Immune Adaptation Research Articles

The compositional behavior of the human T cell receptor repertoire in ovarian cancer compared to healthy donors

The distinctive characteristics of an individual’s T cell receptor repertoire are crucial in recognizing and responding to a diverse array of antigens, contributing to immune specificity and adaptability. The repertoire, famously vast due to a series of cellular mechanisms, can be quantified using repertoire sequencing. In this study, we sampled the repertoire of 85 women: ovarian cancer patients (OC) and healthy donors (HD), generating a dataset of T cell clones and their abundance. For the alpha chain we obtained 6.4·106 reads, with an average of 75936 clones per sample, and an average of 30607 clonotypes per sample. For the beta chain we obtained 13.6·106 reads, with an average of 160400 clones per sample, and an average of 70071 clonotypes per sample. The changes in dynamics of the repertoire can be observed in response to disease, with specific clones undergoing clonal expansion and contraction. The data provided here offers a unique view of immune system behavior in health and disease and can be used to stratify OC and HD.

Bat genomes illuminate adaptations to viral tolerance and disease resistance.

Zoonoses are infectious diseases transmitted from animals to humans. Bats have been suggested to harbour more zoonotic viruses than any other mammalian order1. Infections in bats are largely asymptomatic2,3, indicating limited tissue-damaging inflammation and immunopathology. To investigate the genomic basis of disease resistance, the Bat1K project generated reference-quality genomes of ten bat species, including potential viral reservoirs. Here we describe a systematic analysis covering 115 mammalian genomes that revealed that signatures of selection in immune genes are more prevalent in bats than in other mammalian orders. We found an excess of immune gene adaptations in the ancestral chiropteran branch and in many descending bat lineages, highlighting viral entry and detection factors, and regulators of antiviral and inflammatory responses. ISG15, which is an antiviral gene contributing to hyperinflammation during COVID-19 (refs. 4,5), exhibits key residue changes in rhinolophid and hipposiderid bats. Cellular infection experiments show species-specific antiviral differences and an essential role of protein conjugation in antiviral function of bat ISG15, separate from its role in secretion and inflammation in humans. Furthermore, in contrast to humans, ISG15 in most rhinolophid and hipposiderid bats has strong anti-SARS-CoV-2 activity. Our work reveals molecular mechanisms that contribute to viral tolerance and disease resistance in bats.

An essential role for TASL in mouse autoimmune pathogenesis and Toll-like receptor signaling

TASL is an immune adaptor that binds to the solute carrier SLC15A4 and facilitates activation of the transcription factor IRF5 during Toll-like receptor (TLR) signaling. Similar to IRF5 and SLC15A4, single nucleotide polymorphisms (SNPs) within TASL have been implicated in increased susceptibility to systemic lupus erythematosus (SLE) in patients. However, the biological function of TASL in vivo and how SLE-associated SNPs increase disease risk is unknown. Here we report that mice deficient in Tasl lack responses to TLR7/9 stimulation and are protected from autoimmune symptoms induced by Aldara or pristane. Loss of Tasl reduces IRF5 phosphorylation and cytokine production in multiple immune cell types but has no effect on other aspects of TLR signaling. Conversely, an SLE-associated TASL risk variant increases TASL protein expression via codon usage, resulting in augmented cytokine production in human cells. Altogether, our study validates the essential function of TASL in TLR signaling and autoimmune pathogenesis.

The TLR7/9 adaptors TASL and TASL2 mediate IRF5-dependent antiviral responses and autoimmunity in mouse

Endosomal nucleic acid sensing by Toll-like receptors (TLRs) is central to antimicrobial immunity and several autoimmune conditions such as systemic lupus erythematosus (SLE). The innate immune adaptor TASL mediates, via the interaction with SLC15A4, the activation of IRF5 downstream of human TLR7, TLR8 and TLR9, but the pathophysiological functions of this axis remain unexplored. Here we show that SLC15A4 deficiency results in a selective block of TLR7/9-induced IRF5 activation, while loss of TASL leads to a strong but incomplete impairment, which depends on the cell type and TLR engaged. This residual IRF5 activity is ascribed to a previously uncharacterized paralogue, Gm6377, named here TASL2. Double knockout of TASL and TASL2 (TASLDKO) phenocopies SLC15A4-deficient feeble mice showing comparable impairment of innate and humoral responses. Consequently, TASLDKO mice fail to control chronic LCMV infection, while being protected in a pristane-induced SLE disease model. Our study thus demonstrates the critical pathophysiological role of SLC15A4 and TASL/TASL2 for TLR7/9-driven inflammatory responses, further supporting the therapeutic potential of targeting this complex in SLE and related diseases.

