Acinetobacter baumannii phenylacetic acid metabolism influences infection outcome through a direct effect on neutrophil chemotaxis

Innate cellular immune responses are a critical first-line defense against invading bacterial pathogens. Leukocyte migration from the bloodstream to a site of infection is mediated by chemotactic factors that are often host-derived. More recently, there has been a greater appreciation of the importance of bacterial factors driving neutrophil movement during infection. Here, we describe the development of a zebrafish infection model to study Acinetobacter baumannii pathogenesis. By using isogenic A. baumannii mutants lacking expression of virulence effector proteins, we demonstrated that bacterial drivers of disease severity are conserved between zebrafish and mammals. By using transgenic zebrafish with fluorescent phagocytes, we showed that a mutation of an established A. baumannii global virulence regulator led to marked changes in neutrophil behavior involving rapid neutrophil influx to a localized site of infection, followed by prolonged neutrophil dwelling. This neutrophilic response augmented bacterial clearance and was secondary to an impaired A. baumannii phenylacetic acid catabolism pathway, which led to accumulation of phenylacetate. Purified phenylacetate was confirmed to be a neutrophil chemoattractant. These data identify a previously unknown mechanism of bacterial-guided neutrophil chemotaxis in vivo, providing insight into the role of bacterial metabolism in host innate immune evasion. Furthermore, the work provides a potentially new therapeutic paradigm of targeting a bacterial metabolic pathway to augment host innate immune responses and attenuate disease.

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The Resistance to Host Antimicrobial Peptides in Infections Caused by Daptomycin-Resistant Staphylococcus aureus

Antibiotics ◽

10.3390/antibiotics10020096 ◽

2021 ◽

Vol 10 (2) ◽

pp. 96

Author(s):

Md Saruar Bhuiyan ◽

Jhih-Hang Jiang ◽

Xenia Kostoulias ◽

Ravali Theegala ◽

Graham J. Lieschke ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Immune Responses ◽

Antimicrobial Peptides ◽

Innate Immune ◽

Cross Resistance ◽

Infection Model ◽

Innate Immune Responses ◽

Persistent Infections ◽

Zebrafish Infection

Daptomycin is an important antibiotic for the treatment of infections caused by Staphylococcus aureus. The emergence of daptomycin resistance in S. aureus is associated with treatment failure and persistent infections with poor clinical outcomes. Here, we investigated host innate immune responses against clinically derived, daptomycin-resistant (DAP-R) and -susceptible S. aureus paired isolates using a zebrafish infection model. We showed that the control of DAP-R S. aureus infections was attenuated in vivo due to cross-resistance to host cationic antimicrobial peptides. These data provide mechanistic understanding into persistent infections caused by DAP-R S. aureus and provide crucial insights into the adaptive evolution of this troublesome pathogen.

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ROS-dependent innate immune mechanisms control Staphylococcus aureus MRSA virulence in the Drosophila larval model

10.1101/2020.10.02.323444 ◽

2020 ◽

Author(s):

Elodie Ramond ◽

Anne Jamet ◽

Xiongqi Ding ◽

Clémence Bouvier ◽

Louison Lallemant ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Immune Responses ◽

Shigella Flexneri ◽

Light Sheet ◽

Innate Immune ◽

Health Concern ◽

Infection Model ◽

Human Pathogens ◽

Posterior Midgut

AbstractAntibiotics multi-resistant Staphylococcus aureus strains constitute a major public health concern worldwide and are responsible of both healthcare- and community-associated infections. Here we have established a robust and simple S. aureus oral infection model, using Drosophila melanogaster larva, which allowed to follow S. aureus fate at the whole organism level as well as the host immune responses. Fluorescence microscopy and Light sheet 3D imaging revealed bacterial clustering at the posterior midgut that displays neutral pH. Our study demonstrates that S. aureus infection triggers host H2O2 production through Duox enzyme, consequently empowering antimicrobial peptides production through Toll pathway activation. We also show that catalase-mediated quenching of H2O2 not only enhances S. aureus survival but also minimizes host antimicrobial response, hence reducing bacterial clearance in vivo. Finally, we confirm the versatility of this model by demonstrating the colonization and host stimulation capacities of two other bacterial pathogens: Salmonella Typhimurium and Shigella flexneri. Overall, the drosophila larva may constitute a general model to follow in vivo host innate immune responses triggered upon infection with human pathogens.

