The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to pose a significant global public health threat, particularly to older adults, pregnant women, and individuals with underlying chronic conditions. Dysregulated immune responses to SARS-CoV-2 infection are believed to contribute to the progression of COVID-19 in severe cases. Previous studies indicates that a deficiency in type I interferon (IFN-I) immunity accounts for approximately 15 %-20 % of patients with severe pneumonia caused by COVID-19, highlighting the potential therapeutic importance of modulating IFN-I signals. Natural products and their derivatives, due to their structural diversity and novel scaffolds, play a crucial role in drug discovery. Some of these natural products targeting IFN-I have demonstrated applications in infectious diseases and inflammatory conditions. However, the immunomodulatory potential of IFN-I in critical COVID-19 pneumonia and the natural compounds regulating the related signal pathway remain not fully understood. In this review, we offer a comprehensive assessment of the association between IFN-I and severe COVID-19, exploring its mechanisms and integrating information on natural compounds effective for IFN-I regulation. Focusing on the primary targets of IFN-I, we also summarize the regulatory mechanisms of natural products, their impact on IFNs, and their therapeutic roles in viral infections. Collectively, by synthesizing these findings, our goal is to provide a valuable reference for future research and to inspire innovative treatment strategies for COVID-19.

Pluripotent stem cells provide opportunities for treating injuries and previously incurable diseases. A major concern is the immunogenicity of stem cells and their progeny. Here, we have dissected the molecular mechanisms that allow natural killer (NK) cells to respond to human pluripotent stem cells, investigating a wide selection of activating and inhibitory NK-cell receptors and their ligands. Reporter cells expressing the activating receptor NKG2D responded strongly to embryonic stem (ES) cell lines and induced pluripotent stem (iPS) cell lines, whereas reporter cells expressing the activating receptors NKp30, NKp46, KIR2DS1, KIR2DS2, and KIR2DS4 did not respond. Human ES and iPS cells invariably expressed several ligands for NKG2D. Expression of HLA-C and HLA-E was lacking or low, insufficient to trigger reporter cells expressing the inhibitory receptors KIR2DL1, -2DL2, or -2DL3. Similar results were obtained for the pluripotent embryonic carcinoma cell lines NTERA-2 and 2102Ep, and also iPS-cell-derived neural progenitor cells. Importantly, neural progenitor cells and iPS-cell-derived motoneurons also expressed B7H6, the ligand for the activating receptor NKp30. In line with these observations, IL-2-stimulated NK cells showed robust cytotoxic responses to ES and iPS cells as well as to iPS-cell-derived motoneurons. No significant differences in cytotoxicity levels were observed between KIR/HLA matched and mismatched combinations of NK cells and pluripotent targets. Together, these data indicate that pluripotent stem cells and their neural progeny are targets for NK-cell killing both by failing to sufficiently express ligands for inhibitory receptors and by expression of ligands for activating receptors.

Bioorthogonal catalysis has revolutionized the field of chemical biology by enabling selective and controlled chemical transformations within living systems. Research has converged on the development of innovative catalyst scaffolds, seeking to broaden the scope of bioorthogonal reactions, boost their efficiency, and surpass the limitations of conventional catalysts. This review provides a comprehensive overview of the latest advancements in bioorthogonal catalyst research based on different scaffold materials. Through an in-depth analysis of fabrication strategies and applications of bioorthogonal catalysts, this review discusses the design principles, mechanisms of action, and applications of these novel catalysts in chemical biology. Current challenges and future directions in exploring the scaffold diversity are also highlighted. The integration of diverse catalyst scaffolds offers exciting prospects for precise manipulation of biomolecules and the development of innovative therapeutic strategies in chemical biology. In addition, the review fills in the gaps in previous reviews, such as in fully summarizing the presented scaffold materials applied in bioorthogonal catalysts, emphasizing the potential impact on advancing bioorthogonal chemistry, and offering prospects for future development in this field.

Africa swine fever virus (ASFV) is the causative agent of African swine fever (ASF), a highly contagious hemorrhagic disease that can result in up to 100% lethality in both wild and domestic swine, regardless of breed or age. The ongoing ASF pandemic poses significant threats to the pork industry and food security, with serious implications for the sanitary and socioeconomic system. Due to the limited understanding of ASFV pathogenesis and immune protection mechanisms, there are currently no safe and effective vaccines or specific treatments available, complicating efforts for prevention and control. This review summarizes the current understanding of the intricate interplay between ASFV and the host immune system, encompassing both innate and adaptive immune responses to ASFV infection, as well as insights into ASFV pathogenesis and immunosuppression. We aim to provide comprehensive information to support fundamental research on ASFV, highlighting existing gaps and suggesting future research directions. This work may serve as a theoretical foundation for the rational design of protective vaccines against this devastating viral disease.

