Immune Response Research Articles

Identification of SNP and SilicoDArT Markers and Characterization of Their Linked Candidate Genes Associated with Maize Smut Resistance

The implementation of biological advancements in agricultural production is the response to the needs of the agricultural sector in the 21st century, enabling increased production and improved food quality. Biological progress in the maize breeding and seed industries is unique in terms of their social and ecological innovation aspects. It affects agricultural productivity and the adaptation of cultivated maize varieties to market demands and changing climate conditions without compromising the environment. Modern maize resistance breeding relies on a wide range of molecular genetic research techniques. These technologies enable the identification of genomic regions associated with maize smut resistance, which is crucial for characterizing and manipulating these regions. Therefore, the aim of this study was to identify molecular markers (SilicoDArT and SNP) linked to candidate genes responsible for maize smut resistance, utilizing next-generation sequencing, as well as association and physical mapping. By using next-generation sequencing (NGS) and statistical tools, the analyzed maize genotypes were divided into heterotic groups, which enabled the prediction of the hybrid formula in heterosis crosses. In addition, Illumina sequencing identified 60,436 SilicoDArT markers and 32,178 SNP markers (92,614 in total). For association mapping, 32,900 markers (26,234 SilicoDArT and 6666 SNP) meeting the criteria (MAF > 0.25 and the number of missing observations < 10%) were used. Among the selected markers, 61 were highly statistically significant (LOD > 2.3). Among the selected 61 highly statistically significant markers (LOD > 2.3), 10 were significantly associated with plant resistance to maize smut in two locations (Smolice and Kobierzyce). Of the 10 selected markers, 3 SilicoDArT (24016548, 2504588, 4578578) and 3 SNP (4779579, 2467511, 4584208) markers were located within genes. According to literature reports, of these six genes, three (ATAD3, EDM2, and CYP97A3) are characterized proteins that may play a role in the immune response that develops in response to corn smut infection. In the case of genotypes belonging to the same origin groups, markers linked to these genes can be used to select varieties resistant to corn smut. These markers will also be tested on genotypes belonging to other maize origin groups to demonstrate their universality.

Distinct Regions within SAP25 Recruit O-Linked Glycosylation, DNA Demethylation, and Ubiquitin Ligase and Hydrolase Activities to the Sin3/HDAC Complex.

Sin3 is an evolutionarily conserved repressor protein complex mainly associated with histone deacetylase (HDAC) activity. Many proteins are part of Sin3/HDAC complexes, and the function of most of these members remains poorly understood. SAP25, a previously identified Sin3A associated protein of 25 kDa, has been proposed to participate in regulating gene expression programs involved in the immune response but the exact mechanism of this regulation is unclear. SAP25 is not expressed in HEK293 cells, which hence serve as a natural knockout system to decipher the molecular functions uniquely carried out by this Sin3/HDAC subunit. Using molecular, proteomic, protein engineering, and interaction network approaches, we show that SAP25 interacts with distinct enzymatic and regulatory protein complexes in addition to Sin3/HDAC. Additional proteins uniquely recovered from the Halo-SAP25 pull-downs included the SCF E3 ubiquitin ligase complex SKP1/FBXO3/CUL1 and the ubiquitin carboxyl-terminal hydrolase 11 (USP11). Furthermore, mutational analysis demonstrates that distinct regions of SAP25 participate in its interaction with USP11, OGT/TETs, and SCF(FBXO3). These results suggest that SAP25 may function as an adaptor protein to coordinate the assembly of different enzymatic complexes to control Sin3/HDAC-mediated gene expression. The data were deposited with the MASSIVE repository with the identifiers MSV000093576 and MSV000093553.

