Host Immune Cells Research Articles

Microbial Tryptophan Metabolism Tunes Host Immunity, Metabolism, and Extraintestinal Disorders.

The trillions of commensal microorganisms comprising the gut microbiota have received growing attention owing to their impact on host physiology. Recent advances in our understandings of the host–microbiota crosstalk support a pivotal role of microbiota-derived metabolites in various physiological processes, as they serve as messengers in the complex dialogue between commensals and host immune and endocrine cells. In this review, we highlight the importance of tryptophan-derived metabolites in host physiology, and summarize the recent findings on the role of tryptophan catabolites in preserving intestinal homeostasis and fine-tuning immune and metabolic responses. Furthermore, we discuss the latest evidence on the effects of microbial tryptophan catabolites, describe their mechanisms of action, and discuss how perturbations of microbial tryptophan metabolism may affect the course of intestinal and extraintestinal disorders, including inflammatory bowel diseases, metabolic disorders, chronic kidney diseases, and cardiovascular diseases.

Substratum interactions modulate interplay between endothelial cell, epithelial cell, and fibroblast phenotype and immunomodulatory function

Endothelial cells (ECs) sense and adapt to their environment, allowing them to display a range of functional phenotypes and promote vascular homeostasis across organ systems. However, many of these cues are lost when cells are cultured in vitro. This work explores how substratum interactions influence cellular phenotype. Culture conditions, specifically 2D culture on tissue culture polystyrene (TCP) versus 3D culture on collagen scaffolds, had a much greater effect on EC phenotype than did in vivo cell source. The 3D ECs responded to hypoxic gradients by inducing the expression of HIF1-a while 2D ECs underwent endothelial-to-mesenchymal transition. In comparing the effect of culture condition on EC phenotype and function to its effect on epithelial cells (EPs) and fibroblasts (FBs), it is evident that ECs are not simply vascular EPs but are unique in their response. For cell types like ECs, which are particularly responsive to their microenvironment, traditional culture on TCP is insufficient for revealing in vivo behavior. Further applying these findings, we found that culture-condition differentially affected the expression of immunomodulatory factors and in an in vivo model of allotransplantation, 3D culture reduced the cytotoxic response of host immune cells to all three cell types compared to 2D culture.

Superoxide dismutase inhibits cytotoxic killing of Fasciola gigantica newly excysted juveniles expressed by sheep invitro

Fasciola gigantica faces a series of threats from various free radicals produced by the host immune system during its invasion through the abdominal cavity and establishment in the bile duct of ruminants, limiting the fluke viability. The role of the superoxide radical produced by Muzaffarnagari sheep immune effector cells against F. gigantica newly excysted juveniles (NEJs) is highlighted in this study, as is the critical role of superoxide dismutase enzyme (SOD) in dismutation of superoxide radicals derived from host immune effector cells in vitro. Three concentrations of the ovine immune effector cells viz. 2.5, 5, and 10 × 106 cells were tested for their ability to induced cytotoxic killing of the parasite. All the three cell concentrations caused significant (p < 0.01) cytotoxic killing of NEJs in comparison to the control groups. Also, reduction of the immune effector cell concentration directly correlates with the NEJs killing. Attachment of immune effector cells to the parasite tegument in the presence of anti-F. gigantica antibodies was found to be critical in inducing NEJs killing via antibody-dependent cell-mediated cytotoxicity (ADCC). However, the addition of SOD greatly inhibits cytotoxic killing of NEJs, demonstrating the importance of SOD enzyme in fluke survival and parasite evasion of the host immunity. Thus, F. gigantica SOD warrants a promising candidate for immunoprophylactic studies in ruminants against the tropical liver fluke.