CMV-specific T cells, NK cells, and neutralizing antibodies (nAbs) were assessed in a randomized trial of CMV prevention with preemptive antiviral therapy (PET) versus prophylactic antiviral therapy (PRO) in donor-seropositive/recipient-seronegative (D+R-) liver transplant recipients (LTxR) at 100 days (end of intervention) and at 6 and 12 months after transplant. The PET group had significantly increased numbers of circulating polyfunctional T cells, NK cells, and nAbs compared with the PRO group at day 100, and several CMV immune parameters remained significantly higher by 12 months after transplant. Among PET recipients, preceding CMV viremia (vs. no preceding viremia) was associated with significantly higher levels of most CMV immune parameters at day 100. Higher numbers of CMV-specific polyfunctional T cells and NKG2C+ NK cells at day 100 were associated with a decreased incidence of CMV disease in multivariable Cox regression. The strongest associations with protection against CMV disease were with increased numbers of CMV-specific polyfunctional CD4+ T cells, CD3negCD56dimCD57negNKG2Cpos cells, and CD3negCD56dimCD57posNKG2Cpos NK cells. Our results suggest that PET is superior to PRO for CMV disease prevention by allowing low-level CMV replication and associated antigen exposure that is promptly controlled by antiviral therapy and facilitates enhanced CMV protective immunity in D+R- LTxR.

Bioorthogonal nanozymes have emerged as a potent tool in biomedicine due to their unique ability to perform enzymatic reactions that do not interfere with native biochemical processes. The integration of stimuli-responsive mechanisms into these nanozymes has further expanded their potential, allowing for controlled activation and targeted delivery. As such, intelligent bioorthogonal nanozymes have received more and more attention in developing therapeutic approaches. This review provides a comprehensive overview of the recent advances in the development and application of stimuli-responsive bioorthogonal nanozymes. By summarizing the design outlines for anchoring bioorthogonal nanozymes with stimuli-responsive capability, this review seeks to offer valuable insights and guidance for the rational design of these remarkable materials. This review highlights the significant progress made in this exciting field with different types of stimuli and the various applications. Additionally, it also examines the current challenges and limitations in the design, synthesis, and application of these systems, and proposes potential solutions and research directions. This review aims to stimulate further research toward the development of more efficient and versatile stimuli-responsive bioorthogonal nanozymes for biomedical applications.

Immunoglobulin A (IgA) is the predominant mucosal antibody class with both anti- and pro-inflammatory roles1-3. However, the specific role of the IgA receptor cluster of differentiation (CD)89, expressed by a subset of natural killer (NK) cells, is poorly explored. We found that CD89 protein expression on circulating NK cells is infrequent in humans and rhesus macaques, but transcriptomic analysis showed ubiquitous CD89 expression, suggesting an inducible phenotype. Interestingly, CD89+ NK cells were more frequent in cord blood and mucosae, indicating a putative IgA-mediated NK cell function in the mucosae and infant immune system. CD89+ NK cells signaled through upregulated CD3 zeta chain (CD3ζ), spleen tyrosine kinase (Syk), zeta chain-associated protein kinase 70 (ZAP70), and signaling lymphocytic activation molecule family 1 (SLAMF1), but also showed high expression of inhibitory receptors such as killer cell lectin-like receptor subfamily G (KLRG1) and reduced activating NKp46 and NKp30. CD89-based activation or antibody-mediated cellular cytotoxicity with monomeric IgA1 reduced NK cell functions, while antibody-mediated cellular cytotoxicity with combinations of IgG and IgA2 was enhanced compared to IgG alone. These data suggest that functional CD89+ NK cells survey mucosal sites, but CD89 likely serves as regulatory receptor which can be further modulated depending on IgA and IgG subclass. Although the full functional niche of CD89+ NK cells remains unexplored, these intriguing data suggest the CD89 axis could represent a novel immunotherapeutic target in the mucosae or early life.

Hantaviruses cause the acute zoonotic diseases hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Infected patients show strong systemic inflammation and immune cell activation. NK cells are highly activated in HFRS, suggesting that also other innate lymphoid cells (ILCs) might be responding to infection. Here, we characterized peripheral ILC responses, and measured plasma levels of soluble factors and plasma viral load, in 17 Puumala virus (PUUV)-infected HFRS patients. This revealed an increased frequency of ILC2 in patients, in particular the ILC2 lineage-committed c-Kitlo ILC2 subset. Patients' ILCs showed an activated profile with increased proliferation and displayed altered expression of several homing markers. How ILCs are activated during viral infection is largely unknown. When analyzing PUUV-mediated activation of ILCs in vitro we observed that this was dependent on type I interferons, suggesting a role for type I interferons-produced in response to virus infection-in the activation of ILCs. Further, stimulation of naïve ILC2s with IFN-β affected ILC2 cytokine responses in vitro, causing decreased IL-5 and IL-13, and increased IL-10, CXCL10, and GM-CSF secretion. These results show that ILCs are activated in HFRS patients and suggest that the classical antiviral type I IFNs are involved in shaping ILC functions.

