bims-bac4me 2024-05-26 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2024–05–26
forty papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

Exploring the skin microbiome in atopic dermatitis pathogenesis and disease modification.
Early life microbiome influences on development of the mucosal innate immune system.
Linking S. aureus Immune Evasion Mechanisms to Staphylococcal Vaccine Failures.
mTOR signaling is required for phagocyte free radical production, GLUT1 expression, and control of Staphylococcus aureus infection.
Neutrophil Reduction Attenuates the Severity of Lung Injury in the Early Phase of Pneumococcal Pneumonia in Mice.
Chemical interplay between gut microbiota and epigenetics: Implications in circadian biology.
Post-resolution macrophages shape long-term tissue immunity and integrity in a mouse model of pneumococcal pneumonia.
Bizarre bacteria defy textbooks by writing new genes.
A review of chemical signaling mechanisms underlying quorum sensing and its inhibition in Staphylococcus aureus.
Efferocytosis by macrophages in physiological and pathological conditions: regulatory pathways and molecular mechanisms.
Intraspecies warfare restricts strain coexistence in human skin microbiomes.
Metabolic homeostasis of tissue macrophages across the lifespan.
Unraveling the Microbiome-Human Body Axis: A Comprehensive Examination of Therapeutic Strategies, Interactions and Implications.
LPS exposure alleviates multiple tissues damage by facilitating macrophage efferocytosis.
AMPs as Host-Directed Immunomodulatory Agents against Skin Infections Caused by Opportunistic Bacterial Pathogens.
Decoding the complexity of delayed wound healing following Enterococcus faecalis infection.
SIRT5 exacerbates eosinophilic chronic rhinosinusitis through promoting polarization of M2 macrophage.
Decoding macrophage immunometabolism in human viral infection.
Editorial: The early life window of opportunity: role of the microbiome on immune system imprinting.
β-Glucan Subverts the Function of Myeloid Cells in Neonates.
Chemical and biomolecular insights into the Staphylococcus aureus agr quorum sensing system: Current progress and ongoing challenges.
[H3K27 acetylation promotes lncRNA OIP5-AS1 transcription and induces apoptosis of nasal epithelial cells in allergic rhinitis through up-regulation of TLR4].
Decolonization and Pathogen Reduction Approaches to Prevent Antimicrobial Resistance and Healthcare-Associated Infections.
The gut-airway microbiome axis in health and respiratory diseases.
Microbiota and metabolic adaptation shape Staphylococcus aureus virulence and antimicrobial resistance during intestinal colonization.
Mitochondria at the crossroads of health and disease.
Comparative microbiome analysis in cystic fibrosis and non-cystic fibrosis bronchiectasis.
Distinct metabolic responses to heme in inflammatory human and mouse macrophages - Role of nitric oxide.
CRISPRi screens identify the lncRNA, LOUP, as a multifunctional locus regulating macrophage differentiation and inflammatory signaling.
We are what we eat: macrophages and efferocytosis.
Combined metagenomic- and culture-based approaches to investigate bacterial strain-level associations with medication-controlled mild-moderate atopic dermatitis.
IL-33 controls IL-22-dependent antibacterial defense by modulating the microbiota.
In Silico Elucidation of Key Drivers of Staphyloccocus aureus-Staphyloccocus epidermidis-Induced Skin Damage in Atopic Dermatitis Lesions.
Neutrophils Expressing Programmed Death-Ligand 1 Play an Indispensable Role in Effective Bacterial Elimination and Resolving Inflammation in Methicillin-Resistant Staphylococcus aureus Infection.
Type VII secretion system extracellular protein B targets STING to evade host anti-Staphylococcus aureus immunity.
Metabolomic analysis reveals macrophage metabolic reprogramming and polarization under different nutritional cues.
Phage Therapy for Respiratory Infections: Opportunities and Challenges.
Tensor modeling of MRSA bacteremia cytokine and transcriptional patterns reveals coordinated, outcome-associated immunological programs.
The Interplay between Antibiotics and the Host Immune Response in Sepsis: From Basic Mechanisms to Clinical Considerations: A Comprehensive Narrative Review.
Liquid-liquid phase separation in innate immunity.

J Allergy Clin Immunol. 2024 May 16. pii: S0091-6749(24)00501-3. [Epub ahead of print]

Exploring the skin microbiome in atopic dermatitis pathogenesis and disease modification.

Claudia Hülpüsch, Robin Rohayem, Matthias Reiger, Claudia Traidl-Hoffmann.

  Inflammatory skin diseases, like atopic eczema (atopic dermatitis, AD), affect children and adults globally. In AD, the skin barrier is impaired on multiple levels. Underlying factors include genetic, chemical, immunological, and microbial components. Increased skin pH in AD is part of the altered microbial microenvironment that promotes overgrowth of the skin microbiome with Staphylococcus aureus (S. aureus). The secretion of virulence factors, like toxins and proteases, by S. aureus further aggravates the skin barrier deficiency and additionally off-balances the already skewed immune response. Skin commensal bacteria, however, can inhibit the growth and pathogenicity of S. aureus through quorum sensing systems. Therefore, restoring a healthy skin microbiome could contribute to remission induction in AD. This review discusses direct and indirect approaches to targeting the skin microbiome through modulation of the skin pH, UV treatment, and pre-, pro-, and postbiotics. Furthermore, exploratory techniques like skin microbiome transplantation, ozone therapy, and phage therapy are discussed. Finally, we summarize the latest findings on disease and microbiome modification through targeted immunomodulatory, systemic treatments and biologicals. We believe that targeting the skin microbiome should be considered a crucial component of successful AD treatment in the future.

Keywords:  atopic dermatitis; atopic eczema; inflammation; microbiome; microbiota; skin barrier; skin microbiome; therapy

DOI:  https://doi.org/10.1016/j.jaci.2024.04.029
Semin Immunol. 2024 May 23. pii: S1044-5323(24)00023-X. [Epub ahead of print]73 101885

Early life microbiome influences on development of the mucosal innate immune system.

Aline Ignacio, Sonia Czyz, Kathy D McCoy.

  The gut microbiota is well known to possess immunomodulatory capacities, influencing a multitude of cellular signalling pathways to maintain host homeostasis. Although the formation of the immune system initiates before birth in a sterile environment, an emerging body of literature indicates that the neonatal immune system is influenced by a first wave of external stimuli that includes signals from the maternal microbiota. A second wave of stimulus begins after birth and must be tightly regulated during the neonatal period when colonization of the host occurs concomitantly with the maturation of the immune system, requiring a fine adjustment between establishing tolerance towards the commensal microbiota and preserving inflammatory responses against pathogenic invaders. Besides integrating cues from commensal microbes, the neonatal immune system must also regulate responses triggered by other environmental signals, such as dietary antigens, which become more complex with the introduction of solid food during the weaning period. This "window of opportunity" in early life is thought to be crucial for the proper development of the immune system, setting the tone of subsequent immune responses in adulthood and modulating the risk of developing chronic and metabolic inflammatory diseases. Here we review the importance of host-microbiota interactions for the development and maturation of the immune system, particularly in the early-life period, highlighting the known mechanisms involved in such communication. This discussion is focused on recent data demonstrating microbiota-mediated education of innate immune cells and its role in the development of lymphoid tissues.

Keywords:  Early life; Immune system development; Microbiota; Mucosal barrier; Prenatal; Weaning

DOI:  https://doi.org/10.1016/j.smim.2024.101885
Antibiotics (Basel). 2024 Apr 30. pii: 410. [Epub ahead of print]13(5):

Linking S. aureus Immune Evasion Mechanisms to Staphylococcal Vaccine Failures.

Irshad Ahmed Hajam, George Y Liu.

  Vaccination arguably remains the only long-term strategy to limit the spread of S. aureus infections and its related antibiotic resistance. To date, however, all staphylococcal vaccines tested in clinical trials have failed. In this review, we propose that the failure of S. aureus vaccines is intricately linked to prior host exposure to S. aureus and the pathogen's capacity to evade adaptive immune defenses. We suggest that non-protective immune imprints created by previous exposure to S. aureus are preferentially recalled by SA vaccines, and IL-10 induced by S. aureus plays a unique role in shaping these non-protective anti-staphylococcal immune responses. We discuss how S. aureus modifies the host immune landscape, which thereby necessitates alternative approaches to develop successful staphylococcal vaccines.

Keywords:  MRSA; S. aureus; immune evasion; immune imprinting; vaccine interference; vaccines

DOI:  https://doi.org/10.3390/antibiotics13050410
mBio. 2024 May 20. e0086224

mTOR signaling is required for phagocyte free radical production, GLUT1 expression, and control of Staphylococcus aureus infection.