Abstract PO032: Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-TRAIL-R Mediates Cholangiocarcinoma Tumor Immune Evasion by Enhancing Myeloid-Derived Suppressive Cell Population

Abstract Background and Aims: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of TNF superfamily, is predominantly expressed on immune cells. Engagement of TRAIL with its cognate receptor, TRAIL-R (TR), leads to cancer cells apoptosis. Although the anti-tumor role of TRAIL-TR has been extensively studied, TRAIL agonists have had very limited anti-cancer activity in human clinical trials. TRAIL signaling can facilitate the myeloid response. However, this potential immunosuppressive function of TRAIL has not been examined extensively in cancer biology. Cholangiocarcinoma (CCA), a highly lethal biliary tract cancer, has a dense immunosuppressive microenvironment. Accordingly, CCA provides a model to examine the potential immune regulatory function of TRAIL in cancer biology. Methods: Using syngeneic, orthotopic murine models of CCA, (PMID: 29464042), murine CCA cells (SB cells) that express both Trail and Trail receptor (Tr) were implanted into livers of WT Tr− / − and LyzcreTrf/f mice, the latter have a specific deletion of TRAIL-R on myeloid cells. Hence, in this model the host immune cells express Trail but not the receptor; therefore, they would be capable of inducing TRAIL-mediated apoptosis in CCA cells but would be resistant to TRAIL-mediated immunosuppression. After 4 weeks of tumor growth, mice were sacrificed, and tumors were characterized using flow cytometry. Results: We observed that Tr− / − mice had a significant reduction in tumor burden compared to WT mice. Myeloid-derived suppressor cells (MDSCs) were significantly decreased in Tr− / − tumors compared to WT tumors. Implantation of SB cells into LyzcreTrf/f mice resulted in a marked reduction in tumor burden and attenuation of MDSC infiltration compared to Lyzcre mice. In vitro functional studies employing MDSCs from mice deficient in Tr (MDSC-Tr −/−) were carried out. Compared to WT MDSCs, coculture of MDSC-Tr− /- with SB cells resulted in a significant reduction in the proliferation and immunosuppressive function of MDSCs. Moreover, following cocultured with SB cells, immunofluorescence analysis demonstrated that MDSC-Tr− / − had a reduction in the nuclear translocation of the NFkB subunit P65 compared to WT MDSCs. These data suggest that TRAIL-TR augments MDSC proliferation via NFkB. In conclusion, we have demonstrated that Tr− / − mice have a significant reduction in CCA tumor burden and MDSC infiltration. These results indicate that TRAIL-TR facilitates tumor immune escape and progression by fostering MDSC immunosuppressive function and infiltration, in an NFkB-dependent manner. Direct targeting of TRAIL on CCA cells is a potential anti-tumor strategy. Citation Format: Emilien Loeuillard, Jingchun Yang, Dong Haidong, Gregory Gores, Sumera Ilyas. Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-TRAIL-R Mediates Cholangiocarcinoma Tumor Immune Evasion by Enhancing Myeloid-Derived Suppressive Cell Population [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO032.

Outer Membrane Vesicles of Actinobacillus pleuropneumoniae Exert Immunomodulatory Effects on Porcine Alveolar Macrophages.

ABSTRACTOuter membrane vesicles (OMVs) are spontaneously released by Gram-negative bacteria, including Actinobacillus pleuropneumoniae, which causes contagious pleuropneumonia in pigs and leads to considerable economic losses in the swine industry worldwide. A. pleuropneumoniae OMVs have previously been demonstrated to contain Apx toxins and proteases, as well as antigenic proteins. Nevertheless, comprehensive characterizations of their contents and interactions with host immune cells have not been made. Understanding the protein compositions and immunomodulating ability of A. pleuropneumoniae OMVs could help illuminate their biological functions and facilitate the development of OMV-based applications. In the current investigation, we comprehensively characterized the proteome of native A. pleuropneumoniae OMVs. Moreover, we qualitatively and quantitatively compared the OMV proteomes of a wild-type strain and three mutant strains, in which relevant genes were disrupted to increase OMV production and/or produce OMVs devoid of superantigen PalA. Furthermore, the interaction between A. pleuropneumoniae OMVs and porcine alveolar macrophages was also characterized. Our results indicate that native OMVs spontaneously released by A. pleuropneumoniae MIDG2331 appeared to dampen the innate immune responses by porcine alveolar macrophages stimulated by either inactivated or live parent cells. The findings suggest that OMVs may play a role in manipulating the porcine defense during the initial phases of the A. pleuropneumoniae infection.IMPORTANCE Owing to their built-in adjuvanticity and antigenicity, bacterial outer membrane vesicles (OMVs) are gaining increasing attention as potential vaccines for both human and animal use. OMVs released by Actinobacillus pleuropneumoniae, an important respiratory pathogen in pigs, have also been investigated for vaccine development. Our previous studies have shown that A. pleuropneumoniae secretes OMVs containing multiple immunogenic proteins. However, immunization of pigs with these vesicles was not able to relieve the pig lung lesions induced by the challenge with A. pleuropneumoniae, implying the elusive roles that A. pleuropneumoniae OMVs play in host-pathogen interaction. Here, we showed that A. pleuropneumoniae secretes OMVs whose yield and protein content can be altered by the deletion of the nlpI and palA genes. Furthermore, we demonstrate that A. pleuropneumoniae OMVs dampen the immune responses in porcine alveolar macrophages stimulated by A. pleuropneumoniae cells, suggesting a novel mechanism that A. pleuropneumoniae might use to evade host defense.

