diversity and antigenic variability of foot-and-mouth disease virus strains in Egypt.

Foot-and-mouth disease (FMD) continues to pose a significant threat in Egypt, necessitating thorough analyses of FMD virus (FMDV) outbreaks. This study analyzed 144 suspected FMD cases across 52 animal collections during the years 2017-2018 and 2022. Recurrent FMD outbreaks in vaccinated dairy cattle were investigated. Clinical observation, postmortem examination, and histopathological analysis were conducted. Samples were subjected to reverse transcription polymerase chain reaction (RT-PCR) using group-specific in addition to serotype-specific primers, along with direct gene sequencing of the VP1 gene from positive samples, followed by phylogenetic analysis. Signs, postmortem and histopathological lesions consistent with FMD were found. Molecular identification confirmed the presence of serotype A (G-IV topotype), O (O/EA3 topotype), and serotype SAT2 (SAT2/VII/Lib-03 topotype). All detected topotypes were distinct from currently available vaccine strains. Variations in amino acid in the epitopes of the structural protein VP1 were detected. The study highlights the genetic and antigenic variability of FMDV strains circulating in Egypt, indicating potential challenges for vaccine effectiveness.

Elucidating the Role of the T Cell Receptor Repertoire in Myelodysplastic Neoplasms and Acute Myeloid Leukemia.

T cells, as integral components of the adaptive immune system, recognize diverse antigens through unique T cell receptors (TCRs). To achieve this, during T cell maturation, the thymus generates a wide repertoire of TCRs. This is essential for understanding cancer evolution, progression, and the efficacy of immunotherapies. Myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML) are hematological neoplasms that are characterized by immune evasion mechanisms, with immunotherapy giving only modest results thus far. Our review of TCR repertoire dynamics in these diseases reveals distinct patterns: MDS patients show increased TCR clonality with disease progression, while AML exhibits varied TCR signatures depending on disease stage and treatment response. Understanding these patterns has important clinical implications, as TCR repertoire metrics may serve as potential biomarkers for disease progression and treatment response, particularly in the context of immunotherapy and stem cell transplantation. These insights could guide patient stratification and treatment selection, ultimately improving therapeutic outcomes in MDS and AML.

Genetic and Structural Factors Contributing to the Dominance and Persistence of Goose Astrovirus Type 2

: Goose astrovirus (GoAstV) has emerged as a significant pathogen affecting the goose industry in China, with GoAstV-2 becoming the dominant genotype since 2017. This study explores the genetic and structural factors underlying the prevalence of GoAstV-2, focusing on codon usage bias, spike protein variability, and structural stability. Phylogenetic and effective population size analyses revealed that GoAstV-2 experienced rapid expansion between 2017 and 2018, followed by population stabilization. Codon usage analysis indicated that GoAstV-2 exhibited a weaker codon usage bias compared to GoAstV-1, suggesting greater flexibility in synonymous codon usage and potentially enhanced adaptability across host environments. Additionally, GoAstV-2's lower codon adaptation index values point to a divergence from the host’s optimal codon usage, which may reduce competition with host tRNA pools and facilitate viral replication. The spike protein of GoAstV-2 demonstrated significantly lower variability than GoAstV-1, as shown by Shannon entropy analysis, indicating greater structural stability. This stability may reduce the need for frequent mutations, allowing GoAstV-2 to persist in host populations without undergoing constant evolution. The lower antigenic variability likely decreases immune-driven selective pressure, contributing to the viral sustained transmission and long-term persistence. These findings provide new insights into the evolutionary advantages of GoAstV-2 and its epidemiological success, which could inform future control strategies aimed at mitigating its impact on poultry populations.