Although natural killer (NK) cells are recognized for their modulation of immune responses, the mechanisms by which human NK cells mediate immune regulation are unclear. Here, we report that expression of human leukocyte antigen (HLA)-DP, a ligand for the activating NK cell receptor NKp44, is significantly upregulated on CD8+ effector T cells, in particular in human cytomegalovirus (HCMV)+ individuals. HLA-DP+ CD8+ T cells expressing NKp44-binding HLA-DP antigens activate NKp44+ NK cells, while HLA-DP+ CD8+ T cells not expressing NKp44-binding HLA-DP antigens do not. In line with this, frequencies of HLA-DP+ CD8+ T cells are increased in individuals not encoding for NKp44-binding HLA-DP haplotypes, and contain hyper-expanded CD8+ T cell clones, compared to individuals expressing NKp44-binding HLA-DP molecules. These findings identify a molecular interaction facilitating the HLA-DP haplotype-specific editing of HLA-DP+ CD8+ T cell effector populations by NKp44+ NK cells and preventing the generation of hyper-expanded T cell clones, which have been suggested to have increased potential for autoimmunity.

CD155 is an immunoglobulin-like protein overexpressed in almost all the tumor cells, which not only promotes proliferation, adhesion, invasion, and migration of tumor cells, but also regulates immune responses by interacting with TIGIT, CD226 or CD96 receptors expressed on several immune cells, thereby modulating the functionality of these cellular subsets. As a novel immune checkpoint, the inhibition of CD155/TIGIT, either as a standalone treatment or in conjunction with other immune checkpoint inhibitors, has demonstrated efficacy in managing advanced solid malignancies. In this review, we summarize the intricate relationship between on tumor surface CD155 and its receptors, with further discussion on how they regulate the occurrence of tumor immune escape. In addition, novel therapeutic strategies and clinical trials targeting CD155 and its receptors are summarized, providing a strong rationale and way forward for the development of next-generation immunotherapies.

The COVID-19 vaccine has faced increased hesitancy in Ghana and the Volta region in particular since its rollout. Acceptance of the vaccine among intercity commercial drivers is crucial, especially in the Volta region, as they transport people within and outside the country and could fuel the transmission of the virus if not vaccinated.

We therefore established lay beliefs surrounding COVID-19 vaccine refusal among intercity commercial drivers in the Volta region of Ghana, as well as their recommendations for improved vaccine uptake.

We purposively interviewed twenty-five (25) intercity commercial drivers who had not been vaccinated for COVID-19 in the Volta region of Ghana using a semi-structured interview guide and analysed their responses thematically using the ATLAS.ti software.

Various (ten) beliefs surrounding COVID-19 vaccine refusal were identified. These include the nonexistence of COVID-19, being immune to COVID-19, and the belief in the nonexistence of vaccines and vaccines being meant for the sick. Other beliefs identified were the belief that the COVID-19 vaccine is meant to reduce Africa's population, that the vaccine triggers other health complications leading to death, the belief that vaccination could cause financial loss, political mistrust, that the COVID-19 vaccine is not permitted by God, and the belief that prayer prevents COVID-19 infection. They also suggested that the adoption of persuasive communication techniques, the publication of information on those who died of COVID-19, providing evidence of tests conducted on the vaccine, testing people before vaccination, provision of care to those who may experience side effects from the vaccine, and being able to explain why varied vaccines are used for the same virus could help improve vaccine uptake.

Our findings show that there is a general lack of understanding and mistrust surrounding the COVID-19 vaccine among intercity commercial drivers in the Volta region. Hence, health promotion officers and communicators in the region need to be knowledgeable on the vaccine as well as on the conspiracy theories thwarting its uptake to provide comprehensive education to the public and intercity commercial drivers to improve its uptake.

Over the past decade, a group of lymphocyte-like cells called innate lymphoid cells (ILCs) has gained considerable attention due to their crucial role in regulating immunity and tissue homeostasis. ILCs, lacking antigen-specific receptors, are a group of functionally differentiated effector cells that act as tissue-resident sentinels against infections. Numerous studies have elucidated the characteristics of ILC subgroups, but the mechanisms controlling protective or pathological responses to pathogens still need to be better understood. This review summarizes the functions of ILCs in the immunology of infections caused by different intracellular and extracellular pathogens and discusses their possible therapeutic potential.

To stop the spread of the COVID-19 disease, it is crucial to create molecular tools to investigate and diagnose COVID-19. Current efforts focus on developing specific neutralizing monoclonal antibodies (NmAbs) elicited against the receptor-binding domain (RBD).

In the present study, recombinant RBD (rRBD) protein was produced in E. coli, followed by immunizing mice with purified rRBD. ELISA was applied to screen the hybridomas for positive reactivity with rRBD protein. The linear and conformational epitopes of the mAbs were subsequently identified using western blot. Finally, the reactivity, affinity, and neutralization activity of the purified mAbs were evaluated using ELISA.