Association between active pulmonary tuberculosis and miRNA-146a: A preliminary study from Serbia.

Tuberculosis (TB) continues to be a significant public health problem. The role of small non-coding RNAs, such as microRNAs (miRNAs), was investigated extensively in Mycobacterium tuberculosis (MTB) infection as well as in a variety of other pathophysiological processes in recent years. It was found that miRNAs act as regulators of both early reaction to MTB infection and in process of adaptation of the host immune cells during latent course of the disease. Molecule miRNA-146a is expressed exclusively in immune cells and it has the most prominent role in modulation of innate immunity. We investigated the level of expression of miRNA-146a using an RT-qPCR technique in peripheral blood mononuclear cells of 44 patients with active pulmonary TB and 17 healthy individuals. We also analyzed the significance of miRNA-146a rs2910164 SNV for expression profile of miRNA-146a, in order to investigate potential usage of miRNA-146a as a biomarker for TB. There was statistically significant decrease of expression of miRNA-146a in TB group compared to control group. When gender cohorts were analyzed, the expression levels in TB male and TB female subgroup were significantly lower than the expression levels in the same gender control subgroups. Our results indicate that miRNA-146a plays a significant role in the pathogenesis of TB, suggesting that miRNA-146a could be used as a biomarker for active pulmonary TB.

PB1F2 from Influenza A Virus Regulates the Interaction between Cytochrome C and Cardiolipin.

PB1F2 is a membrane associated protein encoded by the influenza virus gene in the host. Similar to endogenous pro-apoptotic proteins, it acts on the mitochondria of the host immune cells, inducing apoptosis of the cells. The PB1F2 protein has been demonstrated to facilitate the release of cytochrome c in addition to impairing the integrity of the inner mitochondrial membrane. This investigation focused on how the protein PB1F2 interacted with cardiolipin and cytochrome c. The regulation of PB1F2 on the binding of cytochrome c to cardiolipin in two kinds of in vitro membrane mimics was investigated by biophysical techniques. PB1F2 aids in the dissociation of cytochrome c-cardiolipin complexes in liposomes and nanodiscs. The results provide novel explanations and evidence for how PB1F2 functions as a viral virulence factor by inducing immune cell death.

The Azithromycin Pro-Drug CSY5669 Boosts Bacterial Killing While Attenuating Lung Inflammation Associated with Pneumonia Caused by Methicillin-Resistant Staphylococcus aureus.

ABSTRACTAntibiotic resistance is a major problem, with methicillin-resistant Staphylococcus aureus (MRSA) being a prototypical example in surgical and community-acquired infections. S. aureus, like many pathogens, is immune evasive and able to multiply within host immune cells. Consequently, compounds that aid host immunity (e.g., by stimulating the host-mediated killing of pathogens) are appealing alternatives or adjuncts to classical antibiotics. Azithromycin is both an antibacterial and an immunomodulatory drug that accumulates in immune cells. We set out to improve the immunomodulatory properties of azithromycin by coupling the immune activators, nitric oxide and acetate, to its core structure. This new compound, designated CSY5669, enhanced the intracellular killing of MRSA by 45% ± 20% in monocyte-derived macrophages and by 55% ± 15% in peripheral blood leukocytes, compared with untreated controls. CSY5669-treated peripheral blood leukocytes produced fewer proinflammatory cytokines, while in both monocyte-derived macrophages and peripheral blood leukocytes, phagocytosis, ROS production, and degranulation were unaffected. In mice with MRSA pneumonia, CSY5669 treatment reduced inflammation, lung pathology and vascular leakage with doses as low as 0.01 μmol/kg p.o. CSY5669 had diminished direct in vitro antibacterial properties compared with azithromycin. Also, CSY5669 was immunomodulatory at concentrations well below 1% of the minimum inhibitory concentration, which would minimize selection for macrolide-resistant bacteria if it were to be used as a host-directed therapy. This study highlights the potential of CSY5669 as a possible adjunctive therapy in pneumonia caused by MRSA, as CSY5669 could enhance bacterial eradication while simultaneously limiting inflammation-associated pathology.