Profiling of Potential Anti-Diabetic Active Compounds in White Tea: An Integrated Study of Polyphenol-Targeted Metabolomics, Network Pharmacology, and Computer Simulation

Diabetes remains a critical global public health challenge, posing a growing threat to human health and well-being. White tea is a lightly fermented tea and one of the six traditional tea categories in China. Owing to its rich content of bioactive compounds such as catechins and alkaloids, it has demonstrated potential anti-diabetic properties. However, its precise bioactive components, mechanisms of action, and relevant molecular targets require further investigation. In this study, an integrated approach combining polyphenol-targeted metabolomics, in vitro antioxidant assays, α-glucosidase inhibition tests, network pharmacology analysis, GEO database exploration, molecular docking, and molecular dynamics simulations was employed to identify the potential anti-diabetic compounds, targets, and mechanisms of white tea. The findings revealed that white tea is particularly abundant in 10 bioactive compounds, including epigallocatechin gallate, epicatechin gallate, and catechin, all of which exhibit significant anti-diabetic potential. These compounds were found to exert their effects by interacting with core molecular targets, namely cathepsin V (CTSV) and nucleotide-binding oligomerization domain-containing protein 1 (NOD1), and engaging in pathways related to signal transduction, apoptosis, and immune responses. This study establishes a strong theoretical basis for advancing white tea research and underscores new opportunities for applying natural products in diabetes therapy.

Gene Expression Profiling and Immune Pathway Dysregulation in Ribonucleoprotein Autoantibody-Positive Systemic Lupus Erythematosus Patients

Background: Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by immune dysregulation and chronic inflammation across various organ systems. While anti-dsDNA and anti-Sm antibodies are commonly associated with SLE, the presence of anti-RNP antibodies is often linked to unique gene expression profiles and immune responses. This study aims to investigate the gene expression profiles in ribonucleoprotein (RNP) autoantibody-positive SLE patients by analyzing publicly available transcriptomic data. Methods: This study analyzed transcriptomic data from the GEO dataset GSE61635, which includes gene expression profiles from 79 anti-RNP-positive SLE patients and 30 healthy controls. Differentially expressed genes (DEGs) were identified using the GEO2R tool with a p-value < 0.05 and |log2fold change| > 1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. Tissue-specific and cell-type enrichment analyses highlighted the involvement of immune tissues. Results: A total of 1891 DEGs were identified between anti-RNP-positive SLE patients and healthy controls. Among the identified DEGs, SLC4A1 and EPB42 were notably downregulated, while PIP4K2A was highly upregulated. Enrichment analyses revealed significant dysregulation in antiviral response and immune regulation pathways. PPI network analysis highlighted key hub genes, suggesting a heightened antiviral state in these patients. Tissue-specific enrichment and cell-type enrichment identified the bone marrow and immune tissues as being highly affected by the altered gene expression. Additionally, gene frequency analysis highlighted RASD2 as being recurrently significant across multiple studies. Conclusions: The findings suggest that anti-RNP-positive SLE patients exhibit distinct gene expression and immune dysregulation profiles, particularly in antiviral and immune regulation pathways. These results provide insights into the molecular mechanisms driving SLE in this patient subset and may guide future therapeutic interventions.

WNV and SLEV coinfection in avian and mosquito hosts: impact on viremia, antibody responses, and vector competence.

West Nile virus (WNV) and St. Louis encephalitis virus (SLEV) are closely related flaviviruses that can cause encephalitis in humans and related diseases in animals. In nature, both are transmitted by Culex, with wild birds, including jays, sparrows, and robins, serving as vertebrate hosts. WNV and SLEV circulate in the same environments and have recently caused concurrent disease outbreaks in humans. The extent that coinfection of mosquitoes or birds may alter transmission dynamics, however, is not well characterized. We therefore sought to determine if coinfection alters infection kinetics and virus levels in birds and infection rates in mosquitoes. Accordingly, American robins (Turdus migratorius), two species of mosquitoes, and vertebrate and invertebrate cells were infected with WNV and/or SLEV to assess how simultaneous exposure may alter infection outcomes. There was variable impact of coinfection in vertebrate cells, with some evidence that SLEV can suppress WNV replication. However, robins had comparable viremia and antibody responses regardless of coinfection. Conversely, in Culex cells and mosquitoes, we saw a minimal impact of simultaneous exposure to both viruses on replication, with comparable infection, dissemination, and transmission rates in singly infected and coinfected mosquitoes. Importantly, while WNV and SLEV levels in coinfected mosquito midguts were positively correlated, we saw no correlation between them in salivary glands and saliva. These results reveal that while coinfection can occur in both avian and mosquito hosts, the viruses minimally impact one another. The potential for coinfection to alter virus population structure or the likelihood of rare genotypes emerging remains unknown.IMPORTANCEWest Nile virus (WNV) and St. Louis encephalitis virus (SLEV) are closely related viruses that are transmitted by the same mosquitoes and infect the same birds in nature. Both viruses circulate in the same regions and have caused concurrent outbreaks in humans. It is possible that mosquitoes, birds, and/or humans could be infected with both WNV and SLEV simultaneously, as has been observed with Zika, chikungunya, and dengue viruses. To study the impact of coinfection, we experimentally infected vertebrate and invertebrate cells, American robins, and two Culex species with WNV and/or SLEV. Robins were efficiently coinfected, with no impact of coinfection on virus levels or immune response. Similarly, in mosquitoes, coinfection did not impact infection rates, and mosquitoes could transmit both WNV and SLEV together. These results reveal that WNV and SLEV coinfection in birds and mosquitoes can occur in nature, which may impact public health and human disease risk.