Christopher J Genito, Benjamin P Darwitz, Callista P Reber, Nathaniel J Moorman, Christina L Graves, Andrew J Monteith, Lance R Thurlow.

  Mammalian target of rapamycin (mTOR) is a key regulator of metabolism in the mammalian cell. Here, we show the essential role for mTOR signaling in the immune response to bacterial infection. Inhibition of mTOR during infection with Staphylococcus aureus revealed that mTOR signaling is required for bactericidal free radical production by phagocytes. Mechanistically, mTOR supported glucose transporter GLUT1 expression, potentially through hypoxia-inducible factor 1α, upon phagocyte activation. Cytokine and chemokine signaling, inducible nitric oxide synthase, and p65 nuclear translocation were present at similar levels during mTOR suppression, suggesting an NF-κB-independent role for mTOR signaling in the immune response during bacterial infection. We propose that mTOR signaling primarily mediates the metabolic requirements necessary for phagocyte bactericidal free radical production. This study has important implications for the metabolic requirements of innate immune cells during bacterial infection as well as the clinical use of mTOR inhibitors.IMPORTANCESirolimus, everolimus, temsirolimus, and similar are a class of pharmaceutics commonly used in the clinical treatment of cancer and the anti-rejection of transplanted organs. Each of these agents suppresses the activity of the mammalian target of rapamycin (mTOR), a master regulator of metabolism in human cells. Activation of mTOR is also involved in the immune response to bacterial infection, and treatments that inhibit mTOR are associated with increased susceptibility to bacterial infections in the skin and soft tissue. Infections caused by Staphylococcus aureus are among the most common and severe. Our study shows that this susceptibility to S. aureus infection during mTOR suppression is due to an impaired function of phagocytic immune cells responsible for controlling bacterial infections. Specifically, we observed that mTOR activity is required for phagocytes to produce antimicrobial free radicals. These results have important implications for immune responses during clinical treatments and in disease states where mTOR is suppressed.

Keywords:  Staphylococcus aureus; immune dysfunction; mTOR

DOI:  https://doi.org/10.1128/mbio.00862-24
Am J Physiol Lung Cell Mol Physiol. 2024 May 21.

Neutrophil Reduction Attenuates the Severity of Lung Injury in the Early Phase of Pneumococcal Pneumonia in Mice.

Hiroki Taenaka, Xiaohui Fang, Mazharul Maishan, Alpa Trivedi, Katherine D Wick, Jeffrey E Gotts, Thomas R Martin, Carolyn S Calfee, Michael A Matthay.

  Neutrophils are the first leukocytes to be recruited to sites of inflammation in response to chemotactic factors released by activated macrophages and pulmonary epithelial and endothelial cells in bacterial pneumonia, a common cause of acute respiratory distress syndrome (ARDS). Although neutrophilic inflammation facilitates the elimination of pathogens, neutrophils also may cause bystander tissue injury. Even though neutrophils in alveolar spaces is a key feature of acute lung injury and ARDS especially from pneumonia, their contribution to the pathogenesis of lung injury is uncertain. The goal of this study was to elucidate the role of neutrophils in a clinically relevant model of bacterial pneumonia. We investigated the effect of reducing neutrophils in a mouse model of pneumococcal pneumonia treated with antibiotics. Neutrophils were reduced with anti-Ly6G monoclonal antibody 24 hours before and immediately preceding infection. Mice were inoculated intranasally with Streptococcus pneumoniae and received ceftriaxone 12 hours after bacterial inoculation. Neutrophil reduction in mice treated with ceftriaxone attenuated hypoxemia, alveolar permeability, epithelial injury, pulmonary edema, and inflammatory biomarker release induced by bacterial pneumonia, even though bacterial loads in the distal air spaces of the lung were modestly increased as compared to antibiotic treatment alone. Thus, when appropriate antibiotics are administered, lung injury in the early phase of bacterial pneumonia is mediated in part by neutrophils. In the early phase of bacterial pneumonia, neutrophils contribute to the severity of lung injury, although they also participate in host defense.

Keywords:  Streptococcus Pneumoniae; acute lung injury; acute respiratory distress syndrome; bacterial pneumonia; neutrophils

DOI:  https://doi.org/10.1152/ajplung.00113.2024
Cell Chem Biol. 2024 May 17. pii: S2451-9456(24)00178-8. [Epub ahead of print]

Chemical interplay between gut microbiota and epigenetics: Implications in circadian biology.

Samskrathi Aravinda Sharma, Sarah Olanrewaju Oladejo, Zheng Kuang.

  Circadian rhythms are intrinsic molecular mechanisms that synchronize biological functions with the day/night cycle. The mammalian gut is colonized by a myriad of microbes, collectively named the gut microbiota. The microbiota impacts host physiology via metabolites and structural components. A key mechanism is the modulation of host epigenetic pathways, especially histone modifications. An increasing number of studies indicate the role of the microbiota in regulating host circadian rhythms. However, the mechanisms remain largely unknown. Here, we summarize studies on microbial regulation of host circadian rhythms and epigenetic pathways, highlight recent findings on how the microbiota employs host epigenetic machinery to regulate circadian rhythms, and discuss its impacts on host physiology, particularly immune and metabolic functions. We further describe current challenges and resources that could facilitate research on microbiota-epigenetic-circadian rhythm interactions to advance our knowledge of circadian disorders and possible therapeutic avenues.

Keywords:  HDAC; SCFAs; circadian clock; histone modification; immunity; metabolism; metabolites; microbiome

DOI:  https://doi.org/10.1016/j.chembiol.2024.04.016
Nat Commun. 2024 May 21. 15(1): 4326

Post-resolution macrophages shape long-term tissue immunity and integrity in a mouse model of pneumococcal pneumonia.

Karen T Feehan, Hannah E Bridgewater, Jan Stenkiewicz-Witeska, Roel P H De Maeyer, John Ferguson, Matthias Mack, Jeremy Brown, Giuseppe Ercoli, Connar M Mawer, Arne N Akbar, James R W Glanville, Parinaaz Jalali, Olivia V Bracken, Anna Nicolaou, Alexandra C Kendall, Michelle A Sugimoto, Derek W Gilroy.

Resolving inflammation is thought to return the affected tissue back to homoeostasis but recent evidence supports a non-linear model of resolution involving a phase of prolonged immune activity. Here we show that within days following resolution of Streptococcus pneumoniae-triggered lung inflammation, there is an influx of antigen specific lymphocytes with a memory and tissue-resident phenotype as well as macrophages bearing alveolar or interstitial phenotype. The transcriptome of these macrophages shows enrichment of genes associated with prostaglandin biosynthesis and genes that drive T cell chemotaxis and differentiation. Therapeutic depletion of post-resolution macrophages, inhibition of prostaglandin E2 (PGE2) synthesis or treatment with an EP4 antagonist, MF498, reduce numbers of lung CD4+/CD44+/CD62L+ and CD4+/CD44+/CD62L-/CD27+ T cells as well as their expression of the α-integrin, CD103. The T cells fail to reappear and reactivate upon secondary challenge for up to six weeks following primary infection. Concomitantly, EP4 antagonism through MF498 causes accumulation of lung macrophages and marked tissue fibrosis. Our study thus shows that PGE2 signalling, predominantly via EP4, plays an important role during the second wave of immune activity following resolution of inflammation. This secondary immune activation drives local tissue-resident T cell development while limiting tissue injury.

DOI: https://doi.org/10.1038/s41467-024-48138-y
Nature. 2024 May 22.

Bizarre bacteria defy textbooks by writing new genes.

Ewen Callaway.



Keywords:  Genomics; Microbiology; Molecular biology

DOI:  https://doi.org/10.1038/d41586-024-01477-8
Bioorg Chem. 2024 May 16. pii: S0045-2068(24)00370-5. [Epub ahead of print]148 107465

A review of chemical signaling mechanisms underlying quorum sensing and its inhibition in Staphylococcus aureus.

Kayeen Vadakkan, Kuppusamy Sathishkumar, Sithara Kuttiyachan Urumbil, Sreejesh Ponnenkunnathu Govindankutty, Ajit Kumar Ngangbam, Bijayalakshmi Devi Nongmaithem.