CAR γδ T cells for cancer immunotherapy. Is the field more yellow than green?

Engineered immune cell therapy to treat malignancies refractory to conventional therapies is modernizing oncology. Although αβ T cells are time-tested chassis for CAR, potential graft versus host disease (GvHD) apart from cytokine toxicity and antigen escape pose limitations to this approach. αβ T cell malignancy challenges isolation and expansion of therapeutic T cells. Moreover, αβ T cells may pose toxicity risk to inflammation sensitive vital tissues bearing the tumor. The HLA independent, multivalent, versatile and systemic anti-tumor immunity increases the desirability of γδ T cells as an alternate chassis for CAR. Indeed, CD19 γδ CAR T cell therapy to treat advanced lymphoma reached a milestone with the fast track status by FDA. However, reduced tumor-toxicity, homing, in vivo persistence and heterogeneity limits the translation of this therapy. The field is gaining momentum in recent years with optimization of gene delivery approaches and mechanistic insights into co-signaling requirements in γδ T cells. There is a renewed interest in customizing design of CAR guided by the biology of the host immune cells. Progress has been made in the current good manufacturing practice compatible expansion and engineering protocols for the δ1 and δ2 T cells. γδ CAR T cells may find its niche in the clinical situations wherein conventional CAR therapy is less suitable due to propensity for cytokine toxicity or off-tumor effect. As the therapy is moving towards clinical trials, this review chronicles the hitherto progress in the therapeutic engineering of γδ T cells for cancer immunotherapy.

Secreted filarial nematode galectins modulate host immune cells.

Lymphatic filariasis (LF) is a mosquito-borne disease caused by filarial nematodes including Brugia malayi. Over 860 million people worldwide are infected or at risk of infection in 72 endemic countries. The absence of a protective vaccine means that current control strategies rely on mass drug administration programs that utilize inadequate drugs that cannot effectively kill adult parasites, thus established infections are incurable. Progress to address deficiencies in the approach to LF control is hindered by a poor mechanistic understanding of host-parasite interactions, including mechanisms of host immunomodulation by the parasite, a critical adaptation for establishing and maintaining infections. The canonical type 2 host response to helminth infection characterized by anti-inflammatory and regulatory immune phenotypes is modified by filarial nematodes during chronic LF. Current efforts at identifying parasite-derived factors driving this modification focus on parasite excretory-secretory products (ESP), including extracellular vesicles (EVs). We have previously profiled the cargo of B. malayi EVs and identified B. malayi galectin-1 and galectin-2 as among the most abundant EV proteins. In this study we further investigated the function of these proteins. Sequence analysis of the parasite galectins revealed highest homology to mammalian galectin-9 and functional characterization identified similar substrate affinities consistent with this designation. Immunological assays showed that Bma-LEC-2 is a bioactive protein that can polarize macrophages to an alternatively activated phenotype and selectively induce apoptosis in Th1 cells. Our data shows that an abundantly secreted parasite galectin is immunomodulatory and induces phenotypes consistent with the modified type 2 response characteristic of chronic LF infection.

Characterization of extracellular vesicles from Lactiplantibacillus plantarum

We investigated the characteristics and functionalities of extracellular vesicles (EVs) from Lactiplantibacillus plantarum (previously Lactobacillus plantarum) towards host immune cells. L. plantarum produces EVs that have a cytoplasmic membrane and contain cytoplasmic metabolites, membrane and cytoplasmic proteins, and small RNAs, but not bacterial cell wall components, namely, lipoteichoic acid and peptidoglycan. In the presence of L. plantarum EVs, Raw264 cells inducibly produced the pro-inflammatory cytokines IL-1β and IL-6, the anti-inflammatory cytokine IL-10, and IF-γ and IL-12, which are involved in the differentiation of naive T-helper cells into T-helper type 1 cells. IgA was produced by PP cells following the addition of EVs. Therefore, L. plantarum EVs activated innate and acquired immune responses. L. plantarum EVs are recognized by Toll-like receptor 2 (TLR2), which activates NF-κB, but not by other TLRs or NOD-like receptors. N-acylated peptides from lipoprotein19180 (Lp19180) in L. plantarum EVs were identified as novel TLR2 ligands. Therefore, L. plantarum induces an immunostimulation though the TLR2 recognition of the N-acylated amino acid moiety of Lp19180 in EVs. Additionally, we detected a large amount of EVs in the rat gastrointestinal tract for the first time, suggesting that EVs released by probiotics function as a modulator of intestinal immunity.