Chimeric antigen receptor with novel intracellular modules improves antitumor performance of T cells

The excessive cytokine release and limited persistence represent major challenges for chimeric antigen receptor T (CAR-T) cell therapy in diverse tumors. Conventional CARs employ an intracellular domain (ICD) from the ζ subunit of CD3 as a signaling module, and it is largely unknown how alternative CD3 chains potentially contribute to CAR design. Here, we obtained a series of CAR-T cells against HER2 and mesothelin using a domain comprising a single immunoreceptor tyrosine-based activation motif from different CD3 subunits as the ICD of CARs. While these reconstituted CARs conferred sufficient antigen-specific cytolytic activity on equipped T cells, they elicited low tonic signal, ameliorated the exhaustion and promoted memory differentiation of these cells. Intriguingly, the CD3ε-derived ICD outperformed others in generation of CAR-T cells that produced minimized cytokines. Mechanistically, CD3ε-based CARs displayed a restrained cytomembrane expression on engineered T cells, which was ascribed to endoplasmic reticulum retention mediated by the carboxyl terminal basic residues. The present study demonstrated the applicability of CAR reconstitution using signaling modules from different CD3 subunits, and depicted a novel pattern of CAR expression that reduces cytokine release, thus paving a way for preparation of CAR-T cells displaying improved safety and persistence against diverse tumor antigens.

Rational selection of TbpB variants yields a bivalent vaccine with broad coverage against Neisseria gonorrhoeae

Neisseria gonorrhoeae is an on-going public health problem due in part to the lack of success with efforts to develop an efficacious vaccine to prevent this sexually transmitted infection. The gonococcal transferrin binding protein B (TbpB) is an attractive candidate vaccine antigen. However, it exhibits high levels of antigenic variability, posing a significant obstacle in evoking a broadly protective immune response. Here, we utilize phylogenetic information to rationally select TbpB variants for inclusion into a gonococcal vaccine and identify two TbpB variants that together elicit a highly cross-reactive antibody response against a diverse panel of TbpB variants and clinically relevant gonococcal strains. This formulation performed well in experimental proxies of real-world usage, including eliciting bactericidal activity against diverse gonococcal strains and decreasing the median duration of colonization after vaginal infection in female mice. These data support the use of a combination of TbpB variants for a broadly protective gonococcal vaccine.

Targeting Plasmodium falciparum chondroitin sulfate a ligand: A highly conserved malaria antigen with potential for pregnancy-associated malaria vaccine development

Background Pregnant women in malaria-endemic regions exhibit heightened susceptibility to Plasmodium falciparum infection due to accumulation of infected red blood cells (iRBCs) in the placenta. This is aided by the variant antigen 2 chondroitin sulfate A (VAR2CSA) protein which remains a target for pregnancy-associated malaria (PAM) vaccine studies. However, polymorphism in this antigen presents a significant challenge in developing broadly efficacious vaccines. This study explored PfCSA-L, a protein co-expressed and co-localized with VAR2CSA, as a potential alternative vaccine target due to its hypothesized role in PAM pathogenesis. Methods Sera and dried blood spots were collected from pregnant women attending antenatal care clinic at Webuye County Hospital, Western Kenya. P. falciparum infection status was confirmed by PCR. Recombinant PfCSA-L, expressed using a eukaryotic wheat germ cell-free system (WGCFS), was used to assess IgG antibody responses via ELISA. Results We observed a statistically significant increase in IgG levels as gestation advanced, suggesting potential exposure-driven antibody maturation against PfCSA-L. Primigravida women exhibited a trend toward higher anti-PfCSA-L antibody levels compared to multigravida during the second visit, possibly reflecting a more vigorous immune response during the first pregnancy. Genetic analysis of field parasite isolates revealed a high conservation of PfCSA-L at both DNA and protein levels. B-cell epitope prediction identified potential targets on the PfCSA-L surface within the conserved region. Conclusion These findings, coupled with the observed IgG response, further positions PfCSA-L as a promising vaccine candidate for PAM. However, further investigations are warranted to elucidate the functional role of anti-PfCSA-L antibodies and definitively validate PfCSA-L and/or the identified epitopes as potential PAM vaccine targets.

Variable surface antigen expression, virulence, and persistent infection by Plasmodium falciparum malaria parasites.

