Antimicrobial Immunity Research Articles

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Apoptosis is a normal physiological process aimed at regulating the size of cells populations by maintaining a balance between cell survival and death. In bacterial and viral infections, apoptosis can be considered as a way to protect the host, responsible for eliminating infected cells without inducing an inflammatory response. Apoptosis is involved in the resolution of inflammation, providing an anti-inflammatory effect. As one of the factors of antimicrobial immunity, apoptosis can help to clear the body from pathogens and provides a material for cross-presentation of microbial antigens to induction of an adaptive immune response. Pathogenic microorganisms use a variety of strategies to regulate apoptosis during their survival and reproduction in the host body. By inducing apoptosis bacteria and viruses contribute to the elimination of protective immune cells. At the same time, by suppressing the processes of apoptosis, pathogens can avoid attacks from the host immune system cells and maintain the replication niches necessary for their survival. The development of drugs for targeted artificial regulation of apoptosis processes opens up new opportunities for the treatment of infectious diseases.

The Unique Microbiome and Innate Immunity During Pregnancy

A successful pregnancy depends on not only the tolerance of the fetal immune system by the mother but also resistance against the threat of hazardous microorganisms. Infection with pathogenic microorganisms during pregnancy may lead to premature delivery, miscarriage, growth restriction, neonatal morbidity, and other adverse outcomes. Moreover, the host also has an intact immune system to avoid these adverse outcomes. It is important to note the presence of normal bacteria in the maternal reproductive tract and the principal role of the maternal-placental-fetal interaction in antimicrobial immunity. Previous studies mainly focused on maternal infection during pregnancy. However, this review summarizes the new views on the study of the maternal microbiome and expounds the innate immune defense mechanism of the maternal vagina and decidua as well as how cytotrophoblasts and syncytiotrophoblasts recognize and kill bacteria in the placenta. Fetal immune systems, thought to be weak, also exhibit an immune defense function that is indispensable for maintaining the safety of the fetus. The skin, lungs, and intestines of the fetus during pregnancy constitute the main immune barriers. These findings will provide a new understanding of the effects of normal microbial flora and how the host resists harmful microbes during pregnancy. We believe that it may also contribute to the reference on the clinical prevention and treatment of gestational infection to avoid adverse pregnancy outcomes.

T cells instruct myeloid cells to produce inflammasome-independent IL-1β and cause autoimmunity.

The cytokine interleukin-1β (IL-1β) is a key mediator of anti-microbial immunity as well as autoimmune inflammation. Production of IL-1β requires transcription by innate immune receptor signaling and maturational cleavage by inflammasomes. Whether this mechanism applies to IL-1β production seen in T cell-driven autoimmune diseases remains unclear. Here, we describe an inflammasome-independent pathway of IL-1β production that was triggered upon cognate interactions between effector CD4+ T cells and mononuclear phagocytes (MPs). The cytokine TNF produced by activated CD4+ T cells engaged its receptor TNFR on MPs, leading to pro-IL-1β synthesis. Membrane-bound FasL, expressed by CD4+ T cells, activated death receptor Fas signaling in MPs resulting in caspase-8-dependent pro-IL-1β cleavage. The T cell-instructed IL-1β resulted in systemic inflammation, while absence of TNFR or Fas signaling protected mice from CD4+ T cell-driven autoimmunity. The TNFR-Fas-caspase-8-dependent pathway provides a mechanistic explanation for IL-1β production and its consequences in CD4+ T cell-driven autoimmune pathology.

Characterization, expression, and antimicrobial activity of histones from Japanese flounder Paralichthys olivaceus

