bims-bac4me 2024-07-07 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2024–07–07
29 papers selected by
Chun-Chi Chang, University Hospital Zurich

Epithelial cells maintain memory of prior infection with Streptococcus pneumoniae through di-methylation of histone H3.
Adaptation to skin mycobiota promotes antibiotic tolerance in Staphylococcus aureus.
Primary nasal influenza infection rewires tissue-scale memory response dynamics.
Staphylococcus aureus Proteases: Orchestrators of Skin Inflammation.
A Streptococcus pneumoniae endolysin mutant protein ΔA146Ply elicits rapid broad-spectrum mucosal protection in mice via upregulation of GPX4 through TLR4/IRG1/NRF2 to alleviate macrophage ferroptosis.
Differential signalling requirements for RIPK1-dependent pyroptosis in neutrophils and macrophages.
Post-COVID-19 pandemic increased incidence of invasive bacterial infections: potential links with altered herd trained immunity.
Integrating functional metagenomics to decipher microbiome-immune interactions.
Fibroblast growth factor signaling in macrophage polarization: impact on health and diseases.
Glutamate oxaloacetate transaminase 1 is dispensable in macrophage differentiation and anti-pathogen response.
Killer immune cells pile on the pressure to slay their foes.
The impact of the host microbiota on Candida albicans infection.
Mucin-induced surface dispersal of Staphylococcus aureus and Staphylococcus epidermidis via quorum-sensing dependent and independent mechanisms.
Peptide maturation molecules act as molecular gatekeepers to coordinate cell-cell communication in Streptococcus pneumoniae.
Kids' noses resist COVID-19.
[Research advances in the development and function of macrophages and classical dendritic cells during resting and infection].
α-Hemolysin-mediated endothelial injury contributes to the development of Staphylococcus aureus-induced dermonecrosis.
The mesenchymal stromal cell secretome promotes tissue regeneration and increases macrophage infiltration in acute and methicillin-resistant Staphylococcus aureus-infected skin wounds in vivo.
Roles of flavoprotein oxidase and the exogenous heme- and quinone-dependent respiratory chain in lactic acid bacteria.
mSphere of Influence: Metabolic redundancies enhance pathogenesis.
High burden of viruses and bacterial pathobionts drives heightened nasal innate immunity in children.
Molecular definition of the endogenous Toll-like receptor signalling pathways.
Editorial: Recent advances in immunometabolism.
Microbes produce biofilms to support their communities in nutrient-limited environments.
Understanding the link between respiratory microbiota and asthma.
Gut-Derived Short-Chain Fatty Acids and Macrophage Modulation: Exploring Therapeutic Potentials in Pulmonary Fungal Infections.
Genome-resolved metagenomics: a game changer for microbiome medicine.
Defining myeloid-derived suppressor cells.
Proteolysis and Contractility Regulate Tissue Opening and Wound Healing by Lung Fibroblasts in 3D Microenvironments.

Nat Commun. 2024 Jul 02. 15(1): 5545

Epithelial cells maintain memory of prior infection with Streptococcus pneumoniae through di-methylation of histone H3.

Christine Chevalier, Claudia Chica, Justine Matheau, Adrien Pain, Michael G Connor, Melanie A Hamon.

Epithelial cells are the first point of contact for bacteria entering the respiratory tract. Streptococcus pneumoniae is an obligate human pathobiont of the nasal mucosa, carried asymptomatically but also the cause of severe pneumoniae. The role of the epithelium in maintaining homeostatic interactions or mounting an inflammatory response to invasive S. pneumoniae is currently poorly understood. However, studies have shown that chromatin modifications, at the histone level, induced by bacterial pathogens interfere with the host transcriptional program and promote infection. Here, we uncover a histone modification induced by S. pneumoniae infection maintained for at least 9 days upon clearance of bacteria with antibiotics. Di-methylation of histone H3 on lysine 4 (H3K4me2) is induced in an active manner by bacterial attachment to host cells. We show that infection establishes a unique epigenetic program affecting the transcriptional response of epithelial cells, rendering them more permissive upon secondary infection. Our results establish H3K4me2 as a unique modification induced by infection, distinct from H3K4me3 or me1, which localizes to enhancer regions genome-wide. Therefore, this study reveals evidence that bacterial infection leaves a memory in epithelial cells after bacterial clearance, in an epigenomic mark, thereby altering cellular responses to subsequent infections and promoting infection.

DOI: https://doi.org/10.1038/s41467-024-49347-1
bioRxiv. 2024 May 05. pii: 2024.05.03.592489. [Epub ahead of print]

Adaptation to skin mycobiota promotes antibiotic tolerance in Staphylococcus aureus.

Caitlin H Kowalski, Susannah Lawhorn, T Jarrod Smith, Rebecca M Corrigan, Matthew F Barber.