Effect of calving season on metritis incidence and bacterial content of the vagina in dairy cows

Heat stress and uterine diseases, including metritis and endometritis, both reduce milk yields and reduce reproductive performance. Bacterial growth is promoted by elevated temperature while heat stress reduces host immune cell function, but it is not known whether increased environmental temperature promotes uterine disease by altering host immunity or bacterial growth. We hypothesize that seasonal variations in environmental temperature influence metritis incidence in the dairy cow independent of bacterial prevalence in the reproductive tract. To investigate how environmental temperature may impact metritis incidence, records of 3507 calvings in Florida over a 5-year period were evaluated. The incidence of metritis increased from 21.1% in the cool season (October through March) to 24.2% during the warm season (April through September, P < 0.05). To elucidate a link between environmental temperature and uterine disease, 102 cows were enrolled during the warm season (September 2017; n = 51) and cool season (February–March 2018; n = 51). Cows were maintained on pasture during the dry period and moved to free stall barns with fans and water soakers immediately prior to calving and remained in that environment after calving. Vaginal mucus was collected and scored on days 7 (to evaluate metritis) and 21 (to evaluate endometritis) postpartum to evaluate the incidence of uterine disease and quantify bacterial content and species using qPCR. Daily milk yield for the first 60 DIM was reduced during the warm season compared with the cool season (32.6 ± 1.62 vs 37.23 ± 1.60 kg, P < 0.05) consistent with effects of prepartum heat stress. Interestingly, more cows had persistent uterine disease on both d 7 and d 21 in the warm season compared with the cool season (58.0 vs 29.4%, P < 0.05). Regardless of calving season the total bacterial content in the vagina was greater on d 7 compared to d 21. While metritis incidence was increased in the warm season, the vaginal content of total bacteria, Escherichia coli, Trueperella pyogenes, Fusobacterium necrophorum and Prevotella melaninogenica were similar during the cool season and the warm season. Our data suggests that prepartum heat stress related to season of calving increased the incidence of metritis and persistence of uterine disease in the dairy cow independent of vaginal bacteria content. The possibility that prepartum heat stress perturbs host immune function and increases the risk of metritis when cows are exposed to an equivalent number of pathogenic bacteria requires further investigation.

An immunogenic cell injury module for the single-cell multiplexed activity metabolomics platform to identify promising anti-cancer natural products

Natural products constitute and significantly impact many current anti-cancer medical interventions. A subset of natural products induces injury processes in malignant cells that recruit and activate host immune cells to produce an adaptive anti-cancer immune response, a process known as immunogenic cell death. However, a challenge in the field is to delineate forms of cell death and injury that best promote durable antitumor immunity. Addressing this with a single-cell chemical biology natural product discovery platform, like multiplex activity metabolomics, would be especially valuable in human leukemia, where cancer cells are heterogeneous and may react differently to the same compounds. Herein, a new ten-color, fluorescent cell barcoding-compatible module measuring six immunogenic cell injury signaling readouts are as follows: DNA damage response (γH2AX), apoptosis (cCAS3), necroptosis (p-MLKL), mitosis (p-Histone H3), autophagy (LC3), and the unfolded protein response (p-EIF2α). A proof-of-concept screen was performed to validate functional changes in single cells induced by secondary metabolites with known mechanisms within bacterial extracts. This assay was then applied in multiplexed activity metabolomics to reveal an unexpected mammalian cell injury profile induced by the natural product narbomycin. Finally, the functional consequences of injury pathways on immunogenicity were compared with three canonical assays for immunogenic hallmarks, ATP, HMGB1, and calreticulin, to correlate secondary metabolite-induced cell injury profiles with canonical markers of immunogenic cell death. In total, this work demonstrated a new phenotypic screen for discovery of natural products that modulate injury response pathways that can contribute to cancer immunogenicity.

