ImmunoHorizons最新文献

Highly pathogenic avian influenza (HPAI) poses an expanding global threat with direct relevance to immunologists studying host-pathogen dynamics, cross-species transmission, and immune responses to emerging viruses. Driven primarily by evolving H5 and H7 influenza A subtypes, HPAI now affects a broadening host range, including spillovers into mammals such as seals, cattle, and humans, raising concern for pandemic potential. Applying a One Health perspective, this review emphasizes the immunological and ecological factors that underlie HPAI emergence and spread. Migratory bird flyways, shared aquatic habitats, and intensive poultry systems create viral mixing zones that promote antigenic diversification and interspecies transmission. Climate change and land-use transformation exacerbate these risks by altering host distributions and increasing interfaces between wildlife, livestock, and people. While poultry vaccines are widely used, human vaccine development faces challenges from antigenic drift, clade variation, and limited cross-protective immunity. Immunologists play a critical role in understanding these dynamics, particularly regarding host immune barriers, viral adaptation, and the development of broad-spectrum or next-generation vaccines. Technological advances in pathogen surveillance, such as AI-driven forecasting, genomic sequencing, and real-time risk mapping, are promising early-warning tools, but require stronger integration across human, animal, and environmental health sectors. Addressing HPAI's complex immunoecological dynamics demands a One Health approach: cross-sectoral data sharing, coordinated response strategies, and investment in resilient health systems. As HPAI continues to evolve and expand its host range, sustained global investment in One Health governance, research, and infrastructure will be vital to prevent future pandemics and safeguard health across species.

The development of effective vaccines against emerging infectious diseases, including avian influenza strains such as H5N1 and H7N9, is hindered by the limited translational fidelity of animal models and the low throughput of traditional preclinical platforms. Human immune organoids are ex vivo, multicellular, lymphoid cultures derived from tonsil, or spleen tissue, offering a physiologically relevant and scalable system to model human germinal center biology and vaccine responses. We describe how tonsil and spleen organoids can support the rationale design of antigen and adjuvant for influenza vaccines. Coupled antigen strategies, which leverage pre-existing memory T cells, can significantly enhance responses to weak antigens, such as avian HA. Moreover, a cytokine screen performed in human immune organoids revealed distinct adjuvanticity profiles and mapped functional axes involving type I interferons and IL-12/IL-21 signaling. We propose a new paradigm: functional systems immunology, combining mechanistic perturbation in human immune organoids with high-dimensional immune profiling. This platform will enable the causal dissection of human immune regulation at a large scale. High-throughput screen of candidates will enable efficient vaccine designs.

Tumor necrosis factor receptor (TNFR)-associated factor 1 (TRAF1) regulates NF-κB signaling and is implicated in chronic autoimmune diseases characterized by persistent inflammation. In addition to its role in restraining linear ubiquitin assembly complex-mediated linear ubiquitination of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) to limit inflammasome activation, TRAF1 also stabilizes cellular inhibitor of apoptosis protein 2 (cIAP2) by protecting it from degradation. Notably, cIAP2 promotes inflammasome activation via K63-linked polyubiquitination of caspase-1. Here, we show that disrupting the TRAF1/cIAP2 interaction (V203A in humans; V196A in mice) reduces inflammasome activation. TRAF1V203A THP-1 cells exhibit diminished caspase-1 ubiquitination, leading to impaired IL-1β secretion. Similarly, TRAF1V196A mice produce significantly lower IL-1β levels after LPS challenge. In a monosodium urate crystal-induced arthritis model, TRAF1V196A mice show reduced joint inflammation, decreased synovial immune cell infiltration, and attenuated disease severity. These findings establish the TRAF1/cIAP2 axis as a key regulator of inflammasome activation and a potential therapeutic target for inflammasome-driven diseases such as gout.