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Mechanistic insights into synergy between nalidixic acid and tetracycline against clinical isolates of Acinetobacter baumannii and Escherichia coli

Communications Biology ◽

10.1038/s42003-021-02074-5 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Amit Gaurav ◽

Varsha Gupta ◽

Sandeep K. Shrivastava ◽

Ranjana Pathania

Keyword(s):

Escherichia Coli ◽

Acinetobacter Baumannii ◽

Nalidixic Acid ◽

Bacterial Infections ◽

Clinical Isolates ◽

Hospital Environment ◽

Infection Model ◽

Drug Resistant ◽

E Coli

AbstractThe increasing prevalence of antimicrobial resistance has become a global health problem. Acinetobacter baumannii is an important nosocomial pathogen due to its capacity to persist in the hospital environment. It has a high mortality rate and few treatment options. Antibiotic combinations can help to fight multi-drug resistant (MDR) bacterial infections, but they are rarely used in the clinics and mostly unexplored. The interaction between bacteriostatic and bactericidal antibiotics are mostly reported as antagonism based on the results obtained in the susceptible model laboratory strain Escherichia coli. However, in the present study, we report a synergistic interaction between nalidixic acid and tetracycline against clinical multi-drug resistant A. baumannii and E. coli. Here we provide mechanistic insight into this dichotomy. The synergistic combination was studied by checkerboard assay and time-kill curve analysis. We also elucidate the mechanism behind this synergy using several techniques such as fluorescence spectroscopy, flow cytometry, fluorescence microscopy, morphometric analysis, and real-time polymerase chain reaction. Nalidixic acid and tetracycline combination displayed synergy against most of the MDR clinical isolates of A. baumannii and E. coli but not against susceptible isolates. Finally, we demonstrate that this combination is also effective in vivo in an A. baumannii/Caenorhabditis elegans infection model (p < 0.001)

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Efficacy of Humanized Cefiderocol Exposures over 72 Hours against a Diverse Group of Gram-Negative Isolates in the Neutropenic Murine Thigh Infection Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01040-18 ◽

2018 ◽

Vol 63 (2) ◽

pp. e01040-18 ◽

Cited By ~ 3

Author(s):

Sean M. Stainton ◽

Marguerite L. Monogue ◽

Masakatsu Tsuji ◽

Yoshinori Yamano ◽

Roger Echols ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Acinetobacter Baumannii ◽

Infection Model ◽

Diverse Group ◽

Gram Negative ◽

Content Type ◽

Adaptive Resistance

ABSTRACT Herein, we evaluated sustainability of humanized exposures of cefiderocol in vivo over 72 h against pathogens with cefiderocol MICs of 0.5 to 16 μg/ml in the neutropenic murine thigh model. In Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae displaying MICs of 0.5 to 8 μg/ml (n = 11), sustained kill was observed at 72 h among 9 isolates. Postexposure MICs revealed a single 2-dilution increase in one animal compared with controls (1/54 samples, 1.8%) at 72 h. Adaptive resistance during therapy was not observed.

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Occurrence of foamy macrophages during the innate response of zebrafish to trypanosome infections

eLife ◽

10.7554/elife.64520 ◽

2021 ◽

Vol 10 ◽

Author(s):

Sem H Jacobs ◽

Eva Dóró ◽

Ffion R Hammond ◽

Mai E Nguyen-Chi ◽

Georges Lutfalla ◽

...

Keyword(s):

Immune Response ◽

Early Response ◽

Innate Immune ◽

Infection Model ◽

Parasite Control ◽

Innate Response ◽

Larval Zebrafish ◽

Inflammatory Profile ◽

Foamy Macrophages

A tightly regulated innate immune response to trypanosome infections is critical to strike a balance between parasite control and inflammation-associated pathology. In this study, we make use of the recently established Trypanosoma carassii infection model in larval zebrafish to study the early response of macrophages and neutrophils to trypanosome infections in vivo. We consistently identified high- and low-infected individuals and were able to simultaneously characterize their differential innate response. Not only did macrophage and neutrophil number and distribution differ between the two groups, but also macrophage morphology and activation state. Exclusive to high-infected zebrafish, was the occurrence of foamy macrophages characterized by a strong pro-inflammatory profile and potentially associated with an exacerbated immune response as well as susceptibility to the infection. To our knowledge this is the first report of the occurrence of foamy macrophages during an extracellular trypanosome infection.