Isolation and immortalization of macrophages derived from fetal porcine small intestine and their susceptibility to porcine viral pathogen infections.

Macrophages are a heterogeneous population of cells that are present in all vertebrate tissues. They play a key role in the innate immune system, and thus, in vitro cultures of macrophages provide a valuable model for exploring their tissue-specific functions and interactions with pathogens. Porcine macrophage cultures are often used for the identification and characterization of porcine viral pathogens. Recently, we have developed a simple and efficient method for isolating primary macrophages from the kidneys and livers of swine. Here, we applied this protocol to fetal porcine intestinal tissues and demonstrated that porcine intestinal macrophages (PIM) can be isolated from mixed primary cultures of porcine small intestine-derived cells. Since the proliferative capacity of primary PIM is limited, we attempted to immortalize them by transferring the SV40 large T antigen and porcine telomerase reverse transcriptase genes using lentiviral vectors. Consequently, immortalized PIM (IPIM) were successfully generated and confirmed to retain various features of primary PIM. We further revealed that IPIM are susceptible to infection by the African swine fever virus and the porcine reproductive and respiratory syndrome virus and support their replication. These findings suggest that the IPIM cell line is a useful tool for developing in vitro models that mimic the intestinal mucosal microenvironments of swine, and for studying the interactions between porcine pathogens and host immune cells.

Challenges and Tissue Engineering Strategies of Periodontal-Guided Tissue Regeneration.

Periodontitis is a chronic infectious oral disease with a high prevalence rate in the world, and is a major cause of tooth loss. Nowadays, people have realized that the local microenvironment that includes proteins, cytokines, and extracellular matrix has a key influence on the functions of host immune cells and periodontal ligament (PDL) stem cells during a chronic infectious disease such as periodontitis. The above pathological process of periodontitis will lead to a defect of periodontal tissues. Through the application of biomaterials, biological agents, and stem cell therapy, guided tissue regeneration (GTR) makes it possible to reconstruct healthy PDL tissue after local inflammation control. To date, substantial advances have been made in periodontal GTR. However, the process of periodontal remodeling experiences complex microenvironment changes, and currently periodontium regeneration still remains to be a challenging feat. In this review, we summarized the main challenges in each stage of periodontal regeneration, and try to put forward appropriate biomaterial treatment mechanisms or potential tissue engineering strategies that provide a theoretical basis for periodontal tissue engineering regeneration research.

Insights Into the Host Contribution of Endocrine Associated Immune-Related Adverse Events to Immune Checkpoint Inhibition Therapy.

Blockade of immune checkpoints transformed the paradigm of systemic cancer therapy, enabling substitution of a cytotoxic chemotherapy backbone to one of immunostimulation in many settings. Invigorating host immune cells against tumor neo-antigens, however, can induce severe autoimmune toxicity which in many cases requires ongoing management. Many immune-related adverse events (irAEs) are clinically and pathologically indistinguishable from inborn errors of immunity arising from genetic polymorphisms of immune checkpoint genes, suggesting a possible shared driver for both conditions. Many endocrine irAEs, for example, have analogous primary genetic conditions with varied penetrance and severity despite consistent genetic change. This is akin to onset of irAEs in response to immune checkpoint inhibitors (ICIs), which vary in timing, severity and nature despite a consistent drug target. Host contribution to ICI response and irAEs, particularly those of endocrine origin, such as thyroiditis, hypophysitis, adrenalitis and diabetes mellitus, remains poorly defined. Improved understanding of host factors contributing to ICI outcomes is essential for tailoring care to an individual’s unique genetic predisposition to response and toxicity, and are discussed in detail in this review.

Plasmodium 6-Cysteine Proteins: Functional Diversity, Transmission-Blocking Antibodies and Structural Scaffolds.

The 6-cysteine protein family is one of the most abundant surface antigens that are expressed throughout the Plasmodium falciparum life cycle. Many members of the 6-cysteine family have critical roles in parasite development across the life cycle in parasite transmission, evasion of the host immune response and host cell invasion. The common feature of the family is the 6-cysteine domain, also referred to as s48/45 domain, which is conserved across Aconoidasida. This review summarizes the current approaches for recombinant expression for 6-cysteine proteins, monoclonal antibodies against 6-cysteine proteins that block transmission and the growing collection of crystal structures that provide insights into the functional domains of this protein family.