All mAbs exhibited similar reactivity trends towards both eukaryotic RBD and prokaryotic rRBD in ELISA. Among them, 2E7-D2 and 2B4-G8 mAbs demonstrated higher reactivity than other mAbs. Additionally, in western blot assays, these two mAbs could detect reducing and non-reducing rRBD, indicating recognition of linear epitopes. Notably, five mAbs effectively blocked rRBD- angiotensin-converting enzyme 2 (ACE2) interaction, while two high-affinity mAbs exhibited potent neutralizing activity against eukaryotic RBD.

In the current study, we generated and characterized new RBD-specific mAbs using the hybridoma technique that recognized linear and conformational epitopes in RBD with neutralization potency. Our mAbs are novel candidates for diagnosing and treating SARS-CoV-2.

Transplantation of HLA and/or KIR mismatched allogeneic hematopoietic stem cells can lead NK cells to different states of activation/inhibition or education/resetting and change anti-tumor immunosurveillance. In this study, we used molecular relapse monitoring to investigate a correlation between either missing ligand recognition or variation of the cognate iKIR-HLA pairs with clinical outcomes in patients with hematological malignancies requiring allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients (N = 418) with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS), or lymphoma receiving T-cell repleted graft from HLA-matched or partly mismatched unrelated donors between 2012 and 2020 in our center were included in this study. Missing-ligand recognition was assessed through the presence or absence of recipients' HLA ligand for a particular inhibitory KIR (iKIR) exhibited by the donor. Inhibitory KIR-HLA pair number variation was defined by loss or gain of a new cognate pair of HLA-KIR within the new HLA environment of the recipient, compared with the donor's one. Considering the results of our research, we drew the following conclusions: (i) loss of iKIR-HLA cognate pair for C1, C2, and/or Bw4 groups led to significant deterioration of disease-free survival (DFS), molecular relapse, overall survival (OS) and non-relapse mortality (NRM) for patients undergoing allo-HSCT in the standard phase of the disease. This phenomenon was not observed in patients who underwent transplantation in advanced hematological cancer. (ii) The missing ligand recognition had no impact if the proportion of HLA mismatches was not considered; however, adjustments of HLA mismatch level in the compared groups highlighted the adverse effect of the missing ligand constellation. (iii) The adverse effect of adjusted missing ligand suggests a predominance of lost NK cell education over lost NK cell inhibition in posttransplant recipients' new HLA environment. Our results suggested that donors with the loss of an iKIR-HLA cognate pair after transplantation should be avoided, and donors who provided an additional iKIR-HLA cognate pair should be preferred in the allo-HSCT donor selection process.

Mushrooms produce many metabolites that show biological activity, which can be obtained from their fruiting body, mycelium or recovered from the culture broth when mushrooms are grown in submerged fermentation. Mushrooms are a source of natural pharmaceuticals; they have been reported to have potential inhibitory or preventive activity against some diseases, including different types of cancer. Cancer represents one of the main causes of death worldwide. It is worth mentioning that despite advances in pharmacological treatments, they still present side effects in patients. In this sense, the study of the use of mushrooms in complementary treatments against cancer is of great interest. Based on studies carried out in vitro and, in some cases, using animal models, it has been observed that mushrooms present preventive, corrective, and therapeutic properties against different types of cancer, by stimulating the immune system, due to their antioxidant, antimutagenic, and anti-inflammatory activities, as well as the regulation of the expression of some cellular processes, cell cycle arrest, and apoptosis, etc. Based on the above, this manuscript shows a review of scientific studies that support the anticancer activity of some mushrooms and/or their bioactive compounds.

Extreme polymorphism of HLA and killer-cell immunoglobulin-like receptors (KIR) differentiates immune responses across individuals. Additional to T cell receptor interactions, subsets of HLA class I act as ligands for inhibitory and activating KIR, allowing natural killer (NK) cells to detect and kill infected cells. We investigated the impact of HLA and KIR polymorphism on the severity of COVID-19. High resolution HLA class I and II and KIR genotypes were determined from 403 non-hospitalized and 1575 hospitalized SARS-CoV-2 infected patients from Italy collected in 2020. We observed that possession of the activating KIR2DS4*001 allotype is associated with severe disease, requiring hospitalization (OR = 1.48, 95% CI 1.20-1.85, pc  = 0.017), and this effect is greater in individuals homozygous for KIR2DS4*001 (OR = 3.74, 95% CI 1.75-9.29, pc  = 0.003). We also observed the HLA class II allotype, HLA-DPB1*13:01 protects SARS-CoV-2 infected patients from severe disease (OR = 0.49, 95% CI 0.33-0.74, pc  = 0.019). These association analyses were replicated using logistic regression with sex and age as covariates. Autoantibodies against IFN-α associated with COVID-19 severity were detected in 26% of 156 hospitalized patients tested. HLA-C*08:02 was more frequent in patients with IFN-α autoantibodies than those without, and KIR3DL1*01502 was only present in patients lacking IFN-α antibodies. These findings suggest that KIR and HLA polymorphism is integral in determining the clinical outcome following SARS-CoV-2 infection, by influencing the course both of innate and adaptive immunity.