The microbiota can promote host health by inhibiting pathogen colonization, yet how host-resident fungi, or the mycobiota, contribute to this process remains unclear. The human skin mycobiota is uniquely stable compared to other body sites and dominated by yeasts of the genus Malassezia . We observe that colonization of human skin by Malassezia sympodialis significantly reduces subsequent colonization by the prominent bacterial pathogen Staphylococcus aureus . M. sympodialis secreted products possess potent bactericidal activity against S. aureus and are sufficient to impair S. aureus skin colonization. This bactericidal activity requires an acidic environment and is exacerbated by free fatty acids, demonstrating a unique synergy with host-derived epidermal defenses. Leveraging experimental evolution to pinpoint mechanisms of S. aureus adaptation in response to the skin mycobiota, we identified multiple mutations in the stringent response regulator Rel that promote survival against M. sympodialis . Similar Rel alleles have been reported in S. aureus clinical isolates, and natural Rel variants are sufficient for tolerance to M. sympodialis antagonism. Partial stringent response activation underlies tolerance to clinical antibiotics, with both laboratory-evolved and natural Rel variants conferring multidrug tolerance. These findings demonstrate the ability of the mycobiota to mediate pathogen colonization resistance, identify new mechanisms of bacterial adaptation in response to fungal antagonism, and reveal the potential for microbiota-driven evolution to shape pathogen antibiotic susceptibility.
Highlights: - M. sympodialis reduces colonization of human skin by S. aureus - Bactericidal activity of M. sympodialis is exacerbated by features of the skin niche - S. aureus Rel variants are sufficient for tolerance to Malassezia antagonism - Evolved tolerance to yeast antagonism coincides with S. aureus multidrug tolerance.

DOI: https://doi.org/10.1101/2024.05.03.592489
Immunity. 2024 Jun 28. pii: S1074-7613(24)00311-X. [Epub ahead of print]

Primary nasal influenza infection rewires tissue-scale memory response dynamics.

Samuel W Kazer, Colette Matysiak Match, Erica M Langan, Marie-Angèle Messou, Thomas J LaSalle, Elise O'Leary, Jessica Marbourg, Katherine Naughton, Ulrich H von Andrian, Jose Ordovas-Montanes.

  The nasal mucosa is often the initial site of respiratory viral infection, replication, and transmission. Understanding how infection shapes tissue-scale primary and memory responses is critical for designing mucosal therapeutics and vaccines. We generated a single-cell RNA-sequencing atlas of the murine nasal mucosa, sampling three regions during primary influenza infection and rechallenge. Compositional analysis revealed restricted infection to the respiratory mucosa with stepwise changes in immune and epithelial cell subsets and states. We identified and characterized a rare subset of Krt13+ nasal immune-interacting floor epithelial (KNIIFE) cells, which concurrently increased with tissue-resident memory T (TRM)-like cells. Proportionality analysis, cell-cell communication inference, and microscopy underscored the CXCL16-CXCR6 axis between KNIIFE and TRM cells. Secondary influenza challenge induced accelerated and coordinated myeloid and lymphoid responses without epithelial proliferation. Together, this atlas serves as a reference for viral infection in the upper respiratory tract and highlights the efficacy of local coordinated memory responses.

Keywords:  airway; epithelial cells; inflammation; influenza; memory; nasal mucosa; respiratory infection; scRNA-seq; single-cell; viral infection

DOI:  https://doi.org/10.1016/j.immuni.2024.06.005
DNA Cell Biol. 2024 Jul 03.

Staphylococcus aureus Proteases: Orchestrators of Skin Inflammation.

Sabrina N Kline, Yoshine Saito, Nathan K Archer.

  Skin homeostasis relies on a delicate balance between host proteases and protease inhibitors along with those secreted from microbial communities, as disruption to this harmony contributes to the pathogenesis of inflammatory skin disorders, including atopic dermatitis and Netherton's syndrome. In addition to being a prominent cause of skin and soft tissue infections, the gram-positive bacterium Staphylococcus aureus is a key player in inflammatory skin conditions due to its array of 10 secreted proteases. Herein we review how S. aureus proteases augment the development of inflammation in skin disorders. These mechanisms include degradation of skin barrier integrity, immune dysregulation and pruritis, and impairment of host defenses. Delineating the diverse roles of S. aureus proteases has the potential to reveal novel therapeutic strategies, such as inhibitors of proteases or their cognate target, as well as neutralizing vaccines to alleviate the burden of inflammatory skin disorders in patients.

Keywords:  Staphylococcus aureus; atopic dermatitis; inflammation; proteases; skin disorders

DOI:  https://doi.org/10.1089/dna.2024.0134
Free Radic Biol Med. 2024 Jun 28. pii: S0891-5849(24)00542-2. [Epub ahead of print]222 344-360

A Streptococcus pneumoniae endolysin mutant protein ΔA146Ply elicits rapid broad-spectrum mucosal protection in mice via upregulation of GPX4 through TLR4/IRG1/NRF2 to alleviate macrophage ferroptosis.

Yuan Yuan, Wenlong Xu, Lian Li, Ting Guo, Bichen Liu, Jiangming Xiao, Yibin Yin, Xuemei Zhang.