Histone proteins are not only structurally important for chromosomal DNA packaging but also involved in the regulation of gene expression and the immune response of host against pathogens. Japanese flounder (Paralichthys olivaceus) as one of the most important marine flatfish, suffered from widespread outbreaks of diseases, and its immunological functioning remained to be elucidated. In the present study, we reported the expression patterns of four histones (H1, H2A, H3, and H3.3) and functional characterization of the histone H3.3 from flounder. Quantitative real time RT-PCR (RT-qPCR) analysis showed that expression of the four histones occurred in multiple tissues, but their levels of expression were relatively high in immune organs, and inducible in response to pathogens infection. Infection with extracellular and intracellular bacterial pathogens and viral pathogen regulated the expression of histones in a manner that depended on tissue type, pathogen, and infection stage. Specifically, H1 expression was highly induced by intracellular viral pathogens; H2AX and H3 expressions were highly induced by intracellular bacterial pathogen; dissimilarly, H3.3 expression was slightly induced by extracellular bacterial pathogen, but was inhibited by intracellular bacterial and viral pathogens. To further investigate H3.3 function, recombinant H3.3 (rH3.3) was obtained, and in vitro experiments showed rH3.3 possessed the capability of binding to both Gram-negative and Gram-positive bacteria and inhibiting the growth of some target bacteria. Consistently, In vivo results showed that overexpression of H3.3 promoted the host defense against invading pathogenic microorganism and regulated the expressions of several cytokines. These results suggested that flounder histones exhibit different expression patterns in response to the infection of different microbial pathogens, and H3.3 serves as an immune-related protein and plays an important role in antimicrobial immunity of Japanese flounder. Taken together, this study is the first report about the expression profile of different histones upon different kind of pathogens and anti-infectious immunity of H3.3 in teleost, which offered new insights into the immunological function of histones in teleost.

Vaccination Against Poly-N-Acetylglucosamine Decreases Neutrophil Activation and Gvhd While Maintaining Microbial Diversity

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative therapy for different malignant and non-malignant hematologic diseases. Major life-threatening complications after allo-HCT are acute graft-versus-host disease (aGVHD) and severe infections. The incidence of GVHD after allo-HCT remains high, despite prophylactic immunosuppressive medication. According to the CIBMTR database, 60% of patients undergoing allo-HCT develop at least grade II-IV aGVHD. Microbial invasion into the intestinal mucosa after allo-HCT triggers the activation of neutrophil granulocytes (neutrophils) and requires antibiotic treatment to prevent sepsis. However, antibiotics lead to a loss of microbial diversity, which is connected to a higher incidence of aGVHD. Anti-microbial therapies which eliminate invading bacteria and diminish neutrophil-mediated damage without reducing the diversity of the microbiota are therefore highly desirable. A potential solution for this could be the use of anti-microbial antibodies that target and mark invading pathogens resulting in their elimination by innate immune cells. Therefore we investigated the potency of both active and passive immunization against the conserved microbial surface polysaccharide Poly-N-acetylglucosamine (PNAG) which is expressed on various pathogens in a murine aGVHD model. We could detect reduced aGVHD related mortality in mice which underwent treatment with an antibody against PNAG (anti-PNAG) or were actively immunized against PNAG. Sequencing analysis of the microbiota before and after allo-HCT showed that anti-PNAG treatment did not have any effect luminal microbial diversity. Mechanistically, we could show that anti-PNAG antibody treatment caused more abundant neutrophil recruitment to the intestinal submucosa. This supports the concept that neutrophils are able to effectively eliminate any opsonized bacteria in this tissue, leading to reduced local inflammation. In agreement with this we observed lower intestinal inflammation and reduced myeloperoxidase activity as well as proliferation of neutrophils in the small intestine of mice treated with anti-PNAG antibody. We demonstrate the potency of targeting PNAG as a novel antimicrobial treatment option in aGVHD by reducing uncontrolled neutrophil activation and thereby interfering with aGVHD without affecting commensal intestinal microbial diversity. Anti-PNAG-antibodies enhance anti-microbial immunity, while reducing the activation of neutrophil-mediated downstream immunopathology which is a novel approach to reduce the severity of GVHD. This could be translated into a clinical application given the modest toxicity profile of vaccination and the availability of fully human anti-PNAG antibodies, both of which have been tested in phase 1 trials in humans (ClinicalTrials.gov Identifier: NCT02853617). Disclosures Cywes-Bentley: OneBiopharma, Inc.: Honoraria. Koenecke:Novartis: Other: none. Pier:OneBiopharma, Inc.: Equity Ownership, Honoraria; Alopexx Vaccine, LLC: Equity Ownership, Honoraria.

Mannose-binding lectin (MBL) in adult patients with inflammatory bowel disease.