Natural killer (NK) cells are important antiviral effector cells and also involved in tumor clearance. NK cells express IFNAR, rendering them responsive to Type I IFNs. To evaluate Type I IFN-mediated modulation of NK cell functions, individual Type I IFNs subtypes were assessed for their ability to activate NK cells. Different Type I IFN subtypes displayed a broad range in the capacity to induce and modulate NK cell activation and degranulation, measured by CD69 and CD107a expression in response to leukemia cell line K562. When including biological sex as a variable in the analysis, transwell co-cultures of NK cells with either male- or female-derived PBMCs or pDCs stimulated with the TLR7/8 agonist CL097 showed that NK cells were more activated by CL097-stimulated cells derived from females. These sex-specific differences were linked to higher CL097-induced IFNα production by pDCs derived from females, indicating an extrinsic sex-specific effect of Type I IFNs on NK cell function. Interestingly, in addition to the extrinsic effect, we also observed NK cell-intrinsic sex differences, as female NK cells displayed higher activation levels after IFNα-stimulation and after co-culture with CL097-stimulated pDCs, suggesting higher activation of IFNα-signaling transduction in female NK cells. Taken together, the results from these studies identify both extrinsic and intrinsic sex-specific differences in Type I IFN-dependent NK cell functions, contributing to a better understanding of sex-specific differences in innate immunity.

Multiple studies have broadened the roles of natural killer (NK) cells functioning as purely innate lymphocytes by demonstrating that they are capable of putative antigen-specific immunological memory against multiple infectious agents including HIV-1 and influenza. However, the mechanisms underlying antigen specificity remain unknown. Here, we demonstrate that antigen-specific human NK cell memory develops upon exposure to both HIV and influenza, unified by a conserved and epitope-specific targetable mechanism largely dependent on the activating CD94/NKG2C receptor and its ligand HLA-E. We validated the permanent acquisition of antigen specificity by individual memory NK cells by single-cell cloning. We identified elevated expression of KLRG1, α4β7, and NKG2C as biomarkers of antigen-specific NK cell memory through complex immunophenotyping. Last, we uncovered individual HLA-E-restricted peptides that may constitute the dominant NK cell response in HIV-1- and influenza-infected persons in vivo. Our findings clarify the mechanisms contributing to antigen-specific memory NK cell responses and suggest that they could be potentially targeted therapeutically for vaccines or other therapeutic interventions.

Replicating SARS-CoV-2 has been shown to degrade HLA class I on target cells to evade the cytotoxic T-cell (CTL) response. HLA-I downregulation can be sensed by NK cells to unleash killer cell immunoglobulin-like receptor (KIR)-mediated self-inhibition by the cognate HLA-I ligands. Here, we investigated the impact of HLA and KIR genotypes and HLA-KIR combinations on COVID-19 outcome. We found that the peptide affinities of HLA alleles were not correlated with COVID-19 severity. The predicted poor binders for SARS-CoV-2 peptides belong to HLA-B subtypes that encode KIR ligands, including Bw4 and C1 (introduced by B*46:01), which have a small F pocket and cannot accommodate SARS-CoV-2 CTL epitopes. However, HLA-Bw4 weak binders were beneficial for COVID-19 outcome, and individuals lacking the HLA-Bw4 motif were at higher risk for serious illness from COVID-19. The presence of the HLA-Bw4 and KIR3DL1 combination had a 58.8% lower risk of developing severe COVID-19 (OR = 0.412, 95% CI = 0.187-0.904, p = 0.02). This suggests that HLA-Bw4 alleles that impair their ability to load SARS-CoV-2 peptides will become targets for NK-mediated destruction. Thus, we proposed that the synergistic responsiveness of CTLs and NK cells can efficiently control SARS-CoV-2 infection and replication, and NK-cell-mediated anti-SARS-CoV-2 immune responses being mostly involved in severe infection when the level of ORF8 is high enough to degrade HLA-I. The HLA-Bw4/KIR3DL1 genotype may be particularly important for East Asians undergoing COVID-19 who are enriched in HLA-Bw4-inhibitory KIR interactions and carry a high frequency of HLA-Bw4 alleles that bind poorly to coronavirus peptides.

Natural killer (NK) cells play an important first-line role against tumour and viral infections and are regulated by inhibitory receptor expression. Among these inhibitory receptors, the expression, function, and mechanism of cluster of differentiation 47 (CD47) on NK cells during human immunodeficiency virus (HIV) infection remain unclear.