  Staphylococcus aureus is a significant bacterium responsible for multiple infections and is a primary cause of fatalities among patients in hospital environments. The advent of pathogenic bacteria such as methicillin-resistant S. aureus revealed the shortcomings of employing antibiotics to treat bacterial infectious diseases. Quorum sensing enhances S. aureus's survivability through signaling processes. Targeting the key components of quorum sensing has drawn much interest nowadays as a promising strategy for combating infections caused by bacteria. Concentrating on the accessory gene regulator quorum-sensing mechanism is the most commonly suggested anti-virulence approach for S.aureus. Quorum quenching is a common strategy for controlling illnesses triggered by microorganisms since it reduces the pathogenicity of bacteria and improves bacterial biofilm susceptibility to antibiotics, thus providing an intriguing prospect for drug discovery. Quorum sensing inhibition reduces selective stresses and constrains the emergence of antibiotic resistance while limiting bacterial pathogenicity. This review examines the quorum sensing mechanisms involved in S. aureus, quorum sensing targets and gene regulation, environmental factors affecting quorum sensing, quorum sensing inhibition, natural products as quorum sensing inhibitory agents and novel therapeutical strategies to target quorum sensing in S. aureus as drug developing technique to augment conventional antibiotic approaches.

Keywords:  Quorum sensing inhibition; Quorum sensing mechanisms; Staphylococcus aureus

DOI:  https://doi.org/10.1016/j.bioorg.2024.107465
Front Immunol. 2024 ;15 1275203

Efferocytosis by macrophages in physiological and pathological conditions: regulatory pathways and molecular mechanisms.

Yan Ran Sheng, Wen Ting Hu, Siman Chen, Xiao Yong Zhu.

  Efferocytosis is defined as the highly effective phagocytic removal of apoptotic cells (ACs) by professional or non-professional phagocytes. Tissue-resident professional phagocytes ("efferocytes"), such as macrophages, have high phagocytic capacity and are crucial to resolve inflammation and aid in homeostasis. Recently, numerous exciting discoveries have revealed divergent (and even diametrically opposite) findings regarding metabolic immune reprogramming associated with efferocytosis by macrophages. In this review, we highlight the key metabolites involved in the three phases of efferocytosis and immune reprogramming of macrophages under physiological and pathological conditions. The next decade is expected to yield further breakthroughs in the regulatory pathways and molecular mechanisms connecting immunological outcomes to metabolic cues as well as avenues for "personalized" therapeutic intervention.

Keywords:  combination therapy; efferocytosis; macrophages; metabolic reprogramming; molecular mechanisms

DOI:  https://doi.org/10.3389/fimmu.2024.1275203
bioRxiv. 2024 May 07. pii: 2024.05.07.592803. [Epub ahead of print]

Intraspecies warfare restricts strain coexistence in human skin microbiomes.

Christopher P Mancuso, Jacob S Baker, Evan Qu, A Delphine Tripp, Ishaq O Balogun, Tami D Lieberman.

Determining why only a fraction of encountered or applied bacterial strains engraft in a given person's microbiome is crucial for understanding and engineering these communities 1 . Previous work has established that metabolism can determine colonization success in vivo 2-4 , but relevance of bacterial warfare in preventing engraftment has been less explored. Here, we demonstrate that intraspecies warfare presents a significant barrier to strain transmission in the skin microbiome by profiling 14,884 pairwise interactions between Staphylococcus epidermidis cultured from eighteen human subjects from six families. We find that intraspecies antagonisms are abundant; these interactions are mechanistically diverse, independent of the relatedness between strains, and consistent with rapid evolution via horizontal gene transfer. Ability to antagonize more strains is associated with reaching a higher fraction of the on-person S. epidermidis community. Moreover, antagonisms are significantly depleted among strains residing on the same person relative to random assemblages. Two notable exceptions, in which bacteria evolved to become sensitive to antimicrobials found on the same host, are explained by mutations that provide phage resistance, contextualizing the importance of warfare among other lethal selective pressures. Taken together, our results emphasize that accounting for intraspecies bacterial warfare is essential to the design of long-lasting probiotic therapeutics.

DOI: https://doi.org/10.1101/2024.05.07.592803
Trends Endocrinol Metab. 2024 May 18. pii: S1043-2760(24)00111-5. [Epub ahead of print]

Metabolic homeostasis of tissue macrophages across the lifespan.

Stefanie K Wculek, Stephan Forisch, Verónica Miguel, David Sancho.

  Macrophages are present in almost all organs. Apart from being immune sentinels, tissue-resident macrophages (TRMs) have organ-specific functions that require a specialized cellular metabolism to maintain homeostasis. In addition, organ-dependent metabolic adaptations of TRMs appear to be fundamentally distinct in homeostasis and in response to a challenge, such as infection or injury. Moreover, TRM function becomes aberrant with advancing age, contributing to inflammaging and organ deterioration, and a metabolic imbalance may underlie TRM immunosenescence. Here, we outline current understanding of the particular metabolic states of TRMs across organs and the relevance for their function. Moreover, we discuss the concomitant aging-related decline in metabolic plasticity and functions of TRMs, highlighting potential novel therapeutic avenues to promote healthy aging.

Keywords:  aging; macrophage; metabolism; organ homeostasis; tissue residency

DOI:  https://doi.org/10.1016/j.tem.2024.04.017
Int J Mol Sci. 2024 May 20. pii: 5561. [Epub ahead of print]25(10):

Unraveling the Microbiome-Human Body Axis: A Comprehensive Examination of Therapeutic Strategies, Interactions and Implications.

Gabriel Olteanu, Maria-Alexandra Ciucă-Pană, Ștefan Sebastian Busnatu, Dumitru Lupuliasa, Sorinel Marius Neacșu, Magdalena Mititelu, Adina Magdalena Musuc, Corina-Bianca Ioniță-Mîndrican, Steluța Constanța Boroghină.

  This review scrutinizes the intricate interplay between the microbiome and the human body, exploring its multifaceted dimensions and far-reaching implications. The human microbiome, comprising diverse microbial communities inhabiting various anatomical niches, is increasingly recognized as a critical determinant of human health and disease. Through an extensive examination of current research, this review elucidates the dynamic interactions between the microbiome and host physiology across multiple organ systems. Key topics include the establishment and maintenance of microbiota diversity, the influence of host factors on microbial composition, and the bidirectional communication pathways between microbiota and host cells. Furthermore, we delve into the functional implications of microbiome dysbiosis in disease states, emphasizing its role in shaping immune responses, metabolic processes, and neurological functions. Additionally, this review discusses emerging therapeutic strategies aimed at modulating the microbiome to restore host-microbe homeostasis and promote health. Microbiota fecal transplantation represents a groundbreaking therapeutic approach in the management of dysbiosis-related diseases, offering a promising avenue for restoring microbial balance within the gut ecosystem. This innovative therapy involves the transfer of fecal microbiota from a healthy donor to an individual suffering from dysbiosis, aiming to replenish beneficial microbial populations and mitigate pathological imbalances. By synthesizing findings from diverse fields, this review offers valuable insights into the complex relationship between the microbiome and the human body, highlighting avenues for future research and clinical interventions.

Keywords:  dysbiosis; intestinal microbiota; microbiota fecal transplantation; probiotics; short-chain fatty acids

DOI:  https://doi.org/10.3390/ijms25105561
Int Immunopharmacol. 2024 May 20. pii: S1567-5769(24)00803-8. [Epub ahead of print]135 112283

LPS exposure alleviates multiple tissues damage by facilitating macrophage efferocytosis.

Yuwen Han, Jiukun Hu, Jinlin Pan, Xueyan Song, Yuanshuai Zhou, Jun Zhang, Yue Yang, Xiaohua Shi, Minxuan Sun, Jiao Yang.

  Toll-like receptors (TLRs) play a crucial role in mediating immune responses by recognizing pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), as well as facilitating apoptotic cell (ACs) clearance (efferocytosis), thus contributing significantly to maintaining homeostasis and promoting tissue resolution. In this study, we investigate the impact of TLR agonists on macrophage efferocytosis. Our findings demonstrate that pretreatment with the TLR agonist lipopolysaccharide (LPS) significantly enhances macrophage phagocytic ability, thereby promoting efferocytosis both in vitro and in vivo. Moreover, LPS pretreatment confers tissue protection against damage by augmenting macrophage efferocytic capacity in murine models. Further examination reveals that LPS modulates efferocytosis by upregulating the expression of Tim4.These results underscore the pivotal role of TLR agonists in regulating the efferocytosis process and suggest potential therapeutic avenues for addressing inflammatory diseases. Overall, our study highlights the intricate interplay between LPS pretreatment and efferocytosis in maintaining tissue homeostasis and resolving inflammation.

Keywords:  Efferocytosis; Inflammation; LPS; Macrophage; Tissue resolution

DOI:  https://doi.org/10.1016/j.intimp.2024.112283
Antibiotics (Basel). 2024 May 13. pii: 439. [Epub ahead of print]13(5):

AMPs as Host-Directed Immunomodulatory Agents against Skin Infections Caused by Opportunistic Bacterial Pathogens.