The immune landscape of fetal chorionic villous tissue in term placenta.

The immune compartment within fetal chorionic villi is comprised of fetal Hofbauer cells (HBC) and invading placenta-associated maternal monocytes and macrophages (PAMM). Recent studies have characterized the transcriptional profile of the first trimester (T1) placenta; however, the phenotypic and functional diversity of chorionic villous immune cells at term (T3) remain poorly understood. To address this knowledge gap, immune cells from human chorionic villous tissues obtained from full-term, uncomplicated pregnancies were deeply phenotyped using a combination of flow cytometry, single-cell RNA sequencing (scRNA-seq, CITE-seq) and chromatin accessibility profiling (snATAC-seq). Our results indicate that, relative to the first trimester, the frequency of fetal macrophages (HBC, proliferating HBC) is significantly reduced, whereas that of infiltrating maternal monocytes/macrophages (PAMM1b, PAMM1a, PAMM2, MAC_1) increased in T3. PAMM1b and HBCs exhibit the most phagocytic capacity at term highlighting their regulatory role in tissue homeostasis in late pregnancy. The transcriptional profiles of resident villous immune subsets exhibit a heightened activation state relative to the relative to T1, likely to support labor and parturition. Additionally, we provide one of the first insights into the chromatin accessibility profile of villous myeloid cells at term. We next stratified our findings by pre-pregnancy BMI since maternal pregravid obesity is associated with several adverse pregnancy outcomes. Pregravid obesity increased inflammatory gene expression, particularly among HBC and PAMM1a subsets, but dampened the expression of antimicrobial genes, supporting a tolerant-like phenotype of chorionic villous myeloid cells. We report a decline in HBC abundance accompanied by an increase in infiltrating maternal macrophages, which aligns with reports of heightened chorionic villous inflammatory pathologies with pregravid obesity. Finally, given the shared fetal yolk-sac origin of HBCs and microglia, we leveraged an in vitro model of umbilical cord blood-derived microglia to investigate the impact of pregravid obesity on fetal neurodevelopment. Our findings reveal increased expression of activation markers albeit dampened phagocytic capacity in microglia with pregravid obesity. Overall, our study highlights immune adaptations in the fetal chorionic villous with gestational age and pregravid obesity, as well as insight towards microglia dysfunction possibly underlying poor neurodevelopmental outcomes in offspring of women with pregravid obesity.

Comprehensive Analysis of TSPAN32 Regulatory Networks and Their Role in Immune Cell Biology.

Tetraspanin 32 (TSPAN32), a member of the tetraspanin superfamily, is one of several tumor-suppressing subtransferable fragments located in the imprinted gene domain of chromosome 11p15.5, a critical tumor-suppressor gene region. Although the biology of TSPAN32 remains largely unexplored, accumulating evidence suggests its involvement in hematopoietic functions. In this study, we performed a comprehensive analysis of the expression patterns and regulatory roles of TSPAN32. Notably, TSPAN32 is highly expressed in immune cells, particularly in natural killer (NK) cells and CD8+ T cells. The observed downregulation of TSPAN32 during immune cell activation highlights its potential role as a regulator of immune cell activation and metabolic adaptations, which are crucial for effective immune responses against pathogens and tumors. Moreover, the modulation of biological processes following TSPAN32 knockout further supports its critical role in regulating immune cell physiology and responses. These findings not only shed light on the biology of TSPAN32 but also provide the basis for exploring its diagnostic, prognostic, and therapeutic potential in autoimmune and inflammatory disorders, as well as in hematopoietic cancers.

A guide to selecting high-performing antibodies for STING1 (Uniprot ID: Q86WV6) for use in western blot, immunoprecipitation, and immunofluorescence

Stimulator of interferon genes protein (STING1) is an immune adaptor protein which promotes innate immune defense mechanisms against pathogens. To enhance our understanding of STING1-associated disease, it is essential to make high-performing antibodies accessible to the scientific community. This study aims to improve reliability of STING1 research as we have characterized sixteen STING1 commercial antibodies for western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. These studies are part of a larger, collaborative initiative seeking to address antibody reproducibility issues by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.