Fresh peripheral blood mononuclear cells (PBMCs) were collected from people living with HIV (PLWH) and HIV negative controls (NC) subjects. Soluble ligand expression levels of CD47 were measured using ELISA. HIV viral proteins or Toll-like receptor 7/8 (TLR7/8) agonist was used to investigate the mechanisms underlying the upregulation of CD47 expression. The effect of CD47 on NK cell activation, proliferation, and function were evaluated by flow cytometry. RNA-seq was used to identify downstream pathways for CD47 and its ligand interactions. A small molecule inhibitor was used to restore the inhibition of NK cell function by CD47 signalling.

CD47 expression was highly upregulated on the NK cells from PLWH, which could be due to activation of the Toll-like receptor 7/8 (TLR7/8) pathway. Compared with NC subjects, PLWH subjects exhibited elevated levels of CD47 ligands, thrombospondin-1 (TSP1), and counter ligand signal regulatory protein-α (SIRPα). The TSP1-CD47 axis drives the suppression of interferon gamma (IFN-γ) production and the activation of the Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway in NK cells. After treatment with a STAT3 inhibitor, the NK cells from PLWH showed significantly improved IFN-γ production.

The current data indicate that the binding of the inhibitory receptor CD47 to plasma TSP1 suppresses NK cell IFN-γ production by activating the JAK/STAT3 pathway during HIV infection. Our results suggest that CD47 and its related signalling pathways could be targets for improving NK cell function in people living with HIV.

Changes in lifestyle induce an increase in patients with hyperuricemia (HUA), leading to gout, gouty arthritis, renal damage, and cardiovascular injury. There is a strong inflammatory response in the process of HUA, while dysregulation of immune cells, including monocytes, macrophages, and T cells, plays a crucial role in the inflammatory response. Recent studies have indicated that urate has a direct impact on immune cell populations, changes in cytokine expression, modifications in chemotaxis and differentiation, and the provocation of immune cells by intrinsic cells to cause the aforementioned conditions. Here we conducted a detailed review of the relationship among uric acid, immune response, and inflammatory status in hyperuricemia and its complications, providing new therapeutic targets and strategies.

To investigate the changes and mechanism of Siglec-9 on NK cells in peripheral blood of patients with severe fever with thrombocytopenia syndrome (SFTS).

First, we used single-cell RNA sequencing to analyze the frequency of NK cells in Peripheral Blood Mononuclear Cells (PBMCs) of SFTS patients and healthy controls (HCs), as well as the differences in the genes on NK cells. Secondly, we analyzed the expression of Siglec-9 and other receptors on NK cells by flow cytometry. Thirdly, we analyzed the correlation between Siglec-9 on NK cells and DBV viral load in plasma.

Compared with HCs, the frequency of NK cells in peripheral blood of SFTS patients was significantly decreased, and the activating receptors on NK cells were reduced. The expression of Siglec-9 on NK cells and the frequency of Siglec-9+NK cells decreased significantly in SFTS patients. The expression of Siglec-9 on CD16+CD56dim NK cells was negatively correlated with DBV viral load. In addition, Siglec-9+NK cells expressed higher levels of activating receptors and exhibited stronger effector functions than Siglec-9-NK cells.

The decreased expression of Siglec-9 on NK cells predicts NK cell dysfunction in SFTS patients, suggesting that Siglec-9 may be a potential marker for functional NK cell subsets in SFTS patients.

Immigrants represented 21.8% of cases in a Spanish cohort of hospitalised patients with COVID-19, a proportion exceeding the percentage of immigrants in that area's total population. Among the ethnic-related genetic risk factors for COVID-19, human leukocyte antigen (HLA) genotypes in diverse populations might bias the response to SARS-CoV-2 infection and/or progression. Similarly, genetic differences in natural killer-activating and inhibitory receptors could play a role in the immune system's response to the viral infection.

We characterised HLA alleles and KIR genes in 52 Ecuadorian patients hospitalised for moderate and severe COVID-19 and 87 Ecuadorian controls from the general population living in the same area.

There was a significantly increased frequency of the HLA-B*39 antigen and the activating KIR2DS4 receptor in the presence of its HLA-C*04 ligand in the COVID-19 group when compared with the control group. In contrast, there was a significant reduction in the frequency of carriers of KIR2DL1 and of the KIR3DL1/Bw4 receptor/ligand combination among COVID-19 group. On the other hand, HLA-A*24:02 and HLA-DRB1*09:01 alleles showed significantly lower frequencies specifically in the severe COVID-19 group.

HLA-B*39 alleles might be genetic risk factors for developing COVID-19 in Ecuadorian individuals. In the presence of its ligand C*04, the natural killer-activating receptor KIR2DS4 might also increase the risk of developing COVID-19, while, in the presence of HLA-Bw4 alleles, the inhibitory receptor KIR3DL1 might play a protective role. Patients with COVID-19 who carry HLA-A*24:02 and HLA-DRB1*09:01 alleles might be protected against more severe forms of COVID-19.