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The Sp1-Responsive microRNA-15b Negatively Regulates Rhabdovirus-Triggered Innate Immune Responses in Lower Vertebrates by Targeting TBK1

Frontiers in Immunology ◽

10.3389/fimmu.2020.625828 ◽

2021 ◽

Vol 11 ◽

Author(s):

Renjie Chang ◽

Qing Chu ◽

Weiwei Zheng ◽

Lei Zhang ◽

Tianjun Xu

Keyword(s):

Immune Response ◽

Immune Responses ◽

Innate Immune ◽

Infection Model ◽

Regulation Mechanism ◽

Type I ◽

Innate Immune Responses ◽

Positive Role ◽

Siniperca Chuatsi ◽

Antiviral Immune Response

As is known to all, the production of type I interferon (IFN) plays pivotal roles in host innate antiviral immunity, and its moderate production play a positive role in promoting the activation of host innate antiviral immune response. However, the virus will establish a persistent infection model by interfering with the production of IFN, thereby evading the organism inherent antiviral immune response. Therefore, it is of great necessity to research the underlying regulatory mechanisms of type I IFN appropriate production under viral invasion. In this study, we report that a Sp1–responsive miR-15b plays a negative role in siniperca chuatsi rhabdovirus (SCRV)-triggered antiviral response in teleost fish. We found that SCRV could dramatically upregulate miiuy croaker miR-15b expression. Enhanced miR-15b could negatively regulate SCRV-triggered antiviral genes and inflammatory cytokines production by targeting TANK-binding kinase 1 (TBK1), thereby accelerating viral replication. Importantly, we found that miR-15b feedback regulates antiviral innate immune response through NF-κB and IRF3 signaling pathways. These findings highlight that miR-15b plays a crucial role in regulating virus–host interactions, which outlines a new regulation mechanism of fish’s innate immune responses.

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Host Innate Immune Responses to Acinetobacter baumannii Infection

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2020.00486 ◽

2020 ◽

Vol 10 ◽

Author(s):

Wangxue Chen

Keyword(s):

Immune Responses ◽

Acinetobacter Baumannii ◽

Innate Immune ◽

Innate Immune Responses

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Anti-multidrug-resistant Acinetobacter baumannii activity of DS-8587: In vitro activity and in vivo efficacy in a murine calf muscle infection model

Journal of Infection and Chemotherapy ◽

10.1016/j.jiac.2014.01.011 ◽

2014 ◽

Vol 20 (5) ◽

pp. 312-316 ◽

Cited By ~ 4

Author(s):

Saito Higuchi ◽

Yuichi Kurosaka ◽

Saori Uoyama ◽

Kumi Yoshida ◽

Megumi Chiba ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Multidrug Resistant ◽

Calf Muscle ◽

Vitro Activity ◽

Infection Model ◽

In Vitro Activity ◽

In Vivo Efficacy ◽

Muscle Infection

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Investigation of Novel pmrB and eptA Mutations in Isogenic Acinetobacter baumannii Isolates Associated with Colistin Resistance and Increased Virulence In Vivo

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01586-18 ◽

2019 ◽

Vol 63 (3) ◽

Cited By ~ 18

Author(s):

Stefanie Gerson ◽

Jonathan W. Betts ◽

Kai Lucaßen ◽

Carolina Silva Nodari ◽

Julia Wille ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Lipid A ◽

Galleria Mellonella ◽

Resistance Mechanism ◽

Resistant Isolate ◽

Infection Model ◽

Colistin Resistance ◽

Strain Specificity ◽

Content Type

ABSTRACT Colistin resistance in Acinetobacter baumannii is of great concern and is a threat to human health. In this study, we investigate the mechanisms of colistin resistance in four isogenic pairs of A. baumannii isolates displaying an increase in colistin MICs. A mutation in pmrB was detected in each colistin-resistant isolate, three of which were novel (A28V, I232T, and ΔL9-G12). Increased expression of pmrC was shown by semi-quantitative reverse transcription-PCR (qRT-PCR) for three colistin-resistant isolates, and the addition of phosphoethanolamine (PEtN) to lipid A by PmrC was revealed by mass spectrometry. Interestingly, PEtN addition was also observed in some colistin-susceptible isolates, indicating that this resistance mechanism might be strain specific and that other factors could contribute to colistin resistance. Furthermore, the introduction of pmrAB carrying the short amino acid deletion ΔL9-G12 into a pmrAB knockout strain resulted in increased pmrC expression and lipid A modification, but colistin MICs remained unchanged, further supporting the strain specificity of this colistin resistance mechanism. Of note, a mutation in the pmrC homologue eptA and a point mutation in ISAba1 upstream of eptA were associated with colistin resistance and increased eptA expression, which is a hitherto undescribed resistance mechanism. Moreover, no cost of fitness was observed for colistin-resistant isolates, while the virulence of these isolates was increased in a Galleria mellonella infection model. Although the mutations in pmrB were associated with colistin resistance, PEtN addition appears not to be the sole factor leading to colistin resistance, indicating that the mechanism of colistin resistance is far more complex than previously suspected and is potentially strain specific.

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