Microbial and Transcriptomic Landscape Associated With Neutrophil Extracellular Traps in Perianal Fistulizing Crohn's Disease.

Perianal fistulizing Crohn's disease (pfCD) poses significant healing challenges, closely associated with neutrophil extracellular traps (NETs). This study aimed to investigate the microbe-host interactions influencing NETs in pfCD. From January 2019 to July 2022, patients with pfCD were screened at Ren Ji Hospital. Patients in remission following comprehensive treatment were recruited. We documented clinical characteristics, medication regimens, healing outcomes, and infliximab levels in fistula tissues. NET positivity was confirmed by positive results in citrullinated histone H3 (CitH3) enzyme-linked immunosorbent assay (ELISA) and dual immunofluorescence staining for myeloperoxidase and CitH3. Microbial and transcriptomic profiles from fistula tissues, obtained during surgery, were analyzed using 16S rRNA gene sequencing and RNA sequencing. Differences in microbiome and transcriptomic profiles were evaluated, and their relationships were assessed using Mantel's and Spearman's coefficients. Significant differences in microbial communities were found between groups (P = .007). Representatively differential microbes such as Prevotella bivia, Streptococcus gordonii, and Bacteroides dorei were enriched in NETs-positive fistulas (P < .05). Functional analysis of microbes revealed reduced ubiquinol biosynthesis and butanoate production in NETs-negative fistulas (P < .05). Transcriptomic analysis indicated increased neutrophil and monocyte infiltration in NETs-positive fistulas, associated with pathways involving bacterial response, neutrophil chemotaxis, secretory processes, and peptidase activity (P < .05). Species prevalent in NETs-positive fistulas correlated positively with immune responses and wound healing pathways, whereas bacteria in NETs-negative fistulas correlated negatively. NETs were negatively associated with tissue infliximab levels (P = .001) and healing outcomes (P = .025). Our findings reveal unique microbial and transcriptomic signatures associated with NETs in pfCD, highlighting their profound influence on clinical outcomes.

Pseudorabies virus infection triggers mitophagy to dampen the interferon response and promote viral replication.

Pseudorabies virus (PRV) utilizes multiple strategies to inhibit type I interferon (IFN-I) production and signaling to achieve innate immune evasion. Among several other functions, mitochondria serve as a crucial immune hub in the initiation of innate antiviral responses. It is currently unknown whether PRV inhibits innate immune responses by manipulating mitochondria. In this study, we found that PRV infection damages mitochondrial structure and function, as shown by mitochondrial membrane potential depolarization, reduction in mitochondrial numbers, and an imbalance in mitochondrial dynamics. In addition, PRV infection triggered PINK1-Parkin-mediated mitophagy to eliminate the impaired mitochondria, which resulted in a suppression of IFN-I production, thereby promoting viral replication. Furthermore, we found that mitophagy resulted in the degradation of the mitochondrial antiviral signaling protein, which is located on the mitochondrial outer membrane. In conclusion, the data of the current study indicate that PRV-induced mitophagy represents a previously uncharacterized PRV evasion mechanism of the IFN-I response, thereby promoting virus replication.IMPORTANCEPseudorabies virus (PRV), a pathogen that induces different disease symptoms and is often fatal in domestic animals and wildlife, has caused great economic losses to the swine industry. Since 2011, different PRV variant strains have emerged in Asia, against which current commercial vaccines may not always provide optimal protection in pigs. In addition, there are indications that some of these PRV variant strains may sporadically infect people. In the current study, we found that PRV infection causes mitochondria injury. This is associated with the induction of mitophagy to eliminate the damaged mitochondria, which results in suppressed antiviral interferon production and signaling. Hence, our study reveals a novel mechanism that is used by PRV to antagonize the antiviral host immune response, providing a theoretical basis that may contribute to the research toward and development of new vaccines and antiviral drugs.