N-butylbenzenesulfonamide (NBBS) is a high-production volume plasticizer that is an emerging contaminant of concern for environmental and human health. To understand the risks and health effects of exposure to NBBS, studies were conducted in adult-exposed mice and developmentally exposed rats to evaluate the potential for NBBS to modulate the immune system. Beginning between 8 and 9 weeks of age, dosed feed containing NBBS at concentrations of 0, 313, 625, 1250, 2500, and 5000 ppm was continuously provided to B6C3F1/N female mice for 28 days. Dosed feed was also continuously provided to time-mated Harlan Sprague Dawley (Sprague Dawley SD) rats at concentrations of 0-, 250-, 500-, and 1000-ppm NBBS from gestation day 6 to postnatal day 28 and in F1 rats until 11-14 weeks of age. Functional assessments of innate, humoral, and cell-mediated immunity were conducted in adult female mice and F1 rats following exposure to NBBS. In female mice, NBBS treatment suppressed the antibody-forming cell (AFC) response to SRBC with small increases in T-cell responses and natural killer (NK)-cell activity. In developmentally exposed rats, NBBS treatment-related immune effects were sex dependent. A positive trend in NK-cell activity occurred in male F1 rats while a negative trend occurred in female F1 rats. The AFC response to SRBC was decreased in female F1 rats but not in male F1 rats. These data provide evidence that oral exposure to NBBS has the potential to produce immunomodulatory effects on both innate and adaptive immune responses, and these effects appear to have some dependence on species, sex, and period of exposure (developmental vs adult).

Regulating natural killer (NK) cell responses in hematological malignancies largely depend on molecular interactions between killer cell immunoglobulin-like receptors (KIR) and human leukocyte antigen (HLA) class I ligands. The goal of the current study was to examine the key functions of KIR genes, gene combinations of KIR-HLA, and KIR genotypes in genetic predisposition to aplastic anemia (AA). Herein, the genotyping of 16 KIR genes and HLA-A, -B, and -C ligands were performed in 72 AA patients and 150 healthy controls using PCR evaluations with sequence-specific primers using standard assays. According to the obtained results, AA patients had an increased incidence of activating KIR and KIR2DS4 (P = 0.465 × 10-4, Pc = 0.837 × 10-3, OR = 20.81, 95% CI = 2.786-155.5) compared to controls. KIR/HLA class I ligand profile KIR2DS4/C1 (P = 0.350 × 10-4, Pc = 0.630 × 10-3, OR = 8.944, 95% CI = 2.667-29.993) was significantly elevated in AA patients compared to healthy controls. Genotype AA1 (P = 0.003, OR = 2.351, 95% CI = 1.325-4.172) were increased, and AA195 (P = 0.006, OR = 0.060, 95% CI = 0.004-1.023) was decreased among AA cases compared to controls. Our findings indicated that KIR2DS4 may play a role in the pathogenesis of AA. This study revealed the contribution of KIR genes in the etiology of AA cases.

Tick-borne encephalitis virus (TBEV) is a flavivirus commonly found in at least 27 European and Asian countries. It is an emerging public health problem, with steadily increasing case numbers over recent decades. Tick-borne encephalitis virus affects between 10,000 and 15,000 patients annually. Infection occurs through the bite of an infected tick and, much less commonly, through infected milk consumption or aerosols. The TBEV genome comprises a positive-sense single-stranded RNA molecule of ∼11 kilobases. The open reading frame is > 10,000 bases long, flanked by untranslated regions (UTR), and encodes a polyprotein that is co- and post-transcriptionally processed into three structural and seven non-structural proteins. Tick-borne encephalitis virus infection results in encephalitis, often with a characteristic biphasic disease course. After a short incubation time, the viraemic phase is characterised by non-specific influenza-like symptoms. After an asymptomatic period of 2-7 days, more than half of patients show progression to a neurological phase, usually characterised by central and, rarely, peripheral nervous system symptoms. Mortality is low-around 1% of confirmed cases, depending on the viral subtype. After acute tick-borne encephalitis (TBE), a minority of patients experience long-term neurological deficits. Additionally, 40%-50% of patients develop a post-encephalitic syndrome, which significantly impairs daily activities and quality of life. Although TBEV has been described for several decades, no specific treatment exists. Much remains unknown regarding the objective assessment of long-lasting sequelae. Additional research is needed to better understand, prevent, and treat TBE. In this review, we aim to provide a comprehensive overview of the epidemiology, virology, and clinical picture of TBE.