SUMMARYThe human malaria parasite Plasmodium falciparum is known for its ability to maintain lengthy infections that can extend for over a year. This property is derived from the parasite's capacity to continuously alter the antigens expressed on the surface of the infected red blood cell, thereby avoiding antibody recognition and immune destruction. The primary target of the immune system is an antigen called PfEMP1 that serves as a cell surface receptor and enables infected cells to adhere to the vascular endothelium and thus avoid filtration by the spleen. The parasite's genome encodes approximately 60 antigenically distinct forms of PfEMP1, each encoded by individual members of the multicopy var gene family. This provides the parasite with a repertoire of antigenic types that it systematically cycles through over the course of an infection, thereby maintaining an infection until the repertoire is exhausted. While this model of antigenic variation based on var gene switching explains the dynamics of acute infections in individuals with limited anti-malarial immunity, it fails to explain reports of chronic, asymptomatic infections that can last over a decade. Recent field studies have led to a re-evaluation of previous conclusions regarding the prevalence of chronic infections, and the application of new technologies has provided insights into the molecular mechanisms that enable chronic infections and how these processes evolved.

Co-infection of Newcastle Disease and Avian Colibacillosis in a 4-week-old Broiler Flock in Maiduguri, Nigeria

Newcastle disease (ND) and avian colibacillosis (AC) outbreak occurred in a 200-bird commercial broiler flock in Maiduguri, Nigeria. Despite vaccinations, the flock experienced a 60% morbidity and 45% mortality rate. Symptoms observed among the flock included weakness, inappetence, diarrhea, nervous signs, and emaciation. Laboratory tests confirmed ND and AC infections. Haemagglutination and haemagglutination inhibition was used to identify NDV infection while bacteriological culture and identification was used isolated Escherichia coli (E. coli). The outbreak highlights the economic impact of these diseases on the poultry industry in Nigeria. Recommendations include improved biosecurity measures, regular vaccination, and timely treatment of secondary bacterial infections. Public health concerns also arise due to the zoonotic potential of ND. The vaccine failure in this case may be due to break in cold chain due to power outage, antigenic variation or inappropriate handling. Further research is needed to investigate vaccine failures and develop more effective prevention strategies.

Casein Kinases 2-dependent phosphorylation of the placental ligand VAR2CSA regulates Plasmodium falciparum-infected erythrocytes cytoadhesion.

Placental malaria is characterized by the massive accumulation and sequestration of infected erythrocytes in the placental intervillous blood spaces, causing severe birth outcomes. The variant surface antigen VAR2CSA is associated with Plasmodium falciparum sequestration in the placenta via its capacity to adhere to chondroitin sulfate A. We have previously shown that the extracellular region of VAR2CSA is phosphorylated on several residues and that the phosphorylation enhances the adhesive properties of CSA-binding infected erythrocytes. Here, we aimed to identify the kinases mediating this phosphorylation. We report that human and Plasmodium falciparum Casein Kinase 2α are involved in the phosphorylation of the extracellular region of VAR2CSA. We notably show that both CK2α can phosphorylate the extracellular region of recombinant and immunoprecipitated VAR2CSA. Mass spectrometry analysis of recombinant VAR2CSA phosphorylated by recombinant Human and P. falciparum CK2α combined with site-directed mutagenesis led to the identification of residue S1068 in VAR2CSA, which is phosphorylated by both enzymes and is associated with CSA binding. Furthermore, using CRISPR/Cas9 we generated a parasite line in which phosphoresidue S1068 was changed to alanine. This mutation strongly impairs infected erythrocytes adhesion by abolishing VAR2CSA translocation to the surface of infected erythrocytes. We also report that two specific CK2 inhibitors reduce infected erythrocytes adhesion to CSA and decrease the phosphorylation of the recombinant extracellular region of VAR2CSA using either infected erythrocytes lysates as a source of kinases or recombinant Human and P. falciparum casein kinase 2. Taken together, these results undoubtedly demonstrate that host and P. falciparum CK2α phosphorylate the extracellular region of VAR2CSA and that this post-translational modification is important for VAR2CSA trafficking and for infected erythrocytes adhesion to CSA.

Identification of novel PfEMP1 variants containing domain cassettes 11, 15 and 8 that mediate the Plasmodium falciparum virulence-associated rosetting phenotype.