Inflammatory bowel disease (IBD) refers to disorders associated with progressive inflammatory processes in the gastrointestinal system. IBD consists of two major forms, Crohn's disease (CD), and ulcerative colitis (UC). IBD became a global disease in the 21st century. Its pathogenesis is still not fully understood. Mannose-binding lectin (MBL) is a pattern-recognising molecule, involved in anti-microbial and anti-cancer immunity. It is able to opsonize microorganisms and abnormal host cells, and to initiate complement activation. The aim of this study was to investigate possible involvement of MBL in inflammatory bowel disease in adults. Forty persons diagnosed with CD and 28 with ulcerative colitis were recruited. The control group consisted of 136 healthy persons. Single nucleotide polymorphisms of the MBL2 gene (localised to both promoter and exon 1) were determined as were serum MBL concentrations. The exon 1 variant alleles and MBL deficiency-associated genotypes were more frequent among patients compared with controls, although this difference was not statistically significant. No differences of MBL levels were found between the major groups. However in MBL2 A/A homozygous IBD patients, the median was significantly higher than in corresponding healthy subjects. That was particularly evident in the case of active Crohn's disease (1493 ng/ml vs. 800 ng/ml, p = 0.021). It may suggest that MBL and MBL-dependent complement activation contributes to excessive inflammation and its adverse effects in the course of CD. It cannot also be excluded that high MBL activity constitutes in some cases part of a multifactorial network conducing to development of CD.

Insilico Alpha-Helical Structural Recognition of Temporin Antimicrobial Peptides and Its Interactions with Middle East Respiratory Syndrome-Coronavirus.

Many antimicrobial peptides (AMPs) have multiple antimicrobial immunity effects. One such class of peptides is temporins. Temporins are the smallest (AMPs) found in nature and are highly active against gram-positive bacteria. Nowadays, there was a rapid increase in the availability of the 3D structure of proteins in PDB (protein data bank). The conserved residues and 3D structural conformations of temporins (AMPs) were still unknown. The present study explores the sequence analysis, alpha-helical structural conformations of temporins. The sequence of temporins was deracinated from APD3 database, the three-dimensional structure was constructed by homology modeling studies. The sequence analysis results show that the conserved residues among the peptide sequences, the maximum of the sequences are 70% alike to each other. The secondary structure prediction results revealed that 99% of temporin (AMPs) exhibited in alpha-helical form. The 3D structure speculated using RAMPAGE exposes the alpha-helical conformation in all temporins (AMPs). The phylogenetic analysis reveals the evolutionary relationships of temporins (AMPs), which are branched into seven clusters. As a result, we identified a list of potential temporin AMPs which docked to the antiviral protein (MERS-CoV), it shows good protein-peptide binding. This computational approach may serve as a good model for the rationale design of temporin based antibiotics.Electronic supplementary materialThe online version of this article (10.1007/s10989-019-09951-y) contains supplementary material, which is available to authorized users.

Microbial Danger Signals Control Transcriptional Induction of Distinct MHC Class I L Lineage Genes in Atlantic Salmon.

Antigen processing and presentation by major histocompatibility complex (MHC) molecules is a cornerstone in vertebrate immunity. Like mammals, teleosts possess both classical MHC class I and multiple families of divergent MHC class I genes. However, while certain mammalian MHC class I-like molecules have proven to be integral in immune regulation against a broad array of pathogens, the biological relevance of the different MHC class I lineages in fish remains elusive. This work focuses on MHC class I L lineage genes and reveals unique regulatory patterns of six genes (Sasa-lia, Sasa-lda, Sasa-lca, Sasa-lga, Sasa-lha, and Sasa-lfa) in antimicrobial immunity of Atlantic salmon (Salmo salar L.). Using two separate in vivo challenge models with different kinetics and immune pathologies combined with in vitro stimulation using viral and bacterial TLR ligands, we show that de novo synthesis of different L lineage genes is distinctly regulated in response to various microbial stimuli. Prior to the onset of classical MHC class I gene expression, lia was rapidly and systemically induced in vivo by the single-stranded (ss) RNA virus salmonid alpha virus 3 (SAV3) but not in response to the intracellular bacterium Piscirickettsia salmonis. In contrast, lga expression was upregulated in response to both viral and bacterial stimuli. A role for distinct MHC class I L-lineage genes in anti-microbial immunity in salmon was further substantiated by a marked upregulation of lia and lga gene expression in response to type I IFNa stimulation in vitro. Comparably, lha showed no transcriptional induction in response to IFNa stimulation but was strongly induced in response to a variety of viral and bacterial TLR ligands. In sharp contrast, lda showed no response to viral or bacterial challenge. Similarly, induction of lca, which is predominantly expressed in primary and secondary lymphoid tissues, was marginal with the exception of a strong and transient upregulation in pancreas following SAV3 challenge Together, these findings suggest that certain Atlantic salmon MHC class I L lineage genes play important and divergent roles in early anti-microbial response and that their regulation, in response to different activation signals, represents a system for selectively promoting the expression of distinct non-classical MHC class I genes in response to different types of immune challenges.