Antiretroviral therapy (ART) induces persistent suppression of HIV-1 replication and gradual recovery of T-cell counts, and consequently, morbidity and mortality from HIV-related illnesses have been significantly reduced. However, in approximately 30% of people living with HIV (PLHIV) on ART, CD4+ T-cell counts fail to normalize despite ART and complete suppression of HIV viral load, resulting in severe immune dysfunction, which may represent an increased risk of clinical progression to AIDS and non-AIDS events as well as increased mortality. These patients are referred to as "immune inadequate responders", "immunodiscordant responders" or "immune nonresponders (INR)". The molecular mechanisms underlying poor CD4+ T-cell recovery are still unclear. In this sense, the use of omics sciences has shed light on possible factors involved in the activity and metabolic dysregulation of immune cells during the failure of CD4+ T-cell recovery in INR. Moreover, identification of key molecules by omics approaches allows for the proposal of potential biomarkers or therapeutic targets to improve CD4+ T-cell recovery and the quality of life of these patients. Hence, this review aimed to summarize the information obtained through different omics concerning the molecular factors and pathways associated with the INR phenotype to better understand the complexity of this immunological status in HIV infection.

Current antiretroviral therapies (ART) for human immunodeficiency virus (HIV) are not curative, as the virus persists in latent reservoirs, requiring lifelong adherence to ART and increasing the risk of co-morbidities. "Shock and kill" approaches to reactivate HIV from latent reservoirs followed by administration of anti-HIV drugs represent a promising strategy for eradicating latent HIV. To achieve effective shock and kill, we describe a strategy to eradicate the HIV reservoir that combines latency reversing agents (LRAs), broadly neutralizing antibodies (bnAbs), and natural killer (NK) cells. This strategy utilizes a polymer nanodepot (ND) that co-encapsulates the LRA and bnAb to reactivate latent infection and elicit enhanced cytotoxicity from co-administered NK cells.

Poly(lactic-co-glycolic acid) (PLGA) NDs were synthesized using the nanoprecipitation method to co-encapsulate an LRA (TNF-α) and a bnAb (3BNC117) (TNF-α-3BNC117-NDs). ACH-2 cells were used as a cellular model of latent HIV infection. An NK92 subline, genetically modified to constitutively express the Fc receptor CD16, was administered to ACH-2 cells in combination with TNF-α-3BNC117-NDs. ACH-2 cell death and extracellular p24 were measured via flow cytometry and ELISA, respectively.

Stable PLGA NDs co-encapsulated TNF-α and 3BNC117 with high efficiencies and released these agents in physiological conditions. NK92 phenotype remained similar in the presence of TNF-α-3BNC117-NDs. TNF-α released from NDs efficiently reactivated HIV in ACH-2 cells, as measured by a 3.0-fold increase in the frequency of intracellular p24 positive cells. Released 3BNC117 neutralized and bound reactivated virus, targeting 57.5% of total ACH-2 cells. Critically, TNF-α-3BNC117-NDs significantly enhanced NK92 cell-mediated killing of ACH-2 cells (1.9-fold) and reduced extracellular levels of p24 to baseline.

These findings suggest the therapeutic potential of our novel ND-based tripartite strategy to reactivate HIV from latently infected cells, generate an HIV-specific site for bnAb binding, and enhance the killing of reactivated HIV-infected target cells by NK92 cells.

According to the WHO's recently released worldwide cancer data for 2020, liver cancer ranks sixth in morbidity and third in mortality among all malignancies. Hepatocellular carcinoma (HCC), the most common kind of liver cancer, accounts approximately for 80% of all primary liver malignancies and is one of the leading causes of death globally. The intractable tumor microenvironment plays an important role in the development and progression of HCC and is one of three major unresolved issues in clinical practice (cancer recurrence, fatal metastasis, and the refractory tumor microenvironment). Despite significant advances, improved molecular and cellular characterization of the tumor microenvironment is still required since it plays an important role in the genesis and progression of HCC. The purpose of this review is to present an overview of the HCC immune microenvironment, distinct cellular constituents, current therapies, and potential immunotherapy methods.

Most human killer cell immunoglobulin-like receptors (KIR) are expressed by natural killer (NK) cells and recognize HLA class I molecules as ligands. KIR3DL3 is a conserved but polymorphic inhibitory KIR recognizing a B7 family ligand, HHLA2, and is implicated for immune checkpoint targeting. The expression profile and biological function of KIR3DL3 have been somewhat elusive, so we searched extensively for KIR3DL3 transcripts, revealing highly enriched expression in γδ and CD8+ T cells rather than NK cells. These KIR3DL3-expressing cells are rare in the blood and thymus but more common in the lungs and digestive tract. High-resolution flow cytometry and single-cell transcriptomics showed that peripheral blood KIR3DL3+ T cells have an activated transitional memory phenotype and are hypofunctional. The T cell receptor (TCR) usage is biased toward genes from early rearranged TCR-α variable segments or Vδ1 chains. In addition, we show that TCR-mediated stimulation can be inhibited through KIR3DL3 ligation. Whereas we detected no impact of KIR3DL3 polymorphism on ligand binding, variants in the proximal promoter and at residue 86 can reduce expression. Together, we demonstrate that KIR3DL3 is up-regulated alongside unconventional T cell stimulation and that individuals may vary in their ability to express KIR3DL3. These results have implications for the personalized targeting of KIR3DL3/HHLA2 checkpoint inhibition.