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a diverse family of variant surface antigens, encoded by var genes, that mediates binding of infected erythrocytes to human cells and plays a key role in parasite immune evasion and malaria pathology. The increased availability of parasite genome sequence data has revolutionised the study of PfEMP1 diversity across multiple P. falciparum isolates. However, making functional sense of genomic data relies on the ability to infer binding phenotype from var gene sequence. For P. falciparum rosetting, the binding of infected erythrocytes to uninfected erythrocytes, the analysis of var gene/PfEMP1 sequences encoding the phenotype is limited, with only eight rosette-mediating PfEMP1 variants described to date. These known rosetting PfEMP1 variants fall into two types, characterised by N-terminal domains known as "domain cassette" 11 (DC11) and DC16. Here we test the hypothesis that DC11 and DC16 are the only PfEMP1 types in the P. falciparum genome that mediate rosetting, by examining a set of thirteen recent culture-adapted Kenyan parasite lines. We first analysed the var gene/PfEMP1 repertoires of the Kenyan lines and identified an average of three DC11 or DC16 PfEMP1 variants per genotype. In vitro rosette selection of the parasite lines yielded four with a high rosette frequency, and analysis of their var gene transcription, infected erythrocyte PfEMP1 surface expression, rosette disruption and erythrocyte binding function identified four novel rosette-mediating PfEMP1 variants. Two of these were of the predicted DC11 type (one showing the dual rosetting/IgM-Fc-binding phenotype), whereas two contained DC15 (DBLα1.2-CIDRα1.5b) a PfEMP1 type not previously associated with rosetting. We also showed that a Thai parasite line expressing a DC8-like PfEMP1 binds to erythrocytes to form rosettes. Hence, these data expand current knowledge of rosetting mechanisms and emphasize that the PfEMP1 types mediating rosetting are more diverse than previously recognised.

Epigenetic phase variation in the gut microbiome enhances bacterial adaptation.

The human gut microbiome within the gastrointestinal tract continuously adapts to variations in diet, medications, and host physiology. A central strategy for genetic adaptation is epigenetic phase variation (ePV) mediated by bacterial DNA methylation, which can regulate gene expression, enhance clonal heterogeneity, and enable a single bacterial strain to exhibit variable phenotypic states. Genome-wide and site-specific ePV have been well characterized in human pathogens' antigenic variation and virulence factor production. However, the role of ePV in facilitating adaptation within the human microbiome remains poorly understood. Here, we comprehensively cataloged genome-wide and site-specific ePV in human infant and adult gut microbiomes. First, using long-read metagenomic sequencing, we detected genome-wide ePV mediated by complex structural variations of DNA methyltransferases, highlighting the ones associated with antibiotics or fecal microbiota transplantation. Second, we analyzed an extensive collection of public short-read metagenomic sequencing datasets, uncovering a greater prevalence of genome-wide ePV in the human gut microbiome. Third, we quantitatively detected site-specific ePVs using single-molecule methylation analysis to identify dynamic variations associated with antibiotic treatment or probiotic engraftment. Finally, we performed an in-depth assessment of an Akkermansia muciniphila isolate from an infant, highlighting that ePV can regulate gene expression and enhance the bacterial adaptive capacity by employing a bet-hedging strategy to increase tolerance to differing antibiotics. Our findings indicate that epigenetic modifications are a common and broad strategy used by bacteria in the human gut to adapt to their environment.

Molecular and phylogenetic analyses of the first complete genome sequence of Duck hepatitis A virus genotype 2 from India.