Combined PARP14 inhibition and PD-1 blockade promotes cytotoxic T cell quiescence and modulates macrophage polarization in relapsed melanoma

BackgroundProgrammed cell death 1 (PD-1) signaling blockade by immune checkpoint inhibitors (ICI) effectively restores immune surveillance to treat melanoma. However, chronic interferon-gamma (IFNγ)-induced immune homeostatic responses in melanoma cells contribute...

STING1 targets MYH9 to drive adipogenesis through the AKT/GSK3β/β-catenin pathway.

Stimulator of interferon response cGAMP interactor 1 (STING1), as an innate immune adaptor protein that mediates DNA sensing, has attracted tremendous biomedical interest. However, several recent researches have revealed the key role of STING1 in regulating the metabolic pathway. Here, we investigated its role in adipocyte differentiation. Preadipocytes with lentivirus-mediated Sting1 knockdown or overexpression were constructed to examine the effect of STING1 on adipocyte differentiation in vitro. Proteomics was performed in adipocytes to explore the mechanisms by which STING1 exerts pro-adipogenesis effects. Coimmunoprecipitation (CoIP)/mass spectrometry (MS) assay were used to identify the interacting partners of STING1. Our results showed that STING1 was upregulated during adipogenic differentiation of 3T3-L1 and white adipose tissue-derived stromal vascular precursor cells (WAT-SVF), accompanied by upregulation of adipocyte marker genes, peroxisome proliferator-activated receptor gamma (Pparg) and CCAAT/enhancer-binding protein beta (Cebpβ). Knockdown or overexpression of Sting1 altered adipogenesis in adipocytes. Mechanistically, proteomics and CoIP/MS assay revealed that STING1 targets non-muscle myosin protein (MYH9) to block its expression, which enhances AKT/GSK3β signaling and mediates β-catenin accumulation, affecting adipogenesis-related genes in adipocytes. These findings suggest that STING1 targeting combined with MYH9 regulates adipocyte differentiation through the AKT/GSK3β/β-catenin pathway. This is a new potential target for the treatment of hypertrophic adipose tissue, or obesity.

Phagocytosis and reactive oxygen species (ROS) production by CH138+ granulocytes isolated from blood, colostrum, and milk of Holstein cows during transition period.

This study investigated the functional activity of CH138 + granulocytes in the blood, colostrum, and transitional milk of Holstein cows throughout the transition period. Thirteen cows were assessed weekly, beginning three weeks before calving (W-3, W-2, and W-1), on the day of calving, and continuing to three weeks postpartum (W1, W2, and W3). Physical examination of the udder tissue, bacterial cultures, and blood immune function tests were performed. Microscopic Somatic Cell Count (MSCC), phagocytosis, and intracellular ROS production by CH138 + granulocytes in colostrum and transitional milk were measured weekly, from calving to W3. Disease incidence was recorded, with four cows developing metritis at W2. Mammary gland edema, affecting parenchymal tissue consistency, was the main physical finding. Non-Aureus Staphylococcus spp. dominated the bacterial isolates from the mammary secretions (67.5 %). MSCC was highest in colostrum and decreased postpartum. Bacterial culture rates peaked at calving; however, colostrogenesis limited the detection of clinical mastitis through specific examinations. Blood neutrophil function decreased at W-2 and W-1, likely increasing the risk of mammary infection and weakening the neutrophil response at calving. This immune suppression, which affects both the mammary gland and systemic immunity, was exacerbated by postpartum metritis. The findings showed heightened vulnerability to bacterial infection postpartum, which was linked to reduced cell viability and CH138 + granulocyte function. Neutrophil function in mammary secretions gradually improves post-calving, supporting immune recovery and declining infection rates. These findings provided valuable insights into the immune adaptations of CH138 + granulocytes in colostrum and transitional milk, enhancing understanding of mammary and systemic immune responses during the transition period.