  Innovative solutions for rapid protection against broad-spectrum infections are very important in dealing with complex infection environments. We utilized a functionally inactive mutated endolysin protein of Streptococcus pneumoniae (ΔA146Ply) to immunize mice against pneumonic infections by multidrug-resistant bacteria, Candida albicans and influenza virus type A. ΔA146Ply protection relied on both immunized tissue-resident and monocyte-derived alveolar macrophages and inhibited infection induced ferroptosis that upregulated expression of GPX4 (glutathione peroxidase) in alveolar macrophages. Ferroptosis resistance endowed macrophages with enhanced phagocytosis by inhibiting lipid peroxidation during infection. Moreover, we demonstrated ΔA146Ply upregulated GPX4 through the TLR4/IRG1/NRF2 pathway. ΔA146Ply also induced ferroptosis inhibition and phagocytosis improvement in human monocytes. This mode of action is a novel and potentially prophylactic and rapid broad-spectrum anti-infection mechanism. Our study provides new insights into protective interventions that act by regulating ferroptosis to improve multiple pathogen resistance via GPX4 targeting.

Keywords:  Broad-spectrum mucosal protection; Ferroptosis; GPX4; Macrophage; ΔA146Ply

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.06.025
Cell Death Dis. 2024 Jul 04. 15(7): 479

Differential signalling requirements for RIPK1-dependent pyroptosis in neutrophils and macrophages.

See Jie Yow, Safwah Nasuha Rosli, Paul E Hutchinson, Kaiwen W Chen.

TLR4 and TNFR1 signalling promotes potent proinflammatory signal transduction events, thus, are often hijacked by pathogenic microorganisms. We recently reported that myeloid cells retaliate Yersinia blockade of TAK1/IKK signalling by triggering RIPK1-dependent caspase-8 activation that promotes downstream GSDMD and GSDME-mediated pyroptosis in macrophages and neutrophils respectively. However, the upstream signalling events for RIPK1 activation in these cells are not well defined. Here, we demonstrate that unlike in macrophages, RIPK1-driven pyroptosis and cytokine priming in neutrophils are driven through TNFR1 signalling, while TLR4-TRIF signalling is dispensable. Furthermore, we demonstrate that activation of RIPK1-dependent pyroptosis in neutrophils during Yersinia infection requires IFN-γ priming, which serves to induce surface TNFR1 expression and amplify soluble TNF secretion. In contrast, macrophages utilise both TNFR1 and TLR4-TRIF signalling to trigger cell death, but only require TRIF but not autocrine TNFR1 for cytokine production. Together, these data highlight the emerging theme of cell type-specific regulation in cell death and immune signalling in myeloid cells.

DOI: https://doi.org/10.1038/s41419-024-06871-8
Pol Arch Intern Med. 2024 Jul 05. pii: 16794. [Epub ahead of print]

Post-COVID-19 pandemic increased incidence of invasive bacterial infections: potential links with altered herd trained immunity.

Janusz Marcinkiewicz.

There has been a global increase in the incidence of various infectious diseases observed since the end of the COVID-19 pandemic. It could be hypothesized that this increase results from two independent phenomena. One is related to impaired immunity of long Covid patients. The second, the major, is associated with the long-term isolation of many people during the global pandemic lockdown resulting in an extreme reduction of contact with natural environmental human microbiota. This, in turn, led to a silencing state of the body's defense systems, including a decline of the pre-pandemic trained immunity (innate memory) that persists only for weeks to months after exposure. This decrease in trained immunity may be especially important for morbidity of infectious diseases without currently available vaccines, such as invasive Group A Streptococcus pyogenes (GAS) infections, primarily streptococcal toxic shock syndrome (STSS). This review discusses the data that support the important role of trained macrophages in host defense and demonstrates the potential clinical implications of β-glucan, the major inducer of trained macrophages, for prophylactic and therapeutic use in a case of impaired personal innate immunity. Altogether, it might be speculated that trained innate immunity within an entire population can lead to the development of Herd Trained Immunity, the novel coined the medical term. HTI can supplement classical antigen-specific herd immunity (memory B and T cells) and plays a key role in preventing various infectious diseases, including invasive GAS infections. Unfortunately, the global HTI has been overthrown during the COVID-19 pandemic but it should be restored shortly.

DOI: https://doi.org/10.20452/pamw.16794
Immunol Cell Biol. 2024 Jul 02.

Integrating functional metagenomics to decipher microbiome-immune interactions.

Puspendu Sardar, Alexandre Almeida, Virginia A Pedicord.

  Microbial metabolites can be viewed as the cytokines of the microbiome, transmitting information about the microbial and metabolic environment of the gut to orchestrate and modulate local and systemic immune responses. Still, many immunology studies focus solely on the taxonomy and community structure of the gut microbiota rather than its functions. Early sequencing-based microbiota profiling approaches relied on PCR amplification of small regions of bacterial and fungal genomes to facilitate identification of the microbes present. However, recent microbiome analysis methods, particularly shotgun metagenomic sequencing, now enable culture-independent profiling of microbiome functions and metabolites in addition to taxonomic characterization. In this review, we showcase recent advances in functional metagenomics methods and applications and discuss the current limitations and potential avenues for future development. Importantly, we highlight a few examples of key areas of opportunity in immunology research where integrating functional metagenomic analyses of the microbiome can substantially enhance a mechanistic understanding of microbiome-immune interactions and their contributions to health and disease states.

Keywords:  Bioinformatics; Functional metagenomics; Immunology; Microbiome

DOI:  https://doi.org/10.1111/imcb.12798
Front Immunol. 2024 ;15 1390453

Fibroblast growth factor signaling in macrophage polarization: impact on health and diseases.