Duck viral hepatitis (DVH) caused by duck hepatitis A virus (DHAV) is a highly contagious and economically important disease of ducklings worldwide. In many parts of the globe, disease outbreaks are reported in spite of vaccinations, probably due to antigenic diversity among DHAV genotypes. We previously reported the first isolation of DHAV-2 (Genotype -2) from ducklings in Tamil Nadu, India. In this study, we discuss the complete genome sequence of this DHAV-2 isolate (OQ862826). The DHAV-2 genome is 7769 bp long, with a 5'-UTR of 653 bp and a 3'-UTR of 366 bp, respectively. Phylogenetic analysis showed clustering of the isolate with DHAV-2, exhibiting 93 % nucleotide identity and 97.5 % amino acid identity with the two Taiwanese DHAV-2 strains reported till date. The genome organization, protease cleavage sites, and protein structures were predicted, revealing conserved motifs/domains essential for virus replication and assembly. Comparative analysis with DHAV-1 (genotype -1) and DHAV-3 (genotype -3) revealed distinct antigenic properties, with conserved functional domains, and also variations within structural and nonstructural proteins. Comparison of the VP1 protein sequences revealed diversity between the genotypes. However, a highly conserved B-cell epitope (174LPSPTY179) similar to previous report in DHAV-1 was observed in all the three DHAV-2 strains. The 2A2 protein, 2C protein, and 3D protein exhibited significant conservation. We identified the critical amino acids required for proteolytic enzyme activity of the 3C protein. The absence of serological cross-neutralization between DHAV-1 and DHAV-2 underscores the importance of genotype-specific vaccines. Our findings provide valuable insights of the molecular signatures of DHAV-2 that could be useful for the development of effective vaccines and diagnostic tools.

Comparative Genomic and Biological Investigation of NADC30‐ and NADC34‐Like PRRSV Strains Isolated in South Korea

Porcine reproductive and respiratory syndrome virus (PRRSV) is a globally endemic, costly swine arterivirus with wide genetic and antigenic variations, leading to the frequent appearance of novel virulent strains that hampers PRRSV control. Recently, NADC30‐like (lineage 1C, L1C) and NADC34‐like (lineage 1A, L1A) PRRSV strains were reported to be prevalent in mainland South Korea and became the main epidemic strains persistently attributed to PRRSV outbreaks nationwide, raising great concern in the domestic pork industry. Although the genotypic and pathotypic variability of NADC30‐ and NADC34‐like viruses has been explored in the United States and China, their genomic and biological characteristics have been scarcely studied in South Korea. Here, NADC34‐like GNU‐2353 and NADC30‐like GNU‐2377 strains were independently identified from vaccinated swine herds experiencing high piglet mortality. Whole‐genome sequencing and phylogenetic analysis revealed that GNU‐2353 and GNU‐2377 clustered into sublineages L1A (NADC34‐like) and L1C (NADC30‐like), respectively, sharing high genomic homology with their corresponding lineage‐representative strains and harboring the same molecular signatures of continuous 100 and discontinuous 131 amino acid deletions in the nsp2‐coding region, respectively. Recombination detection indicated that GNU‐2353 and GNU‐2377 were recombinants and evolved through natural interlineage recombination between NADC34‐like (L1A, major parent) or NADC30‐like (L1C, major parent) and RespPRRS modified live virus (MLV)–like (lineage 5, minor parent) strains, respectively. Both viruses displayed homogenous growth kinetics but replicated faster than the prototype VR‐2332 in a porcine alveolar macrophage cell line (PAM‐KNU). The transcriptional profiles of immune response genes in infected PAM‐KNU cells varied between the isolates and VR‐2332; particularly, interleukin‐10 expression was dramatically upregulated in cells infected with GNU‐2353 and GNU‐2377. Piglets with GNU‐2353 and GNU‐2377 infection had high fever; weight loss; increased viremia and nasal shedding; viral distribution in various tissues; thymic atrophy; and apparent macroscopic and microscopic lung lesions, including interstitial pneumonia and viral colonization, compared with control piglets, suggesting that both isolates were virulent to pigs. Remarkably, GNU‐2353 caused higher fever, mortality rate (40%) with cyanosis, viremia, and viral shedding within 2 weeks and significantly higher viral loads in several organs than GNU‐2377 infection. Thus, NADC34‐like GNU‐2353 was more pathogenic than NADC30‐like GNU‐2377. Our findings provide insights into the current epizootic circumstance of NADC30‐ and NADC34‐like PRRSV in South Korea and can aid in tailoring improved control strategies.

Malaria: Factors affecting disease severity, immune evasion mechanisms, and reversal of immune inhibition to enhance vaccine efficacy.