Hybrid immune individuals who experience an infection after a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine series show evidence of salivary anti-spike and anti-receptor binding domain (RBD) IgA antibodies with broad specificity against different variants. It is unclear how long these antibodies persist and whether they offer protection against new SARS-CoV-2 infections. We compared salivary IgA levels to full-length spike protein and its RBD of the ancestral Wuhan SARS-CoV-2 virus and the Omicron BA.1 variant in a subset of persons participating in a longitudinal study of binding antibody responses to vaccination. We assessed the decay rate of the salivary IgA antibodies in those with hybrid immunity. In our heavily vaccinated population, low levels of salivary IgA to RBD and spike was variably detected in vaccine-only immunity to both Wuhan and Omicron BA.1, but antibody levels were an order of magnitude higher in those with hybrid immunity. In hybrid immune individuals, anti-spike/RBD salivary IgA rapidly decayed over a 4-month observation period. In a multivariate analysis, salivary IgA antibody to Omicron BA.1 was not associated with protection from a new SARS-CoV-2 infection over the subsequent 10 months during the Omicron XBB.1.5, EG.5, and JN waves of infection. In contrast, receipt of a new vaccine dose was significantly associated with protection.

The ability to manipulate the mouse genome has contributed heavily to countless discoveries in biology for several decades. The Cre/loxP system enables conditional and inducible deletion of virtually any sequences in the mouse. Because Cre expression does not always predict Cre activity and does not necessarily mirror expression of the endogenous gene(s) whose cis-acting genetic elements were used to construct a given Cre "driver" mouse line, Cre "reporter" mouse lines have been developed in which expression of Cre is signified by expression of one of a variety of fluorescent or otherwise easily detectable proteins, including EYFP, tdTomato, and βgal. It is shown here that one such widely utilized Cre reporter mouse line, which expresses EYFP following Cre-mediated recombination, fails to detect a significant fraction of Cre+ T cells, as detected with an otherwise identical tdTomato-expressing Cre reporter. Given the wide use of this and similar Cre reporter mouse lines, these findings have potentially significant implications for a diverse array of studies.

Plasmodium falciparum malaria and Epstein-Barr virus (EBV) coinfections have been associated with an increased risk of developing the EBV-associated cancer endemic Burkitt lymphoma (eBL). In children living in malaria-endemic areas, repeated episodes of malaria may alter the immune system's ability to suppress EBV, creating a permissive environment for eBL pathogenesis. However, the malaria-driven mechanisms involved remain undefined, including whether malaria-induced immune alterations are EBV-specific or systemic. To identify whether acute clinical P. falciparum malaria affects EBV T-cell immunity, we characterized T-cell activation status and cytokine secretion profiles using flow cytometry. We compared profiles in 10 Kenyan children with acute clinical P. falciparum malaria at baseline and matched 4-week recovery, and 10 healthy community controls following antigenic stimulation with EBV- and cytomegalovirus-specific peptides. The percentage frequency of activation-induced marker cells was comparable within the study cohort across the different stimulations. Furthermore, we observed a shift in cytokine secretion in children with acute malaria during active disease and at 4 weeks postrecovery, favoring IL-10 for both T-cell subsets. Our findings suggest that clinical malaria did not result in the impairment of T-cell activation, but rather induced shifts in cytokine secretion in favor of IL-10. We further demonstrate that malaria-induced T-cell immune alterations are not EBV-specific but rather affect overall immune suppression.