Kynurenine-AhR reduces T-cell infiltration and induces a delayed T-cell immune response by suppressing the STAT1-CXCL9/CXCL10 axis in tuberculosis.

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is a critical global health issue that is complicated by the ability of the pathogen to delay the host's T-cell immune response. This delay in T-cell recruitment to the site of infection is a pivotal survival strategy for Mtb, allowing it to establish a persistent chronic infection. To investigate the underlying mechanisms, this study focused on Mtb's exploitation of host tryptophan metabolism. Mtb upregulates indoleamine 2,3-dioxygenase 1 (IDO1) in inflammatory macrophages, thereby increasing kynurenine (Kyn) production. Kyn then activates the aryl hydrocarbon receptor (AhR), leading to the upregulation of suppressor of cytokine signaling 3 and subsequent inhibition of the JAK-STAT1 signaling pathway. This results in reduced secretion of the chemokines CXCL9 and CXCL10, which are crucial for T-cell recruitment to the lungs. Supported by in vivo mouse models, our findings reveal that disrupting this pathway through AhR knockout significantly enhances T-cell infiltration and activity, thereby undermining Mtb-induced immunosuppression. In contrast, additional Kyn injection obviously inhibited T-cell infiltration and activity. These results highlight potential therapeutic targets of AhR and IDO1, offering new avenues for enhancing the host immune response against tuberculosis and guiding future vaccine development efforts.

Reinventing gut health: leveraging dietary bioactive compounds for the prevention and treatment of diseases

The human gut harbors a complex and diverse microbiota essential for maintaining health. Diet is the most significant modifiable factor influencing gut microbiota composition and function, particularly through bioactive compounds like polyphenols, dietary fibers, and carotenoids found in vegetables, fruits, seafood, coffee, and green tea. These compounds regulate the gut microbiota by promoting beneficial bacteria and suppressing harmful ones, leading to the production of key microbiota-derived metabolites such as short-chain fatty acids, bile acid derivatives, and tryptophan metabolites. These metabolites are crucial for gut homeostasis, influencing gut barrier function, immune responses, energy metabolism, anti-inflammatory processes, lipid digestion, and modulation of gut inflammation. This review outlines the regulatory impact of typical bioactive compounds on the gut microbiota and explores the connection between specific microbiota-derived metabolites and overall health. We discuss how dietary interventions can affect disease development and progression through mechanisms involving these metabolites. We examine the roles of bioactive compounds and their metabolites in the prevention and treatment of diseases including inflammatory bowel disease, colorectal cancer, cardiovascular diseases, obesity, and type 2 diabetes mellitus. This study provides new insights into disease prevention and underscores the potential of dietary modulation of the gut microbiota as a strategy for improving health.

Characterization of HPV6/11-reactive T-cell subsets in papillomas of patients with juvenile-onset recurrent respiratory papillomatosis and identification of HPV11 E7-specific candidate TCR clonotypes.