Luyao Shen, Yongsheng Li, Huakan Zhao.

  Fibroblast growth factors (FGFs) are a versatile family of peptide growth factors that are involved in various biological functions, including cell growth and differentiation, embryonic development, angiogenesis, and metabolism. Abnormal FGF/FGF receptor (FGFR) signaling has been implicated in the pathogenesis of multiple diseases such as cancer, metabolic diseases, and inflammatory diseases. It is worth noting that macrophage polarization, which involves distinct functional phenotypes, plays a crucial role in tissue repair, homeostasis maintenance, and immune responses. Recent evidence suggests that FGF/FGFR signaling closely participates in the polarization of macrophages, indicating that they could be potential targets for therapeutic manipulation of diseases associated with dysfunctional macrophages. In this article, we provide an overview of the structure, function, and downstream regulatory pathways of FGFs, as well as crosstalk between FGF signaling and macrophage polarization. Additionally, we summarize the potential application of harnessing FGF signaling to modulate macrophage polarization.

Keywords:  disease; fibroblast growth factor; fibroblast growth factor receptor; macrophage polarization; signaling pathway

DOI:  https://doi.org/10.3389/fimmu.2024.1390453
Commun Biol. 2024 Jul 05. 7(1): 817

Glutamate oxaloacetate transaminase 1 is dispensable in macrophage differentiation and anti-pathogen response.

Lishan Zhang, Zhengyi Wu, Xuanhui Qiu, Jia Zhang, Shih-Chin Cheng.

Macrophages play a pivotal role in orchestrating the immune response against pathogens. While the intricate interplay between macrophage activation and metabolism remains a subject of intense investigation, the role of glutamate oxaloacetate transaminase 1 (Got1) in this context has not been extensively assessed. Here, we investigate the impact of Got1 on macrophage polarization and function, shedding light on its role in reactive oxygen species (ROS) production, pathogen defense, and immune paralysis. Using genetically modified mouse models, including both myeloid specific knockout and overexpression, we comprehensively demonstrate that Got1 depletion leads to reduced ROS production in macrophages. Intriguingly, this impairment in ROS generation does not affect the resistance of Got1 KO mice to pathogenic challenges. Furthermore, Got1 is dispensable for M2 macrophage differentiation and does not influence the onset of LPS-induced immune paralysis. Our findings underscore the intricate facets of macrophage responses, suggesting that Got1 is dispensable in discrete immunological processes.

DOI: https://doi.org/10.1038/s42003-024-06479-w
Nature. 2024 Jul 02.

Killer immune cells pile on the pressure to slay their foes.



Keywords:  Immunology

DOI:  https://doi.org/10.1038/d41586-024-02137-7
Curr Opin Microbiol. 2024 Jul 01. pii: S1369-5274(24)00083-3. [Epub ahead of print]80 102507

The impact of the host microbiota on Candida albicans infection.

Eve Wl Chow, Li M Pang, Yue Wang.

The human microbiota is a complex microbial ecosystem populated by bacteria, fungi, viruses, protists, and archaea. The coexistence of fungi alongside with many billions of bacteria, especially in the gut, involves complex interactions, ranging from antagonistic to beneficial, between the members of these two kingdoms. Bacteria can impact fungi through various means, such as physical interactions, secretion of metabolites, or alteration of the host immune response, thereby affecting fungal growth and virulence. This review summarizes recent progress in this field, delving into the latest understandings of bacterial-fungal-immune interactions and innovative therapeutic approaches addressing the challenges of treating fungal infections associated with microbiota imbalances.

DOI: https://doi.org/10.1016/j.mib.2024.102507
mBio. 2024 Jul 02. e0156224

Mucin-induced surface dispersal of Staphylococcus aureus and Staphylococcus epidermidis via quorum-sensing dependent and independent mechanisms.

Kristin M Jacob, Santiago Hernández-Villamizar, Neal D Hammer, Gemma Reguera.

  Nasopharyngeal carriage of staphylococci spreads potentially pathogenic strains into (peri)oral regions and increases the chance of cross-infections. Some laboratory strains can also move rapidly on hydrated agar surfaces, but the biological relevance of these observations is not clear. Using soft-agar [0.3% (wt/vol)] plate assays, we demonstrate the rapid surface dispersal of (peri)oral isolates of Staphylococcus aureus and Staphylococcus epidermidis and closely related laboratory strains in the presence of mucin glycoproteins. Mucin-induced dispersal was a stepwise process initiated by the passive spreading of the growing colonies followed by their rapid branching (dendrites) from the colony edge. Although most spreading strains used mucin as a growth substrate, dispersal was primarily dependent on the lubricating and hydrating properties of the mucins. Using S. aureus JE2 as a genetically tractable representative, we demonstrate that mucin-induced dendritic dispersal, but not colony spreading, is facilitated by the secretion of surfactant-active phenol-soluble modulins (PSMs) in a process regulated by the agr quorum-sensing system. Furthermore, the dendritic dispersal of S. aureus JE2 colonies was further stimulated in the presence of surfactant-active supernatants recovered from the most robust (peri)oral spreaders of S. aureus and S. epidermidis. These findings suggest complementary roles for lubricating mucins and staphylococcal PSMs in the active dispersal of potentially pathogenic strains from perioral to respiratory mucosae, where gel-forming, hydrating mucins abound. They also highlight the impact that interspecies interactions have on the co-dispersal of S. aureus with other perioral bacteria, heightening the risk of polymicrobial infections and the severity of the clinical outcomes.
IMPORTANCE: Despite lacking classical motility machinery, nasopharyngeal staphylococci spread rapidly in (peri)oral and respiratory mucosa and cause cross-infections. We describe laboratory conditions for the reproducible study of staphylococcal dispersal on mucosa-like surfaces and the identification of two dispersal stages (colony spreading and dendritic expansion) stimulated by mucin glycoproteins. The mucin type mattered as dispersal required the surfactant activity and hydration provided by some mucin glycoproteins. While colony spreading was a passive mode of dispersal lubricated by the mucins, the more rapid and invasive form of dendritic expansion of Staphylococcus aureus and Staphylococcus epidermidis required additional lubrication by surfactant-active peptides (phenol-soluble modulins) secreted at high cell densities through quorum sensing. These results highlight a hitherto unknown role for gel-forming mucins in the dispersal of staphylococcal strains associated with cross-infections and point at perioral regions as overlooked sources of carriage and infection by staphylococci.