Evaluation of LL 37 Lipoprotein as Innate Immunity Marker among Sudanese Patients Cutaneous Leishmania

Background: The leishmaniasis is a group of diseases with a broad range of clinical manifestations caused by several species of parasites belonging to the genus Leishmania. LL-37/hCAP18, the only cathelicidin in human, is expressed as an 18-kDa preproprotein. The most prominent function of cathelicidins is their ability to inhibit propagation of a diverse range of microorganisms, which occurs at a micromolar range.
 Aim: The study was aimed to evaluate the LL37 plasma level in Leishmania Sudanese patients.
 Materials and Methods: In a case-control study, three hundred subjects were enrolled (200 as case and 100 controls). Five ml. of venous blood was collected in EDTA container, then plasma was obtained and stored frozen at -80ºC. LL 37 was estimated using competitive ELISA. The data were analyzed using SPSS version 21.
 Results: The results revealed that 115 (57%) of Leishimania patients were male and 85 (43%) were female. Plasma LL 37 level was significantly increased in Leishmania patients (1.30±0.71) compared to the control (0.21±0.20) with (p-value 0.000).
 Conclusion: Leishmania patients had higher levels of plasma LL37, suggesting effective anti-microbial immunity process enhancing healing of cutaneous leishmaniasis.
 Keywords: Cathelicidins; LL37, Innate Immunity, Leishmania , Sudan.

Staphylococcus aureus Lipoic Acid Synthesis Limits Macrophage Reactive Oxygen and Nitrogen Species Production To Promote Survival during Infection.

Macrophages are critical mediators of innate immunity and must be overcome for bacterial pathogens to cause disease. The Gram-positive bacterium Staphylococcus aureus produces virulence factors that impede macrophages and other immune cells. We previously determined that production of the metabolic cofactor lipoic acid by the lipoic acid synthetase, LipA, blunts macrophage activation. A ΔlipA mutant was attenuated during infection and was more readily cleared from the host. We hypothesized that bacterial lipoic acid synthesis perturbs macrophage antimicrobial functions and therefore hinders the clearance of S. aureus Here, we found that enhanced innate immune cell activation after infection with a ΔlipA mutant was central to attenuation in vivo, whereas a growth defect imparted by the lipA mutation made a negligible contribution to overall clearance. Macrophages recruited to the site of infection with the ΔlipA mutant produced larger amounts of bactericidal reactive oxygen species (ROS) and reactive nitrogen species (RNS) than those recruited to the site of infection with the wild-type strain or the mutant strain complemented with lipA ROS derived from the NADPH phagocyte oxidase complex and RNS derived from the inducible nitric oxide synthetase, but not mitochondrial ROS, were critical for the restriction of bacterial growth under these conditions. Despite enhanced antimicrobial immunity upon primary infection with the ΔlipA mutant, we found that the host failed to mount an improved recall response to secondary infection. Our data suggest that lipoic acid synthesis in S. aureus promotes bacterial persistence during infection through limitation of ROS and RNS generation by macrophages. Broadly, this work furthers our understanding of the intersections between bacterial metabolism and immune responses to infection.

Antiviral immunity is impaired in COPD patients with frequent exacerbations.