Juvenile-onset recurrent respiratory papillomatosis (JORRP) is caused by persistent infection of epithelial cells by low-risk human papillomavirus (HPV) types 6 and 11. While multiple infiltrated immune cells have been reported to mediate disease progress, knowledge of HPV-reactive T-cell subsets in papillomas remains elusive. Through single-cell RNA sequencing and RNA microarray, we found that CD8+ tissue-resident memory T (CD8+ TRM) cells with strong interferon-gamma (IFN-γ) production expanded, and were negatively correlated to the disease severity in the frequency of surgery. These IFN-γ+ CD8+ memory T cells were readily activated and expanded in vitro by autologous dendritic cells loaded with HPV11 E7 peptide pool. Moreover, T cell receptor (TCR) clonal expansion was observed in JORRP papilloma tissues, indicating a biased TCR repertoire toward HPV-specific recognition. Finally, we identified and characterized HPV11 E7-specific candidate TCR clonotypes from IFN-γ+ CD8+ memory T cells, suggesting their potential application in TCR-engineered T cells (TCR-T) therapy for HPV11-related diseases. Our findings provided insights into the specific local immune response to HPV6/11 infection and highlighted the importance of IFN-γ+ CD8+ TRM cells in anti-HPV6/11 T-cell immunity.IMPORTANCEThe persistent recurrence of human papillomavirus (HPV) 6/11 infection in papillomas underscores the failure of local immune responses in patients with juvenile-onset recurrent respiratory papillomatosis (JORRP). Our previous study demonstrated that T cells constitute the predominant immune cell population in JORRP papilloma tissues. Understanding the T-cell-mediated immune responses within JORRP papilloma tissues is crucial for disease control. In the present study, we characterized CD8+ tissue-resident memory T (CD8+ TRM) cells as the primary T-cell subset responsible for local anti-HPV6/11 immunity. Moreover, we identified two HPV11 E7-specific candidate T cell receptor (TCR) clonotypes out of IFN-γ+ CD8+ memory T cells. Overall, our findings provided insights into the local immune responses to HPV6/11 infection and offered information for developing more effective immunotherapeutic strategies against JORRP.

Alginate-modified graphene oxide anchored with lactoperoxidase as a novel bioactive nanocombination for colorectal cancer therapy

It is imperative to explore new biocompatible drugs with low toxicity for use in medicinal fields such as fighting tumors. Bovine lactoperoxidase (BLPO) stems from the most important enzymes in the bovine whey that provide a proper pattern for nano-formulation with nanomaterials. LPO is a suitable protein to be coated or adsorbed to alginate modified graphene oxide (GO-SA), which forms the modified GO-SA-LPO hybrid structure. This novel combination provides LPO stability with strong anticancer effects and boosts immunity response. The characterization results obtained from different techniques confirmed a successful LPO adsorption on the GO-SA composite surface. Moreover, nano-formulation of LPO with GO-SA composite exhibited a reduction in its size and overall charge. In addition, the experimental results showed greater LPO activity stability in the modified GO-SA-LPO nanocombination than free LPO after storage for 10 weeks at 4 °C. The in vitro study, a crucial step in the validation of our approach, demonstrated that the modified GO-SA-LPO nanocombination showed a potent anticancer selectivity toward colon cancer cell lines more than GO-SA composite or free form of LPO, which enhanced in a dose-dependent manner with high safety manner against normal cells. The apoptotic effect of this novel nanocombination was confirmed by the greatest variations in the expression of both well-known apoptosis genes (p53 and Bcl-2), severe changes in the cellular morphology, DNA fragmentation, and nuclear staining with fluorescence yellow and orange of the target cancer cells. Also, this superior efficacy of the modified GO-SA-LPO nanocombination was induced by suppressing some pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL-6), and necrosis factor-kappa B (NF-ĸB). Our observations presented that the modified nanocombination of LPO may offer a novel remedy for treating colon tumors via induced apoptosis pathway, inflammation reduction, and immune response improvement.

Gut microbiota: a crucial player in the combat against tuberculosis

The mammalian gastrointestinal tract quickly becomes densely populated with foreign microorganisms shortly after birth, thereby establishing a lifelong presence of a microbial community. These commensal gut microbiota serve various functions, such as providing nutrients, processing ingested compounds, maintaining gut homeostasis, and shaping the intestinal structure in the host. Dysbiosis, which is characterized by an imbalance in the microbial community, is closely linked to numerous human ailments and has recently emerged as a key factor in health prognosis. Tuberculosis (TB), a highly contagious and potentially fatal disease, presents a pressing need for improved methods of prevention, diagnosis, and treatment strategies. Thus, we aim to explore the latest developments on how the host’s immune defenses, inflammatory responses, metabolic pathways, and nutritional status collectively impact the host’s susceptibility to or resilience against Mycobacterium tuberculosis infection. The review addresses how the fluctuations in the gut microbiota not only affect the equilibrium of these physiological processes but also indirectly influence the host’s capacity to resist M. tuberculosis. This work highlights the central role of the gut microbiota in the host–microbe interactions and provides novel insights for the advancement of preventative and therapeutic approaches against tuberculosis.