Keywords:  Staphylococcus; dendritic formation; dispersal; motility; mucin; mucosa; quorum sensing; reservoirs

DOI:  https://doi.org/10.1128/mbio.01562-24
Cell Rep. 2024 Jul 03. pii: S2211-1247(24)00761-7. [Epub ahead of print]43(7): 114432

Peptide maturation molecules act as molecular gatekeepers to coordinate cell-cell communication in Streptococcus pneumoniae.

Karina Mueller Brown, Rory Eutsey, Ozcan Gazioglu, Derek Wang, Amanda Vallon, Jason W Rosch, Hasan Yesilkaya, N Luisa Hiller.

  The human pathogen Streptococcus pneumoniae (Spn) encodes several cell-cell communication systems, notably multiple members of the Rgg/SHP and the Tpr/Phr families. Until now, members of these diverse communication systems were thought to work independently. Our study reveals that the ABC transporter PptAB and the transmembrane enzyme Eep act as a molecular link between Rgg/SHP and TprA/PhrA systems. We demonstrate that PptAB/Eep activates the Rgg/SHP systems and represses the TprA/PhrA system. Specifically, they regulate the respective precursor peptides (SHP and PhrA) before these leave the cell. This dual mode of action leads to temporal coordination of these systems, producing an overlap between their respective regulons during host cell infection. Thus, we have identified a single molecular mechanism that targets diverse cell-cell communication systems in Spn. Moreover, these molecular components are encoded by many gram-positive bacteria, suggesting that this mechanism may be broadly conserved.

Keywords:  CP: Microbiology; Eep; Gram-positive; PptAB; RRNPPA; Rgg/SHP; Streptococcus pneumoniae; TprA/PhrA; cell-cell communication; colonization; quorum sensing

DOI:  https://doi.org/10.1016/j.celrep.2024.114432
J Exp Med. 2024 Sep 02. pii: e20241027. [Epub ahead of print]221(9):

Kids' noses resist COVID-19.

Ivan Zanoni.

Children resist COVID-19, and previous studies reported increased innate immunity in their upper airways. A new paper by Watkins et al. (https://doi.org/10.1084/jem.20230911) shows that the nasal mucosa of children is characterized by often asymptomatic viral and/or bacterial infections that dynamically regulate distinct innate immune programs.

DOI: https://doi.org/10.1084/jem.20241027
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2024 Jun;40(6): 556-560

[Research advances in the development and function of macrophages and classical dendritic cells during resting and infection].

Lei Zhang, Jie Cui, Yinpan Liang, Huanhuan Zhang, Shuying Yi.

Macrophages (MACs) and classical dendritic cells (cDCs) represent the front line of immune defense, playing crucial roles in both innate and adaptive immunity due to their remarkable tissue specificity and precise adaptation to environmental cues. MACs contribute to maintaining tissue homeostasis and immune surveillance, while cDCs function as the most efficient antigen-presenting cells, playing a critical role in immune responses. These two cell types share similarities and interconnections. Both MACs and cDCs are capable of recognizing pathogens and tissue damage, secreting cytokines to activate other innate immune cells, and initiating or modulating adaptive immunity through interactions with T cells. In this review, we provide a comprehensive analysis of the research advances in the development and functions of MACs and cDCs during resting and infection processes, elucidate their interrelationships and interactions within the immune system, and offer a theoretical basis for in-depth studies of diseases.
Infect Immun. 2024 Jul 02. e0013324

α-Hemolysin-mediated endothelial injury contributes to the development of Staphylococcus aureus-induced dermonecrosis.

Ching Yang, Frank H Robledo-Avila, Santiago Partida-Sanchez, Christopher P Montgomery.