Subhasree Saha, Devashish Barik, Debabrata Biswas.

  Skin is the primary and largest protective organ of the human body. It produces a number of highly evolved arsenal of factors to counter the continuous assault of foreign materials and pathogens from the environment. One such potent factor is the repertoire of Antimicrobial Peptides (AMPs) that not only directly destroys invading pathogens, but also optimally modulate the immune functions of the body to counter the establishment and spread of infections. The canonical direct antimicrobial functions of these AMPs have been in focus for a long time to design principles for enhanced therapeutics, especially against the multi-drug resistant pathogens. However, in recent times the immunomodulatory functions performed by these peptides at sub-microbicidal concentrations have been a point of major focus in the field of host-directed therapeutics. Such strategies have the added benefit of not having the pathogens develop resistance against the immunomodulatory pathways, since the pathogens exploit these signaling pathways to obtain and survive within the host. Thus, this review summarizes the potent immunomodulatory effect of these AMPs on, specifically, the different host immune cells with the view of providing a platform of information that might help in designing studies to exploit and formulate effective host-directed adjunct therapeutic strategies that would synergies with drug regimens to counter the current diversity of drug-resistant skin opportunistic pathogens.

Keywords:  AMPs; antimicrobial peptides; gram-positive bacteria; immune cells; immunomodulation; multi-drug resistance; skin pathogen

DOI:  https://doi.org/10.3390/antibiotics13050439
Elife. 2024 May 20. pii: RP95113. [Epub ahead of print]13

Decoding the complexity of delayed wound healing following Enterococcus faecalis infection.

Cenk Celik, Stella Tue Ting Lee, Frederick Reinhart Tanoto, Mark Veleba, Kimberly Kline, Guillaume Thibault.

  Wound infections are highly prevalent and can lead to delayed or failed healing, causing significant morbidity and adverse economic impacts. These infections occur in various contexts, including diabetic foot ulcers, burns, and surgical sites. Enterococcus faecalis is often found in persistent non-healing wounds, but its contribution to chronic wounds remains understudied. To address this, we employed single-cell RNA sequencing (scRNA-seq) on infected wounds in comparison to uninfected wounds in a mouse model. Examining over 23,000 cells, we created a comprehensive single-cell atlas that captures the cellular and transcriptomic landscape of these wounds. Our analysis revealed unique transcriptional and metabolic alterations in infected wounds, elucidating the distinct molecular changes associated with bacterial infection compared to the normal wound healing process. We identified dysregulated keratinocyte and fibroblast transcriptomes in response to infection, jointly contributing to an anti-inflammatory environment. Notably, E. faecalis infection prompted a premature, incomplete epithelial-mesenchymal transition in keratinocytes. Additionally, E. faecalis infection modulated M2-like macrophage polarization by inhibiting pro-inflammatory resolution in vitro, in vivo, and in our scRNA-seq atlas. Furthermore, we discovered macrophage crosstalk with neutrophils, which regulates chemokine signaling pathways, while promoting anti-inflammatory interactions with endothelial cells. Overall, our findings offer new insights into the immunosuppressive role of E. faecalis in wound infections.

Keywords:  E. faecalis; Single-cell RNA sequencing; chronic wound infection; host-pathogen interaction; immune evasion; immunomodulation; infectious disease; microbiology; mouse

DOI:  https://doi.org/10.7554/eLife.95113
J Allergy Clin Immunol. 2024 May 16. pii: S0091-6749(24)00500-1. [Epub ahead of print]

SIRT5 exacerbates eosinophilic chronic rhinosinusitis through promoting polarization of M2 macrophage.

Xu-Dong Cha, Qing-Yun Zou, Feng-Zhen Li, Tian-Yu Wang, Sheng-Lei Wang, Bo-Yu Cai, Zhi-Wen Cao, Zhen-Hua Ji, Hai-Bin Liu, Wen-Wen Wang, Teng-Fei Li, Cai-Quan Liang, Wen-Wen Ren, Huan-Hai Liu.

   BACKGROUND: Previous study implied that local M2 polarization of macrophage promoted mucosal edema and exacerbates Th2 type inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP). However, the specific pathogenic role of M2 macrophages and the intrinsic regulators in the development of CRS remains elusive.
OBJECTIVE: We thought to investigate the regulatory role of SIRT5 in the polarization of M2 macrophages and its potential contribution to the development of CRSwNP.
METHODS: RT-qPCR and Western blot analyses were performed to examine the expression levels of SIRT5 and markers of M2 macrophages in sinonasal mucosa samples obtained from both CRS and control groups. Wild-type and Sirt5 knockout mice were used to establish nasal polyp model with Th2 inflammation and investigate the effects of SIRT5 in macrophages on disease development. Furthermore, in vitro experiments were conducted to elucidate the regulatory role of SIRT5 in polarization of M2 macrophages.
RESULTS: Clinical investigations showed that SIRT5 was highly expressed and positively correlated with M2 macrophages markers in eosinophilic polyps. The expression of SIRT5 in M2 macrophages was found to contribute to the development of the disease, which was impaired in Sirt5 deficiency mice. Mechanistically, SIRT5 was shown to enhance the alternative polarization of macrophages through promoting glutaminolysis.
CONCLUSIONS: SIRT5 plays a crucial role in promoting the development of CRSwNP by supporting the alternative polarization of macrophage and thus provides a potential target for CRSwNP interventions.

Keywords:  M2 macrophages; SIRT5; Th2; chronic rhinosinusitis; nasal polyps

DOI:  https://doi.org/10.1016/j.jaci.2024.04.028
Adv Protein Chem Struct Biol. 2024 ;pii: S1876-1623(23)00107-4. [Epub ahead of print]140 493-523

Decoding macrophage immunometabolism in human viral infection.

Takhellambam Malemnganba, Aditi Rattan, Vijay Kumar Prajapati.

  Immune-metabolic interactions play a pivotal role in both host defense and susceptibility to various diseases. Immunometabolism, an interdisciplinary field, seeks to elucidate how metabolic processes impact the immune system. In the context of viral infections, macrophages are often exploited by viruses for their replication and propagation. These infections trigger significant metabolic reprogramming within macrophages and polarization of distinct M1 and M2 phenotypes. This metabolic reprogramming involves alterations in standard- pathways such as the Krebs cycle, glycolysis, lipid metabolism, the pentose phosphate pathway, and amino acid metabolism. Disruptions in the balance of key intermediates like spermidine, itaconate, and citrate within these pathways contribute to the severity of viral diseases. In this chapter, we describe the manipulation of metabolic pathways by viruses and how they crosstalk between signaling pathways to evade the immune system. This intricate interplay often involves the upregulation or downregulation of specific metabolites, making these molecules potential biomarkers for diseases like HIV, HCV, and SARS-CoV. Techniques such as Nuclear Magnetic Resonance (NMR) and Mass Spectrometry, are the evaluative ways to analyze these metabolites. Considering the importance of macrophages in the inflammatory response, addressing their metabolome holds great promise for the creating future therapeutic targets aimed at combating a wide spectrum of viral infections.

Keywords:  Cellular cross-talk; Immunometabolism; Macrophages; Metabolic reprogramming; Viral infection

DOI:  https://doi.org/10.1016/bs.apcsb.2023.12.003
Front Immunol. 2024 ;15 1417060

Editorial: The early life window of opportunity: role of the microbiome on immune system imprinting.

Amir Ardeshir, Thomas Gensollen, Melody Zeng, Ziad Al Nabhani, Richard Blumberg.



Keywords:  dysbiosis; early-life microbiome; health span; immune system development; immunological imprinting; microbiota-targeted interventions; probiotics; window of opportunity

DOI:  https://doi.org/10.3389/fimmu.2024.1417060
J Immunol Res. 2024 ;2024 2765001

β-Glucan Subverts the Function of Myeloid Cells in Neonates.

Yingying Chen, Hui Li, Lin Zhu, Quan Yang, Jie Zhou.

β-Glucan is the main component of the cell wall of pathogen-associated molecular patterns (PAMPs) including various yeast, fungi, or certain bacteria. Previous reports demonstrated that β-glucan was widely investigated as a potent immunomodulators to stimulate innate and adaptive immune responses, which indicated that it could be recommended as an effective adjuvant in immunotherapy. However, the detailed effects of β-glucan on neonatal immunity are still largely unknown. Here, we found that β-glucan did not affect the frequencies and numbers of myeloid cells in the spleen and bone marrow from neonates. Functional assay revealed that β-glucan from neonates compromised the immunosuppressive function of immature myeloid cells, which were myeloid-derived suppressor cells (MDSCs). Flow cytometry or gene expression analysis revealed that β-glucan-derived polymorphonuclear (PMN)-MDSCs produced lower level of reactive oxygen species (ROS) and arginase-1 (Arg1) in neonatal mice. Furthermore, β-glucan administration significantly decreased the frequency and ROS level of PMN-MDSCs in vitro. These observations suggest that β-glucan facilitates the maturation of myeloid cells in early life, which may contribute to its beneficial effects against immune disorders later in life.