Соотношение иммунокомпетентных клеток и индекса NLR у мужчин экстремальных профессий (гидрографов) в Арктическом регионе РФ

Rotational shift work in the Arctic region's northern seas has a substantial influence on the physiological condition of the human body and has a high risk of reducing reserve capacities, particularly the immune system. Assessing immune homeostasis by identifying immune balance, specifically the levels of expression of lymphoproliferation and lymphoapoptosis markers that determine the body's susceptibility to diseases, is important for maintaining public health in the Arctic region's extreme climatic and professional environments. The aim of this study is to assess the ratio of lymphocyte phenotypes CD10, CD71, CD95 and the NLR index in men working on rotating shifts in the Arctic. Materials and Methods. The study comprised 65 healthy adults aged 43,2±2,7 years: 45 males working rotating shifts of less than 3 months, 3 to 6 months, and more than 6 months, and 20 male residents (control). The neutrophil-to-lymphocyte ratio (NLR), lymphocytes with the CD10 marker to CD95, and lymphocytes with the CD71 marker to CD95 were estimated. Results. The median neutrophil to lymphocyte ratio (NLR) among rotating shift hydrographers is within the ideal normal range (1-2), regardless of shift duration, as in contrast to permanent residents, whose median NLR is stress-increased (2-3). In rotating shift workers, the CD10/CD95 ratio is balanced between 0.85 and 1.15, with evidence of a relative rise in CD10 expression levels with shift durations of more than 6 months. In 65% of Arctic inhabitants, CD10 expression levels are quite low. The CD71/CD95 ratio is balanced between 0.85 and 1.1, regardless of shift duration or permanent residence in the Arctic region. Conclusions. In the investigated hydrographers, fluctuations in the median NLR and the CD10/95 ratio are associated with the duration of the shift; the median CD71/95 ratio is least susceptible to fluctuations in both rotating shift workers and the control group; the CD71/95 ratio is stable, determines the immune balance of the surveyed, and can be used to assess the immune system's adaptability to Arctic conditions. Keywords: Arctic, Immune balance, Lymphoproliferation, Lymphopoptosis, Rotational shiftwork, Hydrographers

Adaptation in human immune cells residing in tissues at the frontline of infections

Human immune cells are under constant evolutionary pressure, primarily through their role as first line of defence against pathogens. Most studies on immune adaptation are, however, based on protein-coding genes without considering their cellular context. Here, using data from the Human Cell Atlas, we infer the gene adaptation rate of the human immune landscape at cellular resolution. We find abundant cell types, like progenitor cells during development and adult cells in barrier tissues, to harbour significantly increased adaptation rates. We confirm the adaptation of tissue-resident T and NK cells in the adult lung located in compartments directly facing external challenges, such as respiratory pathogens. Analysing human iPSC-derived macrophages responding to various challenges, we find adaptation in early immune responses. Together, our study suggests host benefits to control pathogen spread at early stages of infection, providing a retrospect of forces that shaped the complexity, architecture, and function of the human body.

BCL2 regulates antibacterial autophagy in the intestinal epithelium

Autophagy is a key innate immune defense mechanism in intestinal epithelial cells. Bacterial invasion of epithelial cells activates antibacterial autophagy through a process that requires the innate immune adaptor protein MYD88, yet how MYD88 signaling connects to the autophagy machinery is unknown. Here, we show that the mouse intestinal pathogen Salmonella enterica Serovar Typhimurium (Salmonella Typhimurium) triggers MYD88 signaling that regulates binding of the anti-autophagy factor B cell lymphoma 2 (BCL2) to the essential autophagy protein Beclin1 (BECN1) in small intestinal enterocytes, a key epithelial cell lineage. Salmonella infection activated the kinase c-Jun N-terminal protein kinase 1 (JNK1) downstream of MYD88. JNK1 induced enterocyte BCL2 phosphorylation, promoting dissociation of the inhibitory BCL2-BECN1 complex and releasing BECN1 to initiate autophagy. Mice with BCL2 phosphorylation site mutations that prevent BCL2-BECN1 dissociation showed increased Salmonella invasion of enterocytes and dissemination to extraintestinal sites. These findings reveal that BCL2 links MYD88 signaling to enterocyte autophagy initiation, providing mechanistic insight into how invading bacteria trigger autophagy in the intestinal epithelium.

Combined Use of Univariate and Multivariate Approaches to Detect Selection Signatures Associated with Milk or Meat Production in Cattle.