  Staphylococcus aureus α-hemolysin (Hla) is a pore-forming toxin critical for the pathogenesis of skin and soft tissue infections, which causes the pathognomonic lesion of cutaneous necrosis (dermonecrosis) in mouse models. To determine the mechanism by which dermonecrosis develops during S. aureus skin infection, mice were given control serum, Hla-neutralizing antiserum, or an inhibitor of Hla receptor [A-disintegrin and metalloprotease 10 (ADAM10) inhibitor] followed by subcutaneous infection by S. aureus, and the lesions were evaluated using immunohistochemistry and immunofluorescence. Hla induced apoptosis in the vascular endothelium at 6 hours post-infection (hpi), followed by apoptosis in keratinocytes at 24 hpi. The loss of vascular endothelial (VE)-cadherin expression preceded the loss of epithelial-cadherin expression. Hla also induced hypoxia in the keratinocytes at 24 hpi following vascular injury. Treatment with Hla-neutralizing antibody or ADAM10 inhibitor attenuated early cleavage of VE-cadherin, cutaneous hypoxia, and dermonecrosis. These findings suggest that Hla-mediated vascular injury with cutaneous hypoxia underlies the pathogenesis of S. aureus-induced dermonecrosis.

Keywords:  Staphylococcus aureus; dermonecrosis; hypoxia; mice; vascular injury; α-hemolysin

DOI:  https://doi.org/10.1128/iai.00133-24
Cytotherapy. 2024 Jun 12. pii: S1465-3249(24)00758-8. [Epub ahead of print]

The mesenchymal stromal cell secretome promotes tissue regeneration and increases macrophage infiltration in acute and methicillin-resistant Staphylococcus aureus-infected skin wounds in vivo.

Aarthi Rajesh, Esther Da Eun Ju, Kelly A Oxford, Rebecca M Harman, Gerlinde R Van de Walle.

   BACKGROUND AIMS: The prevalence of chronic wounds continues to be a burden in human medicine. Methicillin-resistant Staphylococcus aureus (MRSA) is commonly isolated from infected wounds. MRSA infections primarily delay healing by impairing local immune cell functions. This study aimed to investigate the potential of mesenchymal stromal cell (MSC)-secreted bioactive factors, defined as the secretome, to improve innate immune responses in vivo. MSCs were isolated from the bone marrow of horses, which serve as valuable translational models for wound healing. The MSC secretome, collected as conditioned medium (CM), was evaluated in vivo using mouse models of acute and MRSA-infected skin wounds.
METHODS: Punch biopsies were used to create two full-thickness skin wounds on the back of each mouse. Acute wounds were treated daily with control medium or bone marrow-derived MSC (BM-MSC) CM. The antibiotic mupirocin was administered as a positive control for the MRSA-infected wound experiments. Wounds were photographed daily, and wound images were measured to determine the rate of closure. Trichrome staining was carried out to examine wound tissue histologically, and immunofluorescence antibody binding was used to assess immune cell infiltration. Wounds in the MRSA-infected model were swabbed for quantification of bacterial load.
RESULTS: Acute wounds treated with BM-MSC CM showed accelerated wound closure compared with controls, as illustrated by enhanced granulation tissue formation and resolution, increased vasculature and regeneration of hair follicles. This treatment also led to increased neutrophil and macrophage infiltration. Chronic MRSA-infected wounds treated with BM-MSC CM showed reduced bacterial load accompanied by better resolution of granulation tissue formation and increased infiltration of pro-healing M2 macrophages compared with control-treated infected wounds.
CONCLUSIONS: Collectively, our findings indicate that BM-MSC CM exerts pro-healing, immunomodulatory and anti-bacterial effects on wound healing in vivo, validating further exploration of the MSC secretome as a novel treatment option to improve healing of both acute and chronic wounds, especially those infected with antibiotic-resistant bacteria.

Keywords:  equine mesenchymal stromal cells; innate immune cells; methicillin-resistant Staphylococcus aureus; murine skin wound models; secretome

DOI:  https://doi.org/10.1016/j.jcyt.2024.06.007
Biosci Microbiota Food Health. 2024 ;43(3): 183-191

Roles of flavoprotein oxidase and the exogenous heme- and quinone-dependent respiratory chain in lactic acid bacteria.

Yuji Yamamoto.

  Lactic acid bacteria (LAB) are a type of bacteria that convert carbohydrates into lactate through fermentation metabolism. While LAB mainly acquire energy through this anaerobic process, they also have oxygen-consuming systems, one of which is flavoprotein oxidase and the other is exogenous heme- or heme- and quinone-dependent respiratory metabolism. Over the past two decades, research has contributed to the understanding of the roles of these oxidase machineries, confirming their suspected roles and uncovering novel functions. This review presents the roles of these oxidase machineries, which are anticipated to be critical for the future applications of LAB in industry and comprehending the virulence of pathogenic streptococci.

Keywords:  Lactobacillus; NADH oxidase; Streptococcus; electron transport chain; lactic acid bacteria; oxygen; respiration

DOI:  https://doi.org/10.12938/bmfh.2024-002
mSphere. 2024 Jul 03. e0023924

mSphere of Influence: Metabolic redundancies enhance pathogenesis.

McKenzie K Lehman.