DOI: https://doi.org/10.1155/2024/2765001
Isr J Chem. 2023 Jun;pii: e202200096. [Epub ahead of print]63(5-6):

Chemical and biomolecular insights into the Staphylococcus aureus agr quorum sensing system: Current progress and ongoing challenges.

Thomas J Polaske, Korbin H J West, Ke Zhao, Danielle L Widner, Jordan T York, Helen E Blackwell.

  Staphylococcus aureus is a ubiquitous bacterium that has become a major threat to human health due to its extensive toxin production and tremendous capacity for antibiotic resistance (e.g., MRSA "superbug" infections). Amid a worsening antibiotic resistance crisis, new strategies to combat this deadly microbe that remove the selective pressure of traditional approaches are in high demand. S. aureus utilizes an accessory gene regulator (agr) quorum sensing network to monitor its local cellular population and trigger a devastating communal attack, like an invading horde, once a threshold cell density has been reached. The role of the agr system in a range of disease types is still being unraveled. Herein, we discuss the present-day biochemical understanding of agr along with unresolved details, describe its connection to the progression of infection, and review how chemical strategies have been implemented to study and intercept this signaling pathway. This research is illuminating the potential of agr as an anti-virulence target in S. aureus and should inform the study of similar, yet less studied, agr systems in related bacterial pathogens.

Keywords:  Autoinducing peptide; bacteria; cell-cell signaling; chemical probe; quorum sensing

DOI:  https://doi.org/10.1002/ijch.202200096
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2024 May;40(5): 419-427

[H3K27 acetylation promotes lncRNA OIP5-AS1 transcription and induces apoptosis of nasal epithelial cells in allergic rhinitis through up-regulation of TLR4].

Yong Xie, Zhiqiang She, Ronghua Li, Ronghua Wu, Rong Wang, Jiyuan Liu.

Objective To investigate the effect of lysine 27 residue of histone H3 (H3K27) acetylation modification on the transcriptional promotion of long noncoding RNA OPA interacting protein 5-antisense RNA 1 (lncRNA OIP5-AS1) and apoptosis of nasal epithelial cells (NECs) in allergic rhinitis (AR) via regulating Toll-like receptor 4 (TLR4). Methods Interleukin-13 (IL-13) was used to treat NECs to establish an AR cell model. Real-time quantitative PCR was utilized to detect the expressions of OIP5-AS1 and TLR4 in nasal mucosal tissues of AR patients and in the in vitro cell model. The concentrations of macrophage colony-stimulating factor (GM-CSF), eotaxin-1, and mucin 5AC (MUC5AC) were detected by ELISA. The apoptosis of NECs was determined by terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL). A dual-luciferase report experiment was carried out to verify the relationship between OIP5-AS1 and TLR4. Chromatin immunoprecipitation (ChIP) assay was performed to verify H3K27 acetylation of histones in the OIP5-AS1 promoter region. Results Compared with healthy controls and untreated NECs, OIP5-AS1 and TLR4 were both up-regulated in nasal mucosal tissues from AR patients and IL-13-stimulated NECs. Knockdown of OIP5-AS1 decreased the level of TLR4 in IL-13-treated NECs, while overexpression of OIP5-AS1 increased the level of TLR4. Inhibition of OIP5-AS1 reduced the apoptosis rate, and inhibited the secretion of GM-CSF, eotaxin-1, and MUC5AC from IL-13-treated NECs, while overexpression of TLR4 partially reversed the effects of OIP5-AS1 knockdown on NEC apoptosis and the secretion of GM-CSF, eotaxin-1, and MUC5AC. In addition, H3K27 acetylation was markedly enriched in the promoter region of OIP5-AS1, and H3K27 acetylation promoted the expression of OIP5-AS1 in IL-13-treated NECs. Conclusion H3K27 acetylation promotes OIP5-AS1 transcription and induces NEC apoptosis in AR via upregulation of TLR4.
Emerg Infect Dis. 2024 Jun;30(6): 1069-1076

Decolonization and Pathogen Reduction Approaches to Prevent Antimicrobial Resistance and Healthcare-Associated Infections.

Mihnea R Mangalea, Alison Laufer Halpin, Melia Haile, Christopher A Elkins, L Clifford McDonald.

  Antimicrobial resistance in healthcare-associated bacterial pathogens and the infections they cause are major public health threats affecting nearly all healthcare facilities. Antimicrobial-resistant bacterial infections can occur when colonizing pathogenic bacteria that normally make up a small fraction of the human microbiota increase in number in response to clinical perturbations. Such infections are especially likely when pathogens are resistant to the collateral effects of antimicrobial agents that disrupt the human microbiome, resulting in loss of colonization resistance, a key host defense. Pathogen reduction is an emerging strategy to prevent transmission of, and infection with, antimicrobial-resistant healthcare-associated pathogens. We describe the basis for pathogen reduction as an overall prevention strategy, the evidence for its effectiveness, and the role of the human microbiome in colonization resistance that also reduces the risk for infection once colonized. In addition, we explore ideal attributes of current and future pathogen-reducing approaches.

Keywords:  Pathogen reduction; antimicrobial resistance; bacteria; decolonization; healthcare-associated infection; human microbiome; patient safety; transmission prevention

DOI:  https://doi.org/10.3201/eid3006.231338
Nat Rev Microbiol. 2024 May 22.

The gut-airway microbiome axis in health and respiratory diseases.

Mustafa Özçam, Susan V Lynch.

Communication between the gut and remote organs, such as the brain or the cardiovascular system, has been well established and recent studies provide evidence for a potential bidirectional gut-airway axis. Observations from animal and human studies indicate that respiratory insults influence the activity of the gut microbiome and that microbial ligands and metabolic products generated by the gut microbiome shape respiratory immunity. Information exchange between these two large mucosal surface areas regulates microorganism-immune interactions, with significant implications for the clinical and treatment outcomes of a range of respiratory conditions, including asthma, chronic obstructive pulmonary disease and lung cancer. In this Review, we summarize the most recent data in this field, offering insights into mechanisms of gut-airway crosstalk across spatial and temporal gradients and their relevance for respiratory health.

DOI: https://doi.org/10.1038/s41579-024-01048-8
bioRxiv. 2024 May 11. pii: 2024.05.11.593044. [Epub ahead of print]

Microbiota and metabolic adaptation shape Staphylococcus aureus virulence and antimicrobial resistance during intestinal colonization.

Chunyi Zhou, Miranda B Pawline, Alejandro Pironti, Sabrina M Morales, Andrew I Perault, Robert J Ulrich, Magdalena Podkowik, Alannah Lejeune, Ashley DuMont, François-Xavier Stubbe, Aryeh Korman, Drew R Jones, Jonas Schluter, Anthony R Richardson, Paul D Fey, Karl Drlica, Ken Cadwell, Victor J Torres, Bo Shopsin.

Depletion of microbiota increases susceptibility to gastrointestinal colonization and subsequent infection by opportunistic pathogens such as methicillin-resistant Staphylococcus aureus (MRSA). How the absence of gut microbiota impacts the evolution of MRSA is unknown. The present report used germ-free mice to investigate the evolutionary dynamics of MRSA in the absence of gut microbiota. Through genomic analyses and competition assays, we found that MRSA adapts to the microbiota-free gut through sequential genetic mutations and structural changes that enhance fitness. Initially, these adaptations increase carbohydrate transport; subsequently, evolutionary pathways largely diverge to enhance either arginine metabolism or cell wall biosynthesis. Increased fitness in arginine pathway mutants depended on arginine catabolic genes, especially nos and arcC , which promote microaerobic respiration and ATP generation, respectively. Thus, arginine adaptation likely improves redox balance and energy production in the oxygen-limited gut environment. Findings were supported by human gut metagenomic analyses, which suggest the influence of arginine metabolism on colonization. Surprisingly, these adaptive genetic changes often reduced MRSA's antimicrobial resistance and virulence. Furthermore, resistance mutation, typically associated with decreased virulence, also reduced colonization fitness, indicating evolutionary trade-offs among these traits. The presence of normal microbiota inhibited these adaptations, preserving MRSA's wild-type characteristics that effectively balance virulence, resistance, and colonization fitness. The results highlight the protective role of gut microbiota in preserving a balance of key MRSA traits for long-term ecological success in commensal populations, underscoring the potential consequences on MRSA's survival and fitness during and after host hospitalization and antimicrobial treatment.
Importance: The fitness of MRSA depends on its ability to colonize. A key, underappreciated observation is that gut colonization frequently serves as the site for MRSA infections, especially among vulnerable groups such as children and hospitalized adults. By evolving MRSA strains in germ-free mice, we identify molecular mechanisms underlying how MRSA exploits a depletion in host microbiota to enhance gut colonization fitness. This work points to bacterial colonization factors that may be targetable. Our findings indicate that adaptive changes in MRSA often reduce its antimicrobial resistance and virulence, and are suppressed by the presence of native commensal bacteria. This work helps explain the ecology of pathoadaptive variants that thrive in hospital settings but falter under colonization conditions in healthy hosts. Additionally, it illustrates the potential adverse effects of prolonged, broad-spectrum empirical antimicrobial therapy and adds a new type of weight to calls for microbiota transplantation to reduce colonization by antimicrobial-resistant pathogens.