Withania coagulans root powder effect on growth, hematology, digestive enzyme activity, antioxidant status, serum immune response, and tolerance against Aeromonas hydrophila in Common Carp

AbstractObjectiveThe use of plant‐derived products in aquaculture has garnered considerable attention due to their potential benefits. This study investigated the impact of supplementing Withania coagulans root powder (WCRP) in the diet of Common Carp Cyprinus carpio on various parameters, including growth performance, digestive enzymes, hematology, antioxidant activity, and immunological aspects.MethodsCommon Carp (mean weight ± standard deviation = 11.69 ± 0.48 g) were divided into four groups in triplicate, receiving different WCRP concentrations (0.0, 1.0, 1.5, and 2.0%; labeled as WCRP0, WCRP1.0, WCRP1.5, and WCRP2.0, respectively) over a 60‐day period, followed by an experimental challenge with Aeromonas hydrophila to assess the relative percentage survival (RPS) over 14 days.ResultResults showed that Common Carp receiving WCRP1.5 and WCRP2.0 demonstrated significantly improved growth performance, with reduced feed conversion ratios (FCRs) being particularly evident in WCRP1.5. Polynomial contrasts indicated significant linear and quadratic effects on weight gain and FCR. Additionally, WCRP1.5 and WCRP2.0 supplementation led to significantly higher activity of digestive enzymes (lipase and protease). Hematological parameters, including white blood cells, red blood cells, hemoglobin, and hematocrit, were significantly elevated in fish that were fed WCRP1.5 and WCRP2.0 compared to the control group. Moreover, serum parameters, such as total protein, albumin, globulin, lysozyme, catalase, superoxide dismutase, and total immunoglobulins, were significantly enhanced in WCRP1.5‐ and WCRP2.0‐treated fish. Notably, the WCRP1.5 group showed the lowest serum cortisol levels. The RPS was highest in WCRP1.5 (73.77%), followed by WCRP2.0 (70.43%), compared to the other groups.ConclusionIn conclusion, supplementation with WCRP1.5 and WCRP2.0 effectively improved both growth and health parameters in Common Carp.

Envelope domain III E324, E351, and E380 mutations lever adaptive evolution of DENV-1 genotype I.

We provide evidence that minor sequence variation among dengue virus (DENV) strains can result in increased adaptability and virulence, impacting both the biology of the virus and the antiviral immune response. The genetic mutations of DENV-1 gained during continuous transmission and evolution will offer new clues for the design of novel vaccines against flaviviruses.

Metapopulation model of phage therapy of an acute Pseudomonas aeruginosa lung infection.

Phage therapy is increasingly employed as a compassionate treatment for severe infections caused by multidrug-resistant (MDR) bacteria. However, the mixed outcomes observed in larger clinical studies highlight a gap in understanding when phage therapy succeeds or fails. Previous research from our team, using in vivo experiments and single-compartment mathematical models, demonstrated the synergistic clearance of acute P. aeruginosa pneumonia by phage and neutrophils despite the emergence of phage-resistant bacteria. In fact, the lung environment is highly structured, prompting the question of whether immunophage synergy explains the curative treatment of P. aeruginosa when incorporating realistic physical connectivity. To address this, we developed a metapopulation network model mimicking the lung branching structure to assess phage therapy efficacy for MDR P. aeruginosa pneumonia. The model predicts the synergistic elimination of P. aeruginosa by phage and neutrophils but emphasizes potential challenges in spatially structured environments, suggesting that higher innate immune levels may be required for successful bacterial clearance. Model simulations reveal a spatial pattern in pathogen clearance where P. aeruginosa are cleared faster at distal nodes of the bronchial tree than in primary nodes. Interestingly, image analysis of infected mice reveals a concordant and statistically significant pattern: infection intensity clears in the bottom before the top of the lungs. The combined use of modeling and image analysis supports the application of phage therapy for acute P. aeruginosa pneumonia while emphasizing potential challenges to curative success in spatially structured in vivo environments, including impaired innate immune responses and reduced phage efficacy.