BRCA1 (breast cancer 1, early onset) is originally identified as a tumor suppressor in hereditary breast and ovarian cancer. Recent studies have suggested that BRCA1 contributes to the cell fate decisions in mammary epithelium. Although BRCA1 has been shown to be expressed in the thymus, its physiologic role(s) in the thymus remain unclear. In this study, we found that BRCA1 was expressed in a subset of thymic medullary epithelial cells: epithelial cell adhesion molecule (EpCAM, CD326) positive, UEA-1 ligand positive, and Aire negative. To clarify its functional significance, we analyzed the differentiation of thymic epithelial cells in mice in which BRCA1 was specifically deleted in K14-expressing cells. Interestingly, conditional BRCA1-deficient mice displayed enhanced development of Hassall's corpuscles. Notably, thymoproteasome catalytic subunit β5t (proteasome subunit beta 11), a marker of cortical thymic epithelial cells (cTECs), was frequently detected adjacent to Hassall's corpuscles in BRCA1 knockout mice. In addition, medullary β5t+ cells appeared to differentiate into cTECs. In addition, BRCA1 deficiency led to increased generation of regulatory T cells. Thus, BRCA1 was also found to regulate epithelial differentiation in the thymus. Our observations in BRCA1-deficient mice may be relevant to understanding the immune system in human with BRCA1 germline mutations.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) preferentially infects airway epithelial cells. This infection is mediated by the binding of SARS-CoV-2 spike (S) protein to ACE2 expressed on target cells. Patients with allergic (type-2) asthma have been reported to be less susceptible to coronavirus disease 2019 (COVID-19), but these effects are controversial and mechanistically unclear. We previously showed lower expression of ACE2 mRNA in airway epithelial cells from type-2 asthmatics compared to healthy donors. Moreover, we and others demonstrated that the type-2 cytokine interleukin 13 (IL-13) suppresses ACE2 expression and SARS-CoV-2 infection in human epithelial cells. To better understand the relationship between type-2 inflammation, ACE2 expression, and SARS-CoV-2 infection, we investigated the effects of IL-13 on critical steps of epithelial cell infection by SARS-CoV-2: S protein-mediated binding to ACE2 on epithelial cells, and ACE2-mediated SARS-CoV-2 entry into these cells. Recombinant IL-13 significantly inhibited both these processes. This inhibition appeared to be mediated by IL-13-induced suppression of ACE2 transcription because IL-13 failed to affect S protein-mediated viral entry into cells that express ACE2 under the control of an IL-13 unresponsive heterologous promoter. We propose that IL-13 protects epithelial cells from SARS-CoV-2 infection largely by inhibiting ACE2 expression and ACE2-mediated downstream events that allow the virus to access its cellular targets.

Ficolins, encoded by FCN genes, are key pattern recognition molecules of the lectin complement pathway involved in immune complex clearance, a process often impaired in systemic lupus erythematosus (SLE). Genetic polymorphisms in FCN genes may influence disease susceptibility. However, their functional significance in SLE remains unclear. The present study aimed to investigate the association of selected FCN gene single-nucleotide polymorphisms (SNPs) with SLE, lupus nephritis (LN), and serum ficolin levels in a Western Indian cohort. Seven SNPs in FCN1 (rs2989727, rs1071583), FCN2 (rs7851696, rs17549193, rs7865453, rs17514136), and FCN3 (rs3813800) were genotyped in 200 SLE patients and 200 healthy controls using polymerase chain reaction (PCR) sequence-specific primer and PCR restriction fragment length polymorphism. Serum ficolin-1, -2, and -3 levels were measured using ELISA. Statistical analysis included χ2 test, Kruskal-Wallis test, and logistic regression to assess associations and calculate odds ratios with 95% confidence intervals. The analysis identified significant associations of FCN2 rs7851696, rs7865453, and rs17514136, as well as FCN3 rs3813800, with SLE susceptibility. Among LN patients, FCN1 rs2989727 and rs1071583, FCN2 rs17514136, and FCN3 rs3813800 showed significant associations. FCN3 rs3813800 was significantly associated with ficolin-3 levels, while FCN2 rs7865453 was associated with complement component 1q-circulation immune complex levels. These findings provide novel insight into associations of FCN gene polymorphisms with SLE and LN susceptibility, with genotype-phenotype correlations suggesting their biological relevance. Future longitudinal and mechanistic studies are warranted to validate these associations and explore their therapeutic potential.