Malaria is a complex parasitic disease caused by species of Plasmodium parasites. Infection with the parasites can lead to a spectrum of symptoms and disease severity, influenced by various parasite, host, and environmental factors. There have been some successes in developing vaccines against the disease recently, but the vaccine efficacies require improvement. Some issues associated with the difficulties in developing a sterile vaccine include high antigenic diversity, switching expression of the immune targets, and inhibition of immune pathways. Current vaccine research focuses on identifying conserved and protective epitopes, developing multivalent vaccines (including the whole parasite), and using more powerful adjuvants. However, overcoming the systematic immune inhibition and immune cell dysfunction/exhaustion may be required before high titers of protective antibodies can be achieved. Increased expression of surface molecules such as CD86 and MHC II on antigen-presenting cells and blocking immune checkpoint pathways (interactions of PD-1 and PD-L1; CTLA-4 and CD80) using small molecules could be a promising approach for enhancing vaccine efficacy. This assay reviews the factors affecting the disease severity, the genetics of host-parasite interaction, immune evasion mechanisms, and approaches potentially to improve host immune response for vaccine development.

Design and evaluation of a multi-epitope HIV-1 vaccine based on human parvovirus virus-like particles.

The development of a protective HIV vaccine remains a challenge given the high antigenic diversity and mutational rate of the virus, which leads to viral escape and establishment of reservoirs in the host. Modern antigen design can guide immune responses towards conserved sites, consensus sequences or normally subdominant epitopes, thus enabling the development of broadly neutralizing antibodies and polyfunctional lymphocyte responses. Conventional epitope vaccines can often be impaired by low immunogenicity, a limitation that may be overcome by using a carrier system. In this work, Virus-Like Particles (VLPs) of the B19 human parvovirus were used as a carrier system for multiple HIV-1 epitopes displayed on the surface. Epitopes were selected based on being the binding site of broadly neutralizing antibodies (bnAbs) in patients. Full capsid assembly was confirmed by dynamic light scattering and morphology was confirmed by transmission electron imaging. The resulting chimeric VLPs were termed "VLP-MHIV-A". Antigenicity was confirmed by HIV+ patient sera binding to the chimeric VLP-MHIV-A. To evaluate immunogenicity, female C57bl/6 mice were immunized with the chimeric VLPs either via the intramuscular or subcutaneous route, specific humoral and cellular responses were evaluated, and neutralizing activity was measured in an in vitro reporter cell system. Substantial antibodies against whole-VLPs were induced in serum and vaginal lavages for both immunization routes. Antibody responses against the CD4 binding site, V3 loop and several epitopes of gp41 were detected. Both immunization routes demonstrated neutralizing activity; however, the I.M. route was more effective, showing significant neutralizing activity with up to 50% inhibition of a tier 1 clade B virus infection. Taken as a whole, these results show that chimeric VLPs are an effective antigen capable of inducing HIV-1 specific antibodies with neutralizing activity.

Laboratory safety and immunogenicity evaluation of live attenuated avian infectious bronchitis GI-23 virus vaccine.

Avian infectious bronchitis virus (IBV) is responsible for a highly contagious disease that poses a significant threat to the poultry industry due to its high rates of evolution. The occurrence of vaccination failure can frequently be attributed to the emergence of novel strains that exhibit antigenic divergence from conventional vaccine strains. This study aims to evaluate the safety and efficacy of the Eg/1212B-based live attenuated virus vaccine indicated for immunization of chickens against nephropathogenic GI-23 variant strains reported globally. Studies were designed in compliance with European Pharmacopeia Ph. Eur. 0442. The attenuated vaccine virus did not exhibit any tendency to revert or increase in virulence after five back-passages in SPF chickens. Ciliostasis scores and kidney lesions (histology) were comparable between vaccinated and control birds. No chicken showed clinical signs of an infection with IBV or died from causes attributable to the vaccine after receiving a 10× overdose. A single vaccination was able to protect the birds in a challenge model with a recent European wild-type IBV strain. The study demonstrated an onset of immunity of 21days and a duration of immunity lasting up to 56days. Vaccination administered individually through the ocular route resulted in a protection rate of 100% to 85%, whereas mass application by spraying offered a protection rate of 85% to 80%. In conclusion, the safety and efficacy data confirm a positive benefit/risk balance, and the investigated product can be considered a suitable vaccine candidate for controlling avian infectious bronchitis nephropathogenic variant strains related to GI-23.