DOI: https://doi.org/10.1101/2024.05.11.593044
Cell. 2024 May 23. pii: S0092-8674(24)00463-X. [Epub ahead of print]187(11): 2601-2627

Mitochondria at the crossroads of health and disease.

Anu Suomalainen, Jodi Nunnari.

Mitochondria reside at the crossroads of catabolic and anabolic metabolism-the essence of life. How their structure and function are dynamically tuned in response to tissue-specific needs for energy, growth repair, and renewal is being increasingly understood. Mitochondria respond to intrinsic and extrinsic stresses and can alter cell and organismal function by inducing metabolic signaling within cells and to distal cells and tissues. Here, we review how the centrality of mitochondrial functions manifests in health and a broad spectrum of diseases and aging.

DOI: https://doi.org/10.1016/j.cell.2024.04.037
Respir Res. 2024 May 18. 25(1): 211

Comparative microbiome analysis in cystic fibrosis and non-cystic fibrosis bronchiectasis.

Heryk Motta, Júlia Catarina Vieira Reuwsaat, Fernanda Cortez Lopes, Graciele Viezzer, Fabiana Caroline Zempulski Volpato, Afonso Luís Barth, Paulo de Tarso Roth Dalcin, Charley Christian Staats, Marilene Henning Vainstein, Lívia Kmetzsch.

   BACKGROUND: Bronchiectasis is a condition characterized by abnormal and irreversible bronchial dilation resulting from lung tissue damage and can be categorized into two main groups: cystic fibrosis (CF) and non-CF bronchiectasis (NCFB). Both diseases are marked by recurrent infections, inflammatory exacerbations, and lung damage. Given that infections are the primary drivers of disease progression, characterization of the respiratory microbiome can shed light on compositional alterations and susceptibility to antimicrobial drugs in these cases compared to healthy individuals.
METHODS: To assess the microbiota in the two studied diseases, 35 subjects were recruited, comprising 10 NCFB and 13 CF patients and 12 healthy individuals. Nasopharyngeal swabs and induced sputum were collected, and total DNA was extracted. The DNA was then sequenced by the shotgun method and evaluated using the SqueezeMeta pipeline and R.
RESULTS: We observed reduced species diversity in both disease cohorts, along with distinct microbial compositions and profiles of antimicrobial resistance genes, compared to healthy individuals. The nasopharynx exhibited a consistent microbiota composition across all cohorts. Enrichment of members of the Burkholderiaceae family and an increased Firmicutes/Bacteroidetes ratio in the CF cohort emerged as key distinguishing factors compared to NCFB group. Staphylococcus aureus and Prevotella shahii also presented differential abundance in the CF and NCFB cohorts, respectively, in the lower respiratory tract. Considering antimicrobial resistance, a high number of genes related to antibiotic efflux were detected in both disease groups, which correlated with the patient's clinical data.
CONCLUSIONS: Bronchiectasis is associated with reduced microbial diversity and a shift in microbial and resistome composition compared to healthy subjects. Despite some similarities, CF and NCFB present significant differences in microbiome composition and antimicrobial resistance profiles, suggesting the need for customized management strategies for each disease.

Keywords:  Bronchiectasis; Cystic fibrosis; Microbiome; Non-cystic fibrosis; Resistome

DOI:  https://doi.org/10.1186/s12931-024-02835-w
Redox Biol. 2024 May 13. pii: S2213-2317(24)00169-1. [Epub ahead of print]73 103191

Distinct metabolic responses to heme in inflammatory human and mouse macrophages - Role of nitric oxide.

Pooja Pradhan, Vijith Vijayan, Bin Liu, Beatriz Martinez-Delgado, Nerea Matamala, Christoph Nikolin, Robert Greite, David S DeLuca, Sabina Janciauskiene, Roberto Motterlini, Roberta Foresti, Stephan Immenschuh.

  Activation of inflammation is tightly associated with metabolic reprogramming in macrophages. The iron-containing tetrapyrrole heme can induce pro-oxidant and pro-inflammatory effects in murine macrophages, but has been associated with polarization towards an anti-inflammatory phenotype in human macrophages. In the current study, we compared the regulatory responses to heme and the prototypical Toll-like receptor (TLR)4 ligand lipopolysaccharide (LPS) in human and mouse macrophages with a particular focus on alterations of cellular bioenergetics. In human macrophages, bulk RNA-sequencing analysis indicated that heme led to an anti-inflammatory transcriptional profile, whereas LPS induced a classical pro-inflammatory gene response. Co-stimulation of heme with LPS caused opposing regulatory patterns of inflammatory activation and cellular bioenergetics in human and mouse macrophages. Specifically, in LPS-stimulated murine, but not human macrophages, heme led to a marked suppression of oxidative phosphorylation and an up-regulation of glycolysis. The species-specific alterations in cellular bioenergetics and inflammatory responses to heme were critically dependent on the availability of nitric oxide (NO) that is generated in inflammatory mouse, but not human macrophages. Accordingly, studies with an inducible nitric oxide synthase (iNOS) inhibitor in mouse, and a pharmacological NO donor in human macrophages, reveal that NO is responsible for the opposing effects of heme in these cells. Taken together, the current findings indicate that NO is critical for the immunomodulatory role of heme in macrophages.

Keywords:  Heme; Inflammation; Lipopolysaccharide; Macrophages; Mitochondrial metabolism; Nitric oxide

DOI:  https://doi.org/10.1016/j.redox.2024.103191
Proc Natl Acad Sci U S A. 2024 May 28. 121(22): e2322524121

CRISPRi screens identify the lncRNA, LOUP, as a multifunctional locus regulating macrophage differentiation and inflammatory signaling.

Haley Halasz, Eric Malekos, Sergio Covarrubias, Samira Yitiz, Christy Montano, Lisa Sudek, Sol Katzman, S John Liu, Max A Horlbeck, Leila Namvar, Jonathan S Weissman, Susan Carpenter.

  Long noncoding RNAs (lncRNAs) account for the largest portion of RNA from the transcriptome, yet most of their functions remain unknown. Here, we performed two independent high-throughput CRISPRi screens to understand the role of lncRNAs in monocyte function and differentiation. The first was a reporter-based screen to identify lncRNAs that regulate TLR4-NFkB signaling in human monocytes and the second screen identified lncRNAs involved in monocyte to macrophage differentiation. We successfully identified numerous noncoding and protein-coding genes that can positively or negatively regulate inflammation and differentiation. To understand the functional roles of lncRNAs in both processes, we chose to further study the lncRNA LOUP [lncRNA originating from upstream regulatory element of SPI1 (also known as PU.1)], as it emerged as a top hit in both screens. Not only does LOUP regulate its neighboring gene, the myeloid fate-determining factor SPI1, thereby affecting monocyte to macrophage differentiation, but knockdown of LOUP leads to a broad upregulation of NFkB-targeted genes at baseline and upon TLR4-NFkB activation. LOUP also harbors three small open reading frames capable of being translated and are responsible for LOUP's ability to negatively regulate TLR4/NFkB signaling. This work emphasizes the value of high-throughput screening to rapidly identify functional lncRNAs in the innate immune system.

Keywords:  CRISPRi; inflammation; long noncoding RNA; macrophage; short encoded peptide

DOI:  https://doi.org/10.1073/pnas.2322524121
Trends Parasitol. 2024 May 20. pii: S1471-4922(24)00119-3. [Epub ahead of print]

We are what we eat: macrophages and efferocytosis.

Kyle T Cunningham, Rick M Maizels.