Patients with frequent exacerbations represent a chronic obstructive pulmonary disease (COPD) subgroup requiring better treatment options. The aim of this study was to determine the innate immune mechanisms that underlie susceptibility to frequent exacerbations in COPD. We measured sputum expression of immune mediators and bacterial loads in samples from patients with COPD at stable state and during virus-associated exacerbations. In vitro immune responses to rhinovirus infection in differentiated primary bronchial epithelial cells (BECs) sampled from patients with COPD were additionally evaluated. Patients were stratified as frequent exacerbators (≥2 exacerbations in the preceding year) or infrequent exacerbators (<2 exacerbations in the preceding year) with comparisons made between these groups. Frequent exacerbators had reduced sputum cell mRNA expression of the antiviral immune mediators type I and III interferons and reduced interferon-stimulated gene (ISG) expression when clinically stable and during virus-associated exacerbation. A role for epithelial cell-intrinsic innate immune dysregulation was identified: induction of interferons and ISGs during in vitro rhinovirus (RV) infection was also impaired in differentiated BECs from frequent exacerbators. Frequent exacerbators additionally had increased sputum bacterial loads at 2 wk following virus-associated exacerbation onset. These data implicate deficient airway innate immunity involving epithelial cells in the increased propensity to exacerbations observed in some patients with COPD. Therapeutic approaches to boost innate antimicrobial immunity in the lung could be a viable strategy for prevention and treatment of frequent exacerbations.

Less burn, more fat: electronic cigarettes and pulmonary lipid homeostasis.

Electronic nicotine delivery systems (ENDS) are rapidly increasing in popularity due to the perception that they may represent a safe alternative to conventional cigarettes. However, a growing body of evidence indicates that ENDS exposure can disrupt maintenance of pulmonary immune homeostasis and antimicrobial immunity. In this issue of the JCI, Madison et al. demonstrate that in mice, chronic ENDS exposure induces profound alterations in lipid homeostasis. ENDS-exposed mice showed irregularities in the surfactant-secreting lamellar bodies within type 2 alveolar cells and increased intracellular phospholipid accumulation within alveolar macrophages. Moreover, ENDS-exposed mice displayed greater inflammation and tissue damage in response to influenza A, which may be due to downregulated expression of a viral pattern-recognition receptor in alveolar macrophages. Collectively, the results of this study identify previously unrecognized adverse effects of ENDS exposure on pulmonary lipid metabolism, although the implication of these effects on long-term respiratory health requires future exploration.

Infection with Opportunistic Bacteria Triggers Severe Pulmonary Inflammation in Lupus-Prone Mice.

Infection is a common cause of hospitalization and mortality in patients with systemic lupus erythematosus (SLE). How the underlying immune dysfunctions affect the antimicrobial immunity remains largely unknown. In the present study, employing the pulmonary infection model, we determined the antimicrobial defence of lupus-prone mice. After infecting with opportunistic bacterium Haemophilus influenzae (Hi), lupus-prone mice (B6/lpr) exhibited inefficient bacterial elimination and recovered slowly. They generated severer inflammation at the early stage of infection, as excessive accumulation of neutrophils and enhanced production of proinflammatory cytokines were observed in the lung. In addition, a large number of apoptotic cells were detected in the lungs of B6/lpr mice. For adaptive immune responses, B6/lpr mice were capable to generate enough protective Hi-specific Th17 cells. They evoked stronger Hi-specific γδ T17 response in both lungs and spleens. Unexpectedly, both CD4 and γδ T cells from lupus-prone mice showed deficiency in IFN-γ production. For humoral immune responses, compared with those of WT mice, the concentrations of Hi-specific IgA, IgM, and IgG, especially IgG, were significantly higher in the B6/lpr mice. Our findings suggest that lupus mice are capable to generate antibacterial immune responses; however, the overwhelming inflammation and overactivated immune responses increase the severity of infection.

Microbiota-Dependent Regulation of Antimicrobial Immunity in the Lung.

Several body sites, including the intestinal and respiratory tracts, are colonized with a myriad of bacteria, archaea, fungi, and viruses, which are collectively referred to as the "microbiota." The bacterial component of the microbiota in particular has been recognized to influence a multitude of physiological functions, including innate and adaptive immune responses. Germ-free and microbiota-depleted animals display an impaired antimicrobial defense and are therefore highly susceptible to various infections, including those affecting the lung. In this review, we summarize current understanding of how the microbiota affects antimicrobial immunity and disease tolerance during viral and bacterial pulmonary infections. A better understanding of these mechanisms could help to refine clinical approaches to preserve or rescue the microbiota-immune system interplay and protect patients against lung infections.