Acute-phase innate immune responses in SIVmac239-infected Mamu-B*08+ Indian rhesus macaques may contribute to the establishment of elite control

IntroductionSpontaneous control of chronic-phase HIV/SIV viremia is often associated with the expression of specific MHC class I allotypes. HIV/SIV-specific CD8+ cytotoxic T lymphocytes (CTLs) restricted by these MHC class I allotypes appear to be critical for viremic control. Establishment of the elite controller (EC) phenotype is predictable in SIVmac239-infected Indian rhesus macaques (RMs), with approximately 50% of Mamu-B*08+ RMs and 20% of Mamu-B*17+ RMs becoming ECs. Despite extensive characterization of EC-associated CTLs in HIV/SIV-infected individuals, the precise mechanistic basis of elite control remains unknown. Because EC and non-EC viral load trajectories begin diverging by day 14 post-infection, we hypothesized that hyperacute innate immune responses may contribute to viremic control.MethodsTo gain insight into the immunological factors involved in the determination of EC status, we vaccinated 16 Mamu-B*08+ RMs with Vif and Nef to elicit EC-associated CTLs, then subjected these 16 vaccinees and an additional 16 unvaccinated Mamu-B*08+ controls to repeated intrarectal SIVmac239 challenges. We then performed whole-blood transcriptomic analysis of all 32 SIVmac239-infected Mamu-B*08+ RMs and eight SIVmac239-infected Mamu-B*08– RMs during the first 14 days of infection.ResultsVaccination did not provide protection against acquisition, but peak and setpoint viremia were significantly lower in vaccinees relative to controls. We did not identify any meaningful correlations between vaccine-induced CTL parameters and SIVmac239 acquisition rate or chronic-phase viral loads. Ultimately, 13 of 16 vaccinees (81%) and 7 of 16 controls (44%) became ECs (viremia ≤ 10,000 vRNA copies/mL plasma for ≥ 4 weeks). We identified subsets of immunomodulatory genes differentially expressed (DE) between RM groupings based on vaccination status, EC status, and MHC class I genotype. These DE genes function in multiple innate immune processes, including the complement system, cytokine/chemokine signaling, pattern recognition receptors, and interferon-mediated responses.DiscussionA striking difference in the kinetics of differential gene expression among our RM groups suggests that Mamu-B*08-associated elite control is characterized by a robust, rapid innate immune response that quickly resolves. These findings indicate that, despite the association between MHC class I genotype and elite control, innate immune factors in hyperacute SIV infection preceding CTL response development may facilitate the establishment of the EC phenotype.

Breadth and polyfunctionality of T cell responses to human cytomegalovirus in men who have sex with men: relationship with HIV infection and frailty.

T cell responses to chronic cytomegalovirus (CMV) infection have significant biological and clinical implications in HIV infection and aging. Here, we systematically analyzed the breadth, magnitude, and polyfunctionality of T cell responses to multiple CMV antigens in men with and without HIV in the Multicenter AIDS Cohort Study (MACS), a longstanding study of the natural and treated history of HIV-1 infection in men who have sex with men. We found that the breadth and polyfunctionality of T cell responses to CMV were different between men with chronic, treated HIV and those without HIV. The reason for these differences is unknown, but these findings suggest that people with treated HIV may have more frequent CMV reactivation than people without HIV. Differences between people with and without HIV also resembled differences reported between young and older adults without HIV, supporting a role for the immune responses to CMV in the aging process.

Single-Cell Transcriptomics Unveils Skin Cell Specific Antifungal Immune Responses and IL-1Ra- IL-1R Immune Evasion Strategies of Emerging Fungal Pathogen Candida auris.