  McKenzie Lehman works in the field of bacterial pathogenesis and metabolism. In this mSphere of Influence article, she reflects on how three papers entitled "Glycolytic dependency of high-level nitric oxide resistance and virulence in Staphylococcus aureus" by N. P. Vitko, N. A. Spahich, and A. R. Richardson (mBio 6:e00045-15, 2015, https://doi.org/10.1128/mbio.00045-15), "The Staphylococcus aureus cystine transporters TcyABC and TcyP facilitate nutrient sulfur acquisition during infection" by J. M. Lensmire, J. P. Dodson, B. Y. Hsueh, M. R. Wischer, et al. (Infect Immun 88:e00690-19, 2020, https://doi.org/10.1128/iai.00690-19), and "The second messenger c-di-AMP inhibits the osmolyte uptake system OpuC in Staphylococcus aureus" by C. F. Schuster, L. E. Bellows, T. Tosi, I. Campeotto, et al. (Sci Signal 16:ra81, 2016, https://doi.org/10.1126/scisignal.aaf7279) impacted her work on bacterial metabolism and pathogenesis.

Keywords:  Staphylococcus aureus; amino acid transport; metabolism

DOI:  https://doi.org/10.1128/msphere.00239-24
J Exp Med. 2024 Sep 02. pii: e20230911. [Epub ahead of print]221(9):

High burden of viruses and bacterial pathobionts drives heightened nasal innate immunity in children.

Timothy A Watkins, Alex B Green, Julien A R Amat, Nagarjuna R Cheemarla, Katrin Hänsel, Richard Lozano, Sarah N Dudgeon, Gregory Germain, Marie L Landry, Wade L Schulz, Ellen F Foxman.

Studies during the COVID-19 pandemic showed that children had heightened nasal innate immune responses compared with adults. To evaluate the role of nasal viruses and bacteria in driving these responses, we performed cytokine profiling and comprehensive, symptom-agnostic testing for respiratory viruses and bacterial pathobionts in nasopharyngeal samples from children tested for SARS-CoV-2 in 2021-22 (n = 467). Respiratory viruses and/or pathobionts were highly prevalent (82% of symptomatic and 30% asymptomatic children; 90 and 49% for children <5 years). Virus detection and load correlated with the nasal interferon response biomarker CXCL10, and the previously reported discrepancy between SARS-CoV-2 viral load and nasal interferon response was explained by viral coinfections. Bacterial pathobionts correlated with a distinct proinflammatory response with elevated IL-1β and TNF but not CXCL10. Furthermore, paired samples from healthy 1-year-olds collected 1-2 wk apart revealed frequent respiratory virus acquisition or clearance, with mucosal immunophenotype changing in parallel. These findings reveal that frequent, dynamic host-pathogen interactions drive nasal innate immune activation in children.

DOI: https://doi.org/10.1084/jem.20230911
Nature. 2024 Jul 03.

Molecular definition of the endogenous Toll-like receptor signalling pathways.

Daniel Fisch, Tian Zhang, He Sun, Weiyi Ma, Yunhao Tan, Steven P Gygi, Darren E Higgins, Jonathan C Kagan.

Innate immune pattern recognition receptors, such as the Toll-like receptors (TLRs), are key mediators of the immune response to infection and central to our understanding of health and disease1. After microbial detection, these receptors activate inflammatory signal transduction pathways that involve IκB kinases, mitogen-activated protein kinases, ubiquitin ligases and other adaptor proteins. The mechanisms that connect the proteins in the TLR pathways are poorly defined. To delineate TLR pathway activities, we engineered macrophages to enable microscopy and proteomic analysis of the endogenous myddosome constituent MyD88. We found that myddosomes form transient contacts with activated TLRs and that TLR-free myddosomes are dynamic in size, number and composition over the course of 24 h. Analysis using super-resolution microscopy revealed that, within most myddosomes, MyD88 forms barrel-like structures that function as scaffolds for effector protein recruitment. Proteomic analysis demonstrated that myddosomes contain proteins that act at all stages and regulate all effector responses of the TLR pathways, and genetic analysis defined the epistatic relationship between these effector modules. Myddosome assembly was evident in cells infected with Listeria monocytogenes, but these bacteria evaded myddosome assembly and TLR signalling during cell-to-cell spread. On the basis of these findings, we propose that the entire TLR signalling pathway is executed from within the myddosome.

DOI: https://doi.org/10.1038/s41586-024-07614-7
Front Pharmacol. 2024 ;15 1422816

Editorial: Recent advances in immunometabolism.

Ishtiaq Jeelani, Allah Nawaz, Hafiz Muhammad Asif, Ishtiaq Ahmad, Arijeet K Gattu.



Keywords:  immunce cells; immuno-metabolic crosstalk; immunomodulatory compounds; macrophages; metabolism

DOI:  https://doi.org/10.3389/fphar.2024.1422816
Nat Microbiol. 2024 Jul;9(7): 1636-1637

Microbes produce biofilms to support their communities in nutrient-limited environments.

Isis Del Mazo-Monsalvo, Michel Geovanni Santiago-Martínez.

DOI: https://doi.org/10.1038/s41564-024-01743-5
Asian J Surg. 2024 Jun 29. pii: S1015-9584(24)01296-X. [Epub ahead of print]

Understanding the link between respiratory microbiota and asthma.

Chunyuan Tian, Xingxing Yuan, Xing Li, Zhuying Li.



Keywords:  Asthma; Immune modulation; Respiratory microbiota; Therapeutic targets

DOI:  https://doi.org/10.1016/j.asjsur.2024.06.079
Clin Rev Allergy Immunol. 2024 Jul 05.