The battle for oxygen during bacterial and fungal infections.

Bacterial and fungal pathogens face various microenvironmental conditions during infection. In addition to acidosis, nutrient consumption, and hypercapnia, pathogen infections are associated with hypoxia, which is induced by bacterial and fungal respiration during the formation of foci of infection or biofilms. Consequently, the in vivo interaction between host immune cells and pathogens is anticipated to occur mainly under low-oxygen conditions. Various infectious disease models have reported that pathogens benefit from hypoxia, which dampens the oxygen-dependent antimicrobial activities of macrophages and neutrophils, such as the production of reactive oxygen species (ROS). Due to their dual respiration capacity (aerobic and anaerobic) or phenotypical adaptation (e.g., dormancy), pathogens have the capacity to survive and disseminate in the absence of oxygen. In addition, hypoxia modulates various mechanisms of pathogen virulence, promoting the dissemination of pathogens. Further investigations are still required to evaluate the relative importance of oxygen on the capacity of pathogens to invade and colonize host organs and to better understand alternative strategies developed by immune cells to circumvent pathogen dissemination in the absence of oxygen. Addressing this important and fundamental question in various models of infection may direct the development of innovative therapeutic strategies.

Adipose-derived stem cells decolonize skin Staphylococcus aureus by enhancing phagocytic activity of peripheral blood mononuclear cells in the atopic rats.

Staphylococcus aureus (S. aureus) is known to induce apoptosis of host immune cells and impair phagocytic clearance, thereby being pivotal in the pathogenesis of atopic dermatitis (AD). Adipose-derived stem cells (ASCs) exert therapeutic effects against inflammatory and immune diseases. In the present study, we investigated whether systemic administration of ASCs restores the phagocytic activity of peripheral blood mononuclear cells (PBMCs) and decolonizes cutaneous S. aureus under AD conditions. AD was induced by injecting capsaicin into neonatal rat pups. ASCs were extracted from the subcutaneous adipose tissues of naïve rats and administered to AD rats once a week for a month. Systemic administration of ASCs ameliorated AD-like symptoms, such as dermatitis scores, serum IgE, IFN-γ+/IL-4+ cell ratio, and skin colonization by S. aureus in AD rats. Increased FasL mRNA and annexin V+/7-AAD+ cells in the PBMCs obtained from AD rats were drastically reversed when co-cultured with ASCs. In contrast, both PBMCs and CD163+ cells bearing fluorescent zymosan particles significantly increased in AD rats treated with ASCs. Additionally, the administration of ASCs led to an increase in the mRNA levels of antimicrobial peptides, such as cathelicidin and β-defensin, in the skin of AD rats. Our results demonstrate that systemic administration of ASCs led to decolonization of S. aureus by attenuating apoptosis of immune cells in addition to restoring phagocytic activity. This contributes to the improvement of skin conditions in AD rats. Therefore, administration of ASCs may be helpful in the treatment of patients with intractable AD.

Cancer Stem Cell-Associated Immune Microenvironment in Recurrent Glioblastomas.

Glioblastoma multiforme (GBM) is the most incurable tumor (due to the difficulty in complete surgical resection and the resistance to conventional chemo/radiotherapies) that displays a high relapse frequency. Cancer stem cells (CSCs) have been considered as a promising target responsible for therapy resistance and cancer recurrence. CSCs are known to organize a self-advantageous microenvironment (niche) for their maintenance and expansion. Therefore, understanding how the microenvironment is reconstructed by the remaining CSCs after conventional treatments and how it eventually causes recurrence should be essential to inhibit cancer recurrence. However, the number of studies focusing on recurrence is limited, particularly those related to tumor immune microenvironment, while numerous data have been obtained from primary resected samples. Here, we summarize recent investigations on the immune microenvironment from the viewpoint of recurrent GBM (rGBM). Based on the recurrence-associated immune cell composition reported so far, we will discuss how CSCs manipulate host immunity and create the special microenvironment for themselves to regrow. An integrated understanding of the interactions between CSCs and host immune cells at the recurrent phase will lead us to develop innovative therapies and diagnoses to achieve GBM eradication.