  Liebold et al. recently revealed how the identity of dying cells drives distinct changes to the macrophages which engulf and clear them, a process known as efferocytosis. During infection with the helminth Schistosoma mansoni, liver macrophages recapitulate these phenotypes, mediated by Axl/MerTK receptors and regulating egg burdens.

Keywords:  efferocytosis; helminth; macrophage; schistosomiasis

DOI:  https://doi.org/10.1016/j.pt.2024.05.004
J Allergy Clin Immunol Glob. 2024 Aug;3(3): 100259

Combined metagenomic- and culture-based approaches to investigate bacterial strain-level associations with medication-controlled mild-moderate atopic dermatitis.

Nicole M Lane Starr, Numan Al-Rayyan, Jennifer M Smith, Shelby Sandstrom, Mary Hannah Swaney, Rauf Salamzade, Olivia Steidl, Lindsay R Kalan, Anne Marie Singh.

   Background: The skin microbiome is disrupted in atopic dermatitis (AD). Existing research focuses on moderate to severe, unmedicated disease.
Objective: We sought to investigate metagenomic- and culture-based bacterial strain-level differences in mild, medicated AD and the effects these have on human keratinocytes (HKs).
Methods: Skin swabs from anterior forearms were collected from 20 pediatric participants (11 participants with AD sampled at lesional and nonlesional sites and 9 age- and sex-matched controls). Participants had primarily mild to moderate AD and maintained medication use. Samples were processed for microbial metagenomic sequencing and bacterial isolation. Isolates identified as Staphylococcus aureus were tested for enterotoxin production. HK cultures were treated with cell-free conditioned media from representative Staphylococcus species to measure barrier effects.
Results: Metagenomic sequencing identified significant differences in microbiome composition between AD and control groups. Differences were seen at the species and strain levels for Staphylococci, with S aureus found only in participants with AD and differences in Staphylococcus epidermidis strains between control and AD swabs. These strains showed differences in toxin gene presence, which was confirmed in vitro for S aureus enterotoxins. The strain from the participant with the most severe AD produced enterotoxin B levels more than 100-fold higher than the other strains (P < .001). Strains also displayed differential effects on HK metabolism and barrier function.
Conclusions: Strain-level differences in toxin genes from Staphylococcus strains may explain varying effects on HK, with S aureus and non-aureus strains negatively affecting viability and barrier function. These differences are likely important in AD pathogenesis.

Keywords:  Atopic dermatitis; Staphylococcus aureus; Staphylococcus epidermidis; bacterial isolation; human keratinocytes; metagenomics; skin microbiome

DOI:  https://doi.org/10.1016/j.jacig.2024.100259
Proc Natl Acad Sci U S A. 2024 May 28. 121(22): e2310864121

IL-33 controls IL-22-dependent antibacterial defense by modulating the microbiota.

CAPNETZ Study Group

  IL-22 plays a critical role in defending against mucosal infections, but how IL-22 production is regulated is incompletely understood. Here, we show that mice lacking IL-33 or its receptor ST2 (IL-1RL1) were more resistant to Streptococcus pneumoniae lung infection than wild-type animals and that single-nucleotide polymorphisms in IL33 and IL1RL1 were associated with pneumococcal pneumonia in humans. The effect of IL-33 on S. pneumoniae infection was mediated by negative regulation of IL-22 production in innate lymphoid cells (ILCs) but independent of ILC2s as well as IL-4 and IL-13 signaling. Moreover, IL-33's influence on IL-22-dependent antibacterial defense was dependent on housing conditions of the mice and mediated by IL-33's modulatory effect on the gut microbiota. Collectively, we provide insight into the bidirectional crosstalk between the innate immune system and the microbiota. We conclude that both genetic and environmental factors influence the gut microbiota, thereby impacting the efficacy of antibacterial immune defense and susceptibility to pneumonia.

Keywords:  IL-22; IL-33; Streptococcus pneumoniae; microbiota; pneumonia

DOI:  https://doi.org/10.1073/pnas.2310864121
JID Innov. 2024 May;4(3): 100269

In Silico Elucidation of Key Drivers of Staphyloccocus aureus-Staphyloccocus epidermidis-Induced Skin Damage in Atopic Dermatitis Lesions.

Jamie Lee, Ahmad A Mannan, Takuya Miyano, Alan D Irvine, Reiko J Tanaka.

  Staphylococcus aureus (SA) colonizes and can damage skin in atopic dermatitis lesions, despite being commonly found with Staphylococcus epidermidis (SE), a commensal that can inhibit SA's virulence and kill SA. In this study, we developed an in silico model, termed a virtual skin site, describing the dynamic interplay between SA, SE, and the skin barrier in atopic dermatitis lesions to investigate the mechanisms driving skin damage by SA and SE. We generated 106 virtual skin sites by varying model parameters to represent different skin physiologies and bacterial properties. In silico analysis revealed that virtual skin sites with no skin damage in the model were characterized by parameters representing stronger SA and SE growth attenuation than those with skin damage. This inspired an in silico treatment strategy combining SA-killing with an enhanced SA-SE growth attenuation, which was found through simulations to recover many more damaged virtual skin sites to a non-damaged state, compared with SA-killing alone. This study demonstrates that in silico modelling can help elucidate the key factors driving skin damage caused by SA-SE colonization in atopic dermatitis lesions and help propose strategies to control it, which we envision will contribute to the design of promising treatments for clinical studies.

Keywords:  Atopic dermatitis; Mathematical modelling; Microbial interactions; Skin damage

DOI:  https://doi.org/10.1016/j.xjidi.2024.100269
Pathogens. 2024 May 11. pii: 401. [Epub ahead of print]13(5):

Neutrophils Expressing Programmed Death-Ligand 1 Play an Indispensable Role in Effective Bacterial Elimination and Resolving Inflammation in Methicillin-Resistant Staphylococcus aureus Infection.

Azusa Terasaki, Faizan Ahmed, Alato Okuno, Zhenzi Peng, Duo-Yao Cao, Suguru Saito.

  Programmed death ligand 1 (PD-L1) is a co-inhibitory molecule expressed on the surface of various cell types and known for its suppressive effect on T cells through its interaction with PD-1. Neutrophils also express PD-L1, and its expression is elevated in specific situations; however, the immunobiological role of PD-L1+ neutrophils has not been fully characterized. Here, we report that PD-L1-expressing neutrophils increased in methicillin-resistant Staphylococcus aureus (MRSA) infection are highly functional in bacterial elimination and supporting inflammatory resolution. The frequency of PD-L1+ neutrophils was dramatically increased in MRSA-infected mice, and this population exhibited enhanced activity in bacterial elimination compared to PD-L1- neutrophils. The administration of PD-L1 monoclonal antibody did not impair PD-L1+ neutrophil function, suggesting that PD-L1 expression itself does not influence neutrophil activity. However, PD-1/PD-L1 blockade significantly delayed liver inflammation resolution in MRSA-infected mice, as indicated by their increased plasma alanine transaminase (ALT) levels and frequencies of inflammatory leukocytes in the liver, implying that neutrophil PD-L1 suppresses the inflammatory response of these cells during the acute phase of MRSA infection. Our results reveal that elevated PD-L1 expression can be a marker for the enhanced anti-bacterial function of neutrophils. Moreover, PD-L1+ neutrophils are an indispensable population attenuating inflammatory leukocyte activities, assisting in a smooth transition into the resolution phase in MRSA infection.

Keywords:  MRSA; PD-1; PD-L1; immunosuppressive; neutrophil

DOI:  https://doi.org/10.3390/pathogens13050401
Proc Natl Acad Sci U S A. 2024 May 28. 121(22): e2402764121

Type VII secretion system extracellular protein B targets STING to evade host anti-Staphylococcus aureus immunity.

Lin Gao, Tian Tian, Tingrong Xiong, Xiaomei Zhang, Ning Wang, Luxuan Liu, Yun Shi, Qiang Liu, Dongshui Lu, Ping Luo, Weijun Zhang, Ping Cheng, Qiang Gou, Yu Wang, Hao Zeng, Xiaokai Zhang, Quanming Zou.

  Staphylococcus aureus (S. aureus) can evade antibiotics and host immune defenses by persisting within infected cells. Here, we demonstrate that in infected host cells, S. aureus type VII secretion system (T7SS) extracellular protein B (EsxB) interacts with the stimulator of interferon genes (STING) protein and suppresses the inflammatory defense mechanism of macrophages during early infection. The binding of EsxB with STING disrupts the K48-linked ubiquitination of EsxB at lysine 33, thereby preventing EsxB degradation. Furthermore, EsxB-STING binding appears to interrupt the interaction of 2 vital regulatory proteins with STING: aspartate-histidine-histidine-cysteine domain-containing protein 3 (DHHC3) and TNF receptor-associated factor 6. This persistent dual suppression of STING interactions deregulates intracellular proinflammatory pathways in macrophages, inhibiting STING's palmitoylation at cysteine 91 and its K63-linked ubiquitination at lysine 83. These findings uncover an immune-evasion mechanism by S. aureus T7SS during intracellular macrophage infection, which has implications for developing effective immunomodulators to combat S. aureus infections.