The effects of bacteriophages on the expression of genes involved in antimicrobial immunity*

Introduction: Bacteriophages (viruses of bacteria) are used in the treatment of antibiotic‑resistant infections. Moreover, they are an important component of the mucosal microbiota. The objective of this study was to investigate the effects of T4 and A5/80 bacteriophages on the expression of genes involved in antimicrobial immunity, including Toll‑like receptors. Material/Methods: The expression of genes was determined in the A549 cell line using RT2 Profiler PCR Array. Results: Purified T4 and A5/80 phage preparations significantly affected the expression of 7 and 10 out of 84 examined genes, respectively. Discussion: Our results are important for phage therapy of bacterial infections and provide novel insights into the role of phages from the mucosal microbiota. They may also lead to novel applications of phages as antiviral and immunomodulatory agents.

Association Between Impaired Vα7.2+CD161++CD8+ (MAIT) and Vα7.2+CD161-CD8+ T-Cell Populations and Gut Dysbiosis in Chronically HIV- and/or HCV-Infected Patients.

Both HIV and HCV infections feature increased microbial translocation (MT) and gut dysbiosis that affect immune homeostasis and disease outcome. Given their commitment to antimicrobial mucosal immunity, we investigated mucosal-associated invariant T (MAIT) cells and Vα7.2+CD161- T-cell frequency/function and their possible associations with MT and gut dysbiosis, in chronic HIV and/or HCV infections. We enrolled 56 virally infected (VI) patients (pts): 13 HIV+ on suppressive cART (HIV-RNA < 40cp/ml), 13 HCV+ naive to DAA (direct-acting antiviral) anti-HCV agents; 30 HCV+/HIV+ on suppressive cART and naive to anti-HCV. 13 age-matched healthy controls (HC) were enrolled. For Vα7.2+CD161++ and Vα7.2+CD161-CD8+ T cells we assessed: activation (CD69), exhaustion (PD1/CD39), and cytolytic activity (granzymeB/perforin). Following PMA/ionomycin and Escherichia coli stimulation we measured intracellular IL17/TNFα/IFNγ. Markers of microbial translocation (Plasma LPS, 16S rDNA, EndoCAb and I-FABP) were quantified. In 5 patients per group we assessed stool microbiota composition by 16S targeted metagenomics sequencing (alpha/beta diversity, relative abundance). Compared to controls, virally infected pts displayed significantly lower circulating Vα7.2+CD161++CD8+ MAIT cells (p = 0.001), yet expressed higher perforin (p = 0.004) and granzyme B (p = 0.002) on CD8+ MAIT cells. Upon E. coli stimulation, the residual MAIT cells are less functional particularly those from HIV+/HCV+ patients. Conversely, in virally infected pts, Vα7.2+CD161-CD8+ cells were comparable in frequency, highly activated/exhausted (CD69+: p = 0.002; PD-1+: p = 0.030) and with cytolytic potential (perforin+: p < 0.0001), yet were poorly responsive to ex vivo stimulation. A profound gut dysbiosis characterized virally infected pts, especially HCV+/HIV+ co-infected patients, delineating a Firmicutes-poor/Bacteroidetes-rich microbiota, with significant associations with MAIT cell frequency/function. Irrespective of mono/dual infection, HIV+ and HCV+ patients display depleted, yet activated/cytolytic MAIT cells with reduced ex vivo function, suggesting an impoverished pool, possibly due to continuous bacterial challenge. The MAIT cell ability to respond to bacterial stimulation correlates with the presence of Firmicutes and Bacteroidetes, possibly suggesting an association between gut dysbiosis and MAIT cell function and posing viral-mediated dysbiosis as a potential key player in the hampered anti-bacterial MAIT ability.

Expression of IL-5 receptor alpha by murine and human lung neutrophils.