The aim of this study was to investigate the genomic structure of the cattle breeds selected for meat and milk production and to identify selection signatures between them. A total of 391 animals genotyped at 41,258 SNPs and belonging to nine breeds were considered: Angus (N = 62), Charolais (46), Hereford (31), Limousin (44), and Piedmontese (24), clustered in the Meat group, and Brown Swiss (42), Holstein (63), Jersey (49), and Montbéliarde (30), clustered in the Milk group. The population stratification was analyzed by principal component analysis (PCA), whereas selection signatures were identified by univariate (Wright fixation index, FST) and multivariate (canonical discriminant analysis, CDA) approaches. Markers with FST values larger than three standard deviations from the chromosomal mean were considered interesting. Attention was focused on markers selected by both techniques. A total of 10 SNPs located on seven different chromosomes (7, 10, 14, 16, 17, 18, and 24) were identified. Close to these SNPs (±250 kb), 165 QTL and 51 genes were found. The QTL were grouped in 45 different terms, of which three were significant (Bonferroni correction < 0.05): milk fat content, tenderness score, and length of productive life. Moreover, genes mainly associated with milk production, immunity and environmental adaptation, and reproduction were mapped close to the common SNPs. The results of the present study suggest that the combined use of univariate and multivariate approaches can help to better identify selection signatures due to directional selection.

Rodlet Cell Morpho-Numerical Alterations as Key Biomarkers of Fish Responses to Toxicants and Environmental Stressors.

Rodlet cells (RCs) are specialised immune cells found in teleost fish, recognised for their unique morphology and potential roles in both immune responses and environmental adaptation. Herein, current knowledge on RCs is reviewed, focussing on their responsiveness to toxicants and environmental stressors. The historical context of RC research is discussed, including key milestones in the identification and characterisation of these cells. Recent studies highlight RCs' quantitative and qualitative changes in response to various pollutants, such as heavy metals, organic chemicals, and microplastics, underscoring their utility as biomarkers for environmental monitoring and assessment of ecological health. The underlying mechanisms that govern RC responses are explored, noting the limited research available at the molecular level, which hampers a comprehensive understanding of their functionality. Despite this, the consistent patterns of RC responses position them as valuable indicators of environmental health within the One Health framework, linking aquatic ecosystem integrity to broader human and animal health concerns. Additionally, the potential equivalence of RCs in other vertebrates is examined, which may provide insights into their evolutionary significance and functional roles across different species. The urgent need for further research is emphasised to enhance the understanding of RC biology and its applications in toxicology and environmental pathology.

Spatially restricted immune and microbiota-driven adaptation of the gut.

The intestine is characterized by an environment in which host requirements for nutrient and water absorption are consequently paired with the requirements to establish tolerance to the outside environment. To better understand how the intestine functions in health and disease, large efforts have been made to characterize the identity and composition of cells from different intestinal regions1-8. However, the robustness, nature of adaptability and extent of resilience of the transcriptional landscape and cellular underpinning of the intestine in space are still poorly understood. Here we generated an integrated resource of the spatial and cellular landscape of the murine intestine in the steady and perturbed states. Leveraging these data, we demonstrated that the spatial landscape of the intestine was robust to the influence of the microbiota and was adaptable in a spatially restricted manner. Deploying a model of spatiotemporal acute inflammation, we demonstrated that both robust and adaptable features of the landscape were resilient. Moreover, highlighting the physiological relevance and value of our dataset, we identified a region of the middle colon characterized by an immune-driven multicellular spatial adaptation of structural cells to the microbiota. Our results demonstrate that intestinal regionalization is characterized by robust and resilient structural cell states and that the intestine can adapt to environmental stress in a spatially controlled manner through the crosstalk between immunity and structural cell homeostasis.

Metabolomics and transcriptomics analysis reveals the enhancement of growth, anti-oxidative stress and immunity by (-)-epigallocatechin-3-gallate in Litopenaeus vannamei