Keywords:  EsxB; STING; Staphylococcus aureus; inflammation; macrophages

DOI:  https://doi.org/10.1073/pnas.2402764121
Clin Chim Acta. 2024 May 19. pii: S0009-8981(24)01987-9. [Epub ahead of print]560 119735

Metabolomic analysis reveals macrophage metabolic reprogramming and polarization under different nutritional cues.

Zhongxiao Zhang, Zhou Peng, Rui Wang, Xirong Guo, Jianfang Gao.

   BACKGROUND AND AIMS: Obesity-induced chronic inflammation and metabolic abnormalities are highly relevant to the functional dysregulation of macrophages, especially under obese conditions. Hyperglycemia and hyperlipidemia, central to obesity, directly alter macrophage activity. However, the impacts of different nutritional cues on the intricate metabolic networks in macrophages remain unclear.
MATERIALS AND METHODS: In this study, we employed metabolomic approaches to examine the metabolic responses of macrophages to high glucose, high fat and their coexistence, aiming to delineate the molecular mechanisms of nutritional factors on macrophage activation and obesity-related diseases from a metabolic perspective.
RESULTS: Our findings revealed that different nutritional conditions could reprogram key metabolism in macrophages. Additionally, we identified a metabolite derived from macrophages, Long-Chain Phosphatidylcholine (LPC), which exerts beneficial effects on obese mice. It ameliorates the obesity phenotype and improves glucose metabolism profiles. This discovery suggests that LPC has a significant therapeutic potential in the context of obesity-induced metabolic dysfunctions. Our study unveils the metabolic phenotype of macrophages in high-fat and high-sugar environments and uncovers a macrophage-derived metabolite that significantly ameliorates the obesity phenotype.
CONCLUSION: This finding reveals a potential dialogue mechanism between macrophages and adipocytes, shedding light on the complex interplay of immune and metabolic systems in obesity. This discovery not only enhances our understanding of obesity's underlying mechanisms but also opens up new avenues for therapeutic interventions targeting macrophage-adipocyte interactions.

Keywords:  Macrophage; Metabolic reprogramming; Metabolomic; Obesity

DOI:  https://doi.org/10.1016/j.cca.2024.119735
Lung. 2024 May 21.

Phage Therapy for Respiratory Infections: Opportunities and Challenges.

Arya Khosravi, Qingquan Chen, Arne Echterhof, Jonathan L Koff, Paul L Bollyky.

  We are entering the post-antibiotic era. Antimicrobial resistance (AMR) is a critical problem in chronic lung infections resulting in progressive respiratory failure and increased mortality. In the absence of emerging novel antibiotics to counter AMR infections, bacteriophages (phages), viruses that infect bacteria, have become a promising option for chronic respiratory infections. However, while personalized phage therapy is associated with improved outcomes in individual cases, clinical trials demonstrating treatment efficacy are lacking, limiting the therapeutic potential of this approach for respiratory infections. In this review, we address the current state of phage therapy for managing chronic respiratory diseases. We then discuss how phage therapy may address major microbiologic obstacles which hinder disease resolution of chronic lung infections with current antibiotic-based treatment practices. Finally, we highlight the challenges that must be addressed for successful phage therapy clinical trials. Through this discussion, we hope to expand on the potential of phages as an adjuvant therapy in chronic lung infections, as well as the microbiologic challenges that need to be addressed for phage therapy to expand beyond personalized salvage therapy.

Keywords:  Antimicrobial resistance; Bacteriophage; Chronic infections; Phage therapy

DOI:  https://doi.org/10.1007/s00408-024-00700-7
PNAS Nexus. 2024 May;3(5): pgae185

Tensor modeling of MRSA bacteremia cytokine and transcriptional patterns reveals coordinated, outcome-associated immunological programs.

with the MRSA Systems Immunobiology Group

  Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is a common and life-threatening infection that imposes up to 30% mortality even when appropriate therapy is used. Despite in vitro efficacy determined by minimum inhibitory concentration breakpoints, antibiotics often fail to resolve these infections in vivo, resulting in persistent MRSA bacteremia. Recently, several genetic, epigenetic, and proteomic correlates of persistent outcomes have been identified. However, the extent to which single variables or their composite patterns operate as independent predictors of outcome or reflect shared underlying mechanisms of persistence is unknown. To explore this question, we employed a tensor-based integration of host transcriptional and cytokine datasets across a well-characterized cohort of patients with persistent or resolving MRSA bacteremia outcomes. This method yielded high correlative accuracy with outcomes and immunologic signatures united by transcriptomic and cytokine datasets. Results reveal that patients with persistent MRSA bacteremia (PB) exhibit signals of granulocyte dysfunction, suppressed antigen presentation, and deviated lymphocyte polarization. In contrast, patients with resolving bacteremia (RB) heterogeneously exhibit correlates of robust antigen-presenting cell trafficking and enhanced neutrophil maturation corresponding to appropriate T lymphocyte polarization and B lymphocyte response. These results suggest that transcriptional and cytokine correlates of PB vs. RB outcomes are complex and may not be disclosed by conventional modeling. In this respect, a tensor-based integration approach may help to reveal consensus molecular and cellular mechanisms and their biological interpretation.

Keywords:  CD4+ T cells; MRSA; granulocytes; persistence; tensor factorization

DOI:  https://doi.org/10.1093/pnasnexus/pgae185
Antibiotics (Basel). 2024 Apr 28. pii: 406. [Epub ahead of print]13(5):

The Interplay between Antibiotics and the Host Immune Response in Sepsis: From Basic Mechanisms to Clinical Considerations: A Comprehensive Narrative Review.

Martina Tosi, Irene Coloretti, Marianna Meschiari, Sara De Biasi, Massimo Girardis, Stefano Busani.

  Sepsis poses a significant global health challenge due to immune system dysregulation. This narrative review explores the complex relationship between antibiotics and the immune system, aiming to clarify the involved mechanisms and their clinical impacts. From pre-clinical studies, antibiotics exhibit various immunomodulatory effects, including the regulation of pro-inflammatory cytokine production, interaction with Toll-Like Receptors, modulation of the P38/Pmk-1 Pathway, inhibition of Matrix Metalloproteinases, blockade of nitric oxide synthase, and regulation of caspase-induced apoptosis. Additionally, antibiotic-induced alterations to the microbiome are associated with changes in systemic immunity, affecting cellular and humoral responses. The adjunctive use of antibiotics in sepsis patients, particularly macrolides, has attracted attention due to their immune-regulatory effects. However, there are limited data comparing different types of macrolides. More robust evidence comes from studies on community-acquired pneumonia, especially in severe cases with a hyper-inflammatory response. While studies on septic shock have shown mixed results regarding mortality rates and immune response modulation, conflicting findings are also observed with macrolides in acute respiratory distress syndrome. In conclusion, there is a pressing need to tailor antibiotic therapy based on the patient's immune profile to optimize outcomes in sepsis management.

Keywords:  antibiotic therapy; critically ill patients; immune response; sepsis

DOI:  https://doi.org/10.3390/antibiotics13050406
Trends Immunol. 2024 May 17. pii: S1471-4906(24)00097-8. [Epub ahead of print]

Liquid-liquid phase separation in innate immunity.

Dawei Liu, Jinhang Yang, Ileana M Cristea.

  Intrinsic and innate immune responses are essential lines of defense in the body's constant surveillance of pathogens. The discovery of liquid-liquid phase separation (LLPS) as a key regulator of this primal response to infection brings an updated perspective to our understanding of cellular defense mechanisms. Here, we review the emerging multifaceted role of LLPS in diverse aspects of mammalian innate immunity, including DNA and RNA sensing and inflammasome activity. We discuss the intricate regulation of LLPS by post-translational modifications (PTMs), and the subversive tactics used by viruses to antagonize LLPS. This Review, therefore, underscores the significance of LLPS as a regulatory node that offers rapid and plastic control over host immune signaling, representing a promising target for future therapeutic strategies.

Keywords:  DNA sensing; LLPS; PTMs; RNA sensing; immune signaling; innate immunity; membraneless organelles; phase separation; post-translational modification; proteomics; viral infection

DOI:  https://doi.org/10.1016/j.it.2024.04.009