Candida auris is an emerging multidrug-resistant fungal pathogen that preferentially colonizes and persists in skin tissue, yet the host immune factors that regulate the skin colonization of C. auris in vivo are unknown. In this study, we employed unbiased single-cell transcriptomics of murine skin infected with C. auris to understand the cell type-specific immune response to C. auris. C. auris skin infection results in the accumulation of immune cells such as neutrophils, inflammatory monocytes, macrophages, dendritic cells, T cells, and NK cells at the site of infection. We identified fibroblasts as a major non-immune cell accumulated in the C. auris infected skin tissue. The comprehensive single-cell profiling revealed the transcriptomic signatures in cytokines, chemokines, host receptors (TLRs, C-type lectin receptors, NOD receptors), antimicrobial peptides, and immune signaling pathways in individual immune and non-immune cells during C. auris skin infection. Our analysis revealed that C. auris infection upregulates the expression of the IL-1RN gene (encoding IL-1R antagonist protein) in different cell types. We found IL-1Ra produced by macrophages during C. auris skin infection decreases the killing activity of neutrophils. Furthermore, C. auris uses a unique cell wall mannan outer layer to evade IL-1R-signaling mediated host defense. Collectively, our single-cell RNA seq profiling identified the transcriptomic signatures in immune and non-immune cells during C. auris skin infection. Our results demonstrate the IL-1Ra and IL-1R-mediated immune evasion mechanisms employed by C. auris to persist in the skin. These results enhance our understanding of host defense and immune evasion mechanisms during C. auris skin infection and identify potential targets for novel antifungal therapeutics.

A cGAS-mediated type I interferon response in human CD4+ T cells depends on productive infection and is conserved over HIV types and strains.

Human immunodeficiency virus (HIV) type 2 is known to be less pathogenic than HIV-1, possibly due to more effective immune control mechanisms. The mechanism of innate sensing of HIV-2 by T cells is at present unclear. In this study, we show that several primary isolates of HIV-2 (CBL20 and CI85) and HIV-1 (A8 and D2), similar to the molecular clone HIV-1 NL4.3-GFP-I, induce a significant type I interferon response in its main target, activated CD4+ T cells. However, they are unable to do so after shRNA-mediated knock-down of cGAS. In addition, both HIV-1- and HIV-2-induced type I interferon response in CD4+ T cells was dependent on productive infection and integration, as the presence of RT or integrase inhibitor dramatically suppressed the sensing. Our findings collectively showed that the cGAS-dependent type I interferon response of CD4+ T cells to HIV infection is conserved over HIV types and critically depends on productive infection.IMPORTANCEBy unveiling the role of cGAS in sensing Human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) across CD4+ T cells and highlighting its broader relevance that might be mirrored in other cell types, our research provides insights into the uniform mechanism of innate immune activation by different HIV isolates. By demonstrating the necessity of productive infection, we highlight the robust and specific nature of the observed cGAS-mediated innate response, dispelling concerns about contaminating plasmids triggering an immune response. Our preliminary data suggest that the lower pathogenicity of HIV-2 may not be directly correlated to superior innate immune control mediated by cGAS.

A Tumor-Homing Nanoframework for Synergistic Microwave Tumor Ablation and Provoking Strong Anticancer Immunity Against Metastasis.

Microwave thermotherapy (MT) is a clinical local tumor ablation modality, but its applications are limited by its therapeutic efficacy and safety. Therefore, developing sensitizers to optimize the outcomes of MT is in demand in clinical practice. Herein, we engineered a special nanoframework (i.e., FdMI) based on a fucoidan-decorated zirconium metal-organic framework incorporating manganese ions and liquid physisorption for microwave tumor ablation. The monodisperse nanoframework exhibited both microwave thermal effects and microwave dynamic effects, which could effectively kill cancer cells by efficient intracellular drug delivery. Through fucoidan-mediated targeting of P-selectin in the tumor microenvironment (TME), the FdMI effectively accumulated in tumor regions, leading to significant eradication of orthotropic triple-negative breast cancer (TNBC) and aggressive Hepa1-6 liver tumors by the synergistic effects of microwave thermotherapy/dynamic therapy (MT/MDT). The eradication of primary tumors could activate systemic immune responses, which effectively inhibited distant TNBC tumors and lung metastasis of Hepa1-6 liver tumors, respectively. This work not only engineered nanoparticle sensitizers for tumor-targeted synergistic MT/MDT but also demonstrated that nanocarrier-based microwave tumor ablation could stimulate antitumor immunity to effectively inhibit distant and metastatic tumors, demonstrating the high potential for effectively managing advanced malignant tumors.