Gut-Derived Short-Chain Fatty Acids and Macrophage Modulation: Exploring Therapeutic Potentials in Pulmonary Fungal Infections.

Qian Xie, Qinhui Li, Hong Fang, Rong Zhang, Huan Tang, Lin Chen.

  Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, modulate immune cell functions, particularly macrophages. This review explores the potential therapeutic applications of SCFAs in pulmonary fungal infections, a critical concern due to their high mortality rates and antifungal resistance. SCFAs enhance macrophage functions by promoting phagosome-lysosome fusion, increasing reactive oxygen species production, and balancing cytokine responses. Pulmonary fungal infections, caused by pathogens like Aspergillus fumigatus, are prevalent in immunocompromised patients, including those with diabetes, chronic obstructive pulmonary disease, and those on high-dose corticosteroids. SCFAs have shown promise in improving macrophage function in these contexts. However, the application of SCFAs must be balanced against potential side effects, including gut microbiota disruption and metabolic disorders. Further research is needed to optimize SCFA therapy for managing pulmonary fungal infections.

Keywords:  Immunomodulation; Macrophages; Pulmonary fungal infection; Short-chain fatty acids (SCFAs)

DOI:  https://doi.org/10.1007/s12016-024-08999-z
Exp Mol Med. 2024 Jul 01.

Genome-resolved metagenomics: a game changer for microbiome medicine.

Nayeon Kim, Junyeong Ma, Wonjong Kim, Jungyeon Kim, Peter Belenky, Insuk Lee.

Recent substantial evidence implicating commensal bacteria in human diseases has given rise to a new domain in biomedical research: microbiome medicine. This emerging field aims to understand and leverage the human microbiota and derivative molecules for disease prevention and treatment. Despite the complex and hierarchical organization of this ecosystem, most research over the years has relied on 16S amplicon sequencing, a legacy of bacterial phylogeny and taxonomy. Although advanced sequencing technologies have enabled cost-effective analysis of entire microbiota, translating the relatively short nucleotide information into the functional and taxonomic organization of the microbiome has posed challenges until recently. In the last decade, genome-resolved metagenomics, which aims to reconstruct microbial genomes directly from whole-metagenome sequencing data, has made significant strides and continues to unveil the mysteries of various human-associated microbial communities. There has been a rapid increase in the volume of whole metagenome sequencing data and in the compilation of novel metagenome-assembled genomes and protein sequences in public depositories. This review provides an overview of the capabilities and methods of genome-resolved metagenomics for studying the human microbiome, with a focus on investigating the prokaryotic microbiota of the human gut. Just as decoding the human genome and its variations marked the beginning of the genomic medicine era, unraveling the genomes of commensal microbes and their sequence variations is ushering us into the era of microbiome medicine. Genome-resolved metagenomics stands as a pivotal tool in this transition and can accelerate our journey toward achieving these scientific and medical milestones.

DOI: https://doi.org/10.1038/s12276-024-01262-7
Nat Rev Immunol. 2024 Jul 05.

Defining myeloid-derived suppressor cells.

Leila Akkari, Ido Amit, Vincenzo Bronte, Zvi G Fridlender, Dmitry I Gabrilovich, Florent Ginhoux, Catherine C Hedrick, Suzanne Ostrand-Rosenberg.

DOI: https://doi.org/10.1038/s41577-024-01062-0
Adv Healthc Mater. 2024 Jul 05. e2400941

Proteolysis and Contractility Regulate Tissue Opening and Wound Healing by Lung Fibroblasts in 3D Microenvironments.

Hugh Xiao, Kadidia Sylla, Xiangyu Gong, Brendan Wilkowski, Alejandro Rossello-Martinez, Seyma Nayir Jordan, Emmanuel Y Mintah, Allen Zheng, Huanxing Sun, Erica L Herzog, Michael Mak.

  Damage and repair are recurring processes in tissues, with fibroblasts playing key roles by remodeling extracellular matrices (ECM) through protein synthesis, proteolysis, and cell contractility. Dysregulation of fibroblasts can lead to fibrosis and tissue damage, as seen in idiopathic pulmonary fibrosis (IPF). In advanced IPF, tissue damage manifests as honeycombing, or voids in the lungs. This study explores how transforming growth factor-beta (TGF-β), a crucial factor in IPF, induces lung fibroblast spheroids to create voids in reconstituted collagen through proteolysis and cell contractility, a process is termed as hole formation. These voids reduce when proteases are blocked. Spheroids mimic fibroblast foci observed in IPF. Results indicate that cell contractility mediates tissue opening by stretching fractures in the collagen meshwork. Matrix metalloproteinases (MMPs), including MMP1 and MT1-MMP, are essential for hole formation, with invadopodia playing a significant role. Blocking MMPs reduces hole size and promotes wound healing. This study shows how TGF-β induces excessive tissue destruction and how blocking proteolysis can reverse damage, offering insights into IPF pathology and potential therapeutic interventions.

Keywords:  cell mechanics; cell‐matrix interactions; extracellular matrix; fibrosis; matrix metalloproteinases; mechanobiology; tissue remodeling

DOI:  https://doi.org/10.1002/adhm.202400941