(−)-epigallocatechin-3-gallate (EGCG), the main active component of tea polyphenols, has been less studied in Litopenaeus vannamei. Therefore, the potential benefits of EGCG on L. vannamei were explored in this experiment. L. vannamei were fed diets containing EGCG (0, 0.5, and 1.0 g/kg). At the end of the 60-day farming experiment, metabolomics, transcriptomics, quantitative real-time PCR assays, and tissue sections were used to assess and explore the effects of EGCG on growth, antioxidant capacity, and immunity. It was found that the best growth and genes expressions related to antioxidant, anti-stress, apoptosis, and immunity were observed in the group with 0.5 g/kg EGCG. The analysis of hepatopancreatic metabolomics and transcriptomics results revealed bumper differential metabolites and differentially expressed genes (DEGs) associated with nutrient metabolism, digestion, immunity, and environmental adaptation. Many metabolites with anti-inflammatory, antibacterial, antiviral, and antioxidant activities have been identified. A large number of DEGs were enriched in apoptosis, Rap1 signaling pathway, HIF-1 signaling pathway, hippo signaling pathway, chemokine signaling pathway, and signaling pathways related to amino acid and lipid metabolism. In conclusion, dietary 0.5 g/kg EGCG was beneficial for growth, resistance to oxidative stress, and immunity in L. vannamei. The improvement of the properties was attributed to the modulation of signaling pathways, metabolites abundance and genes expressions related to the above properties by EGCG.

Characterization of the Molecular Signature of Human Monocytes in Aging and Myelodysplastic Neoplasms.

• Aging leads to chronic inflammation and immune dysfunction, heightening the risk of myeloid malignancies like MDS and CMML. • Both aging and MDS show alterations in monocyte subtypes and function. Aging boosts inflammatory genes upregulation, whereas MDS favors antigen presentation, reflecting distinct immune and disease-specific adaptations. • MDS shows reduced inflammatory activity in CD14+ cells, whereas CMML exhibits heightened inflammation, highlighting distinct disease mechanisms.

Immune defense adaptation of Strauchbufo raddei population in heavy metal polluted area: Insights from developmental and environmental perspectives

The adjustment of immune defense mechanisms is a crucial aspect of biological adaptation to stressful environments. Amphibians, with their unique metamorphic process, experience distinct life stages and exhibit diverse immune defense components. While previous studies have focused on specific immune changes during particular life stages under stress, this research addresses a critical gap by exploring the adaptive immune defense strategies of Strauchbufo raddei in heavy metal-polluted environments. We conducted laboratory experiments, exposing offspring from both polluted and unpolluted areas to control and heavy metal treatments, while continuously monitoring changes in immune components during key metamorphic stages. Notably, we examined the role of the skin microbiome, a crucial but often overlooked barrier against pathogens. The results indicated that individuals from polluted areas exhibited some tolerance to heavy metal exposure, though overall immune function remained diminished. During metamorphosis, when immune defenses are most vulnerable, the skin microbiome rapidly enriched beneficial bacteria, preventing pathogenic colonization and playing a pivotal role in maintaining immune defense in contaminated environments. Moreover, our research highlights energy allocation strategies involving corticosterone and body fat content, enabling populations to maintain development despite immune compromise. The immune adaptations observed may be fixed through genetic assimilation, suggesting a rapid evolutionary response to environmental stress. However, this reduces phenotypic plasticity, making populations more vulnerable to future environmental changes. This study provides key insights into the survival strategies of amphibian populations in heavy metal-contaminated areas, laying the foundation for future research on molecular and evolutionary adaptations.

PANoptosis Regulation in Reservoir Hosts of Zoonotic Viruses.

Zoonotic viruses originating from reservoir hosts, such as bats and birds, often cause severe illness and outbreaks amongst humans. Upon zoonotic virus transmission, infected cells mount innate immune responses that include the activation of programmed cell death pathways to recruit innate immune cells to the site of infection and eliminate viral replication niches. Different inflammatory and non-inflammatory cell death pathways, such as pyroptosis, apoptosis, necroptosis, and PANoptosis can undergo concurrent activation in humans leading to mortality and morbidity during zoonosis. While controlled activation of PANoptosis is vital for viral clearance during infection and restoring tissue homeostasis, uncontrolled PANoptosis activation results in immunopathology during zoonotic virus infections. Intriguingly, animal reservoirs of zoonotic viruses, such as bats and birds, appear to have a unique immune tolerance adaptation, allowing them to host viruses without succumbing to disease. The mechanisms facilitating high viral tolerance in bats and birds are poorly understood. In this perspective review, we discuss the regulation of PANoptotic pathways in bats and birds and indicate how they co-exist with viruses with mild clinical signs and no immunopathology. Understanding the PANoptotic machinery of bats and birds may thus assist us in devising strategies to contain zoonotic outbreaks amongst humans.