INSIHGT: an accessible multi-scale, multi-modal 3D spatial biology platform

AbstractBiological systems are complex, encompassing intertwined spatial, molecular and functional features. However, methodological constraints limit the completeness of information that can be extracted. Here, we report the development of INSIHGT, a non-destructive, accessible three-dimensional (3D) spatial biology method utilizing superchaotropes and host-guest chemistry to achieve homogeneous, deep penetration of macromolecular probes up to centimeter scales, providing reliable semi-quantitative signals throughout the tissue volume. Diverse antigens, mRNAs, neurotransmitters, and post-translational modifications are well-preserved and simultaneously visualized. INSIHGT also allows multi-round, highly multiplexed 3D molecular probing and is compatible with downstream traditional histology and nucleic acid sequencing. With INSIHGT, we map undescribed podocyte-to-parietal epithelial cell microfilaments in mouse glomeruli and neurofilament-intensive inclusion bodies in the human cerebellum, and identify NPY-proximal cell types defined by spatial morpho-proteomics in mouse hypothalamus. We anticipate that INSIHGT can form the foundations for 3D spatial multi-omics technology development and holistic systems biology studies.

Inhibitory KIRs decrease HLA class II-mediated protection in Type 1 Diabetes.

Inhibitory killer cell immunoglobulin-like receptors (iKIRs) are a family of inhibitory receptors that are expressed by natural killer (NK) cells and late-stage differentiated T cells. There is accumulating evidence that iKIRs regulate T cell-mediated immunity. Recently, we reported that T cell-mediated control was enhanced by iKIRs in chronic viral infections. We hypothesized that in the context of autoimmunity, where an enhanced T cell response might be considered detrimental, iKIRs would have an opposite effect. We studied Type 1 diabetes (T1D) as a paradigmatic example of autoimmunity. In T1D, variation in the Human Leucocyte Antigen (HLA) genes explains up to 50% of the genetic risk, indicating that T cells have a major role in T1D etiopathogenesis. To investigate if iKIRs affect this T cell response we asked whether HLA associations were modified by iKIR genes. We conducted an immunogenetic analysis of a case-control T1D dataset (N = 11,961) and found that iKIR genes, in the presence of genes encoding their ligands, have a consistent and significant effect on protective HLA class II genetic associations. Our results were validated in an independent data set. We conclude that iKIRs significantly decrease HLA class II protective associations and suggest that iKIRs regulate CD4+ T cell responses in T1D.

Novel Antigenic Variant Infectious Bursal Disease Virus Outbreaks in Japan from 2014 to 2023 and Characterization of an Isolate from Chicken.

Novel antigenic variant strains of the infectious bursal disease virus (IBDV) classified into genogroup A2d have been found in the western part of Japan since 2017. Novel antigenic variant IBDVs now occur in higher frequencies in poultry houses and have been detected in the eastern part of Japan, indicating the spread of IBDVs despite the usual IBDV vaccination. We isolated a novel antigenic variant IBDV, designated as the B2977CE2C3 strain. The B2977CE2C3 strain had two genogroup A2d specific amino acids-lysine and isoleucine, at 221 and 252 aa-along with the other genogroup A2 common amino acids in the projection domains of the VP2 protein corresponding to the virus-neutralizing epitopes and viral pathogenicity. Experimental infection of the B2977CE2C3 strain did not produce any apparent clinical signs in the specific-pathogen-free chickens during the observation period (21 days), but atrophy of the bursa of Fabricius (BF) was apparent. The mean BF to the body weight ratio was 0.35 in negative control chickens at 21 days post-infection (pi) but 0.06 in the B2977CE2C3 infected group. An extremely high copy number of the IBDV genome (>108 copies/µL) was observed in the BF at 3 days pi, while a high copy number of the IBDV genome (>106 copies/µL) was observed in the thymus, spleen cecal tonsil, and bone marrow even though macroscopic lesions were not apparent in these organs.