The role of eosinophilia in atopic diseases, including asthma, is well established, as is the well-known role of IL-5 as a major eosinophilopoeitin and chemoattractant. Following influenza A virus infection of mice, type 2 innate lymphoid cells are recruited to the respiratory tract and produce large quantities of IL-5, which contributes to the recruitment of eosinophils into the infected lungs during the recovery phase of infection. We demonstrate here that while IL-5 is required for optimal recovery from influenza A virus infection in BALB/c and C57BL/6 mice, the protective effect of IL-5 is independent of eosinophils, suggesting an alternative cellular target. We describe the unexpected finding of IL-5 receptor alpha (CD125) expression on neutrophils infiltrating the inflamed mouse lungs, as well as on neutrophils at other anatomic sites. We extend this finding of neutrophil CD125 expression to humans, specifically to neutrophils found in the bronchoalveolar lavage fluid from the inflamed lungs of children with treatment-refractory asthma. We further demonstrate that the IL-5 receptor on neutrophils is capable of signal transduction. Our data provide further evidence that neutrophils can play a role bridging atopic type 2 and innate anti-microbial immunity.

Old Dog New Tricks; Revisiting How Stroke Modulates the Systemic Immune Landscape

Infections in the post-acute phase of cerebral ischaemia impede optimal recovery by exacerbating morbidity and mortality. Our review aims to reconcile the increased infection susceptibility of patients post-stroke by consolidating our understanding of compartmentalised alterations to systemic immunity. Mounting evidence has catalogued alterations to numerous immune cell populations but an understanding of the mechanisms of long-range communication between the immune system, nervous system and other organs beyond the involvement of autonomic signalling is lacking. By taking our cues from established and emerging concepts of neuro-immune interactions, immune-mediated inter-organ cross-talk, innate immune training and the role of microbiota-derived signals in central nervous system (CNS) function we will explore mechanisms of how cerebral ischaemia could shape systemic immune function. In this context, we will also discuss a key question: how are immune requirements critical for mediating repair of the ischaemic insult balanced by the need for anti-microbial immunity post-stroke, given that they are mediated by mutually exclusive immune networks? Our reformed understanding of the immune landscape post-stroke and novel mechanisms at play could guide targeted therapeutic interventions and initiate a step-change in the clinical management of these infectious complications post-stroke.

Two-component systems regulate ABC transporters in antimicrobial peptide production, immunity and resistance.

Bacteria offer resistance to a broad range of antibiotics by activating their export channels of ATP-binding cassette transporters. These transporters perform a central role in vital processes of self-immunity, antibiotic transport and resistance. The majority of ATP-binding cassette transporters are capable of detecting the presence of antibiotics in an external vicinity and are tightly regulated by two-component systems. The presence of an extracellular loop and an adjacent location of both the transporter and two-component system offers serious assistance to induce a quick and specific response against antibiotics. Both systems have demonstrated their ability of sensing such agents, however, the exact mechanism is not yet fully established. This review highlighted the three key functions of antibiotic resistance, transport and self-immunity of ATP-binding cassette transporters and an adjacent two-component regulatory system.

Human GBP1 is a microbe‐specific gatekeeper of macrophage apoptosis and pyroptosis

The guanylate binding protein (GBP) family of interferon‐inducible GTPases promotes antimicrobial immunity and cell death. During bacterial infection, multiple mouse Gbps, human GBP2, and GBP5 support the activation of caspase‐1‐containing inflammasome complexes or caspase‐4 which trigger pyroptosis. Whether GBPs regulate other forms of cell death is not known. The apicomplexan parasite Toxoplasma gondii causes macrophage death through unidentified mechanisms. Here we report that Toxoplasma‐induced death of human macrophages requires GBP1 and its ability to target Toxoplasma parasitophorous vacuoles through its GTPase activity and prenylation. Mechanistically, GBP1 promoted Toxoplasma detection by AIM2, which induced GSDMD‐independent, ASC‐, and caspase‐8‐dependent apoptosis. Identical molecular determinants targeted GBP1 to Salmonella‐containing vacuoles. GBP1 facilitated caspase‐4 recruitment to Salmonella leading to its enhanced activation and pyroptosis. Notably, GBP1 could be bypassed by the delivery of Toxoplasma DNA or bacterial LPS into the cytosol, pointing to its role in liberating microbial molecules. GBP1 thus acts as a gatekeeper of cell death pathways, which respond specifically to infecting microbes. Our findings expand the immune roles of human GBPs in regulating not only pyroptosis, but also apoptosis.