Aging exacerbates mortality of Acinetobacter baumannii pneumonia and reduces the efficacies of antibiotics and vaccine

Gu, Hao; Liu, Dong; Zeng, Xi; Li, Peng; Yuan, Yue; Chen, Zhi-Fu; Zou, Quanming; Shi, Yun

doi:10.18632/aging.101495

Cited by 17 publications

(25 citation statements)

References 38 publications

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“…Also, the neutrophil depletion studies demonstrated an important pathogenic role for these cells during A. baumannii systemic infection (19). Our previous work showed that neutrophil infiltration with defective bacterial killing function contribute to the severe pneumonia in aged mice (16). The complex role of neutrophil in response to A. baumannii infection may be different in non-lethal model vs. lethal model, or in different stages of lethal infection, which needs further study.…”

Section: Discussionmentioning

confidence: 99%

“…WT and Rag1 −/− mice were infected with A. baumannii as previously described (16). Briefly, Mice were intraperitoneally anesthetized with pentobarbital sodium (62.5 mg/kg) and then non-invasive intratracheally inoculated with different dose (2.5 × 10 6 CFU, 5 × 10 6 CFU, and 2 × 10 7 CFU) of A. baumannii in 20 µl PBS.…”

Section: Mouse Pneumonia Modelmentioning

confidence: 99%

“…Total RNA was extracted using RNAiso Plus (Takara) and reverse transcribed to cDNA using PrimeScript TM RT reagent Kit (Takara). The mRNA expression was detected using SYBR green Premix (Takara) with specific primers described previously (16). Real-time PCR reactions were performed on CFX96 (Bio-Rad).…”

Section: Real-time Pcrmentioning

confidence: 99%

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Transcriptome Profiling of Lung Innate Immune Responses Potentially Associated With the Pathogenesis of Acinetobacter baumannii Acute Lethal Pneumonia

Zeng

et al. 2020

Front. Immunol.

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Acinetobacter baumannii is one of the dominating causes of nosocomial pneumonia, however, very little is known about the host immune response associated with pathogenesis of A. baumannii infection. Here, we used a hypervirulent A. baumannii to establish an acute lethal pneumonia, supported by high bacterial burdens, severe inflammatory cells infiltration and lung damage. The lung transcriptome changes in response to A. baumannii lethal pneumonia were detected by RNA sequencing. The results showed that 6,288 host genes changed expression, with 3,313 upregulated genes and 2,975 downregulated genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that genes related to TNF, cytokine-cytokine receptor interaction, Toll-like receptor, NOD-like receptor, NF-κB, Jak-STAT, HIF-1 signaling pathways, apoptosis, and phagosome were significantly upregulated. Whereas, genes associated with PI3K-AKT signaling pathway, glycolysis/gluconeogenesis, amino acid and fatty acid metabolism were downregulated. Immune cell typing highlighted the inflammatory response of innate immune cells headed by neutrophils. The reliability of RNA sequencing results were verified with selected differentially expressed genes by real-time PCR. This work provides an insight into the pathogenesis of lethal A. baumannii lung infection.

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Section: Discussionmentioning

confidence: 99%

Section: Mouse Pneumonia Modelmentioning

confidence: 99%

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Transcriptome Profiling of Lung Innate Immune Responses Potentially Associated With the Pathogenesis of Acinetobacter baumannii Acute Lethal Pneumonia

Zeng

et al. 2020

Front. Immunol.

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“…We have established a pneumonia model as described previously [ 25 ]. In brief, mice ( n = 5) were anesthetized with pentobarbital sodium (62.5 mg/kg of body weight) [ 26 ] and then challenged with an appropriate dose of different strains of K. pneumoniae in a 20 μ l volume through noninvasive intratracheal inoculation. Mice were monitored for 7 days for survival rate and body weight.…”

Section: Methodsmentioning

confidence: 99%

Innate Immune Effectors Play Essential Roles in Acute Respiratory Infection Caused by Klebsiella pneumoniae

Liu

Chen

Yuan

et al. 2020

Journal of Immunology Research

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Innate immune effectors constitute the first line of host defense against pathogens. However, the roles of these effectors are not clearly defined during Klebsiella pneumoniae (K. pneumoniae) respiratory infection. In the current study, we established an acute pneumonia model of K. pneumoniae respiratory infection in mice and confirmed that the injury was most severe 48 h post infection. Flow cytometric assay demonstrated that alveolar macrophages were the predominant cells in BALF before infection, and neutrophils were quickly recruited after infection, and this was in consistent with the kinetics of chemokine expression. Further, we depleted neutrophils, macrophages, and complement pathways in vivo and challenged these mice with a sublethal dose of K. pneumonia, the result showed that 80%, 60%, and 40% of mice were died in these groups, respectively, while no deaths occurred in the control group. Besides, innate immune effector depleted mice showed higher bacterial burdens in lungs and blood, companied with more severe lung damage and increased levels of cytokine/chemokine expression. These results demonstrated that the innate immune effectors are critical in the early controlling of K. pneumoniae infection, and neutrophils are the most important. Thus, alternative strategies targeting these innate immune effectors may be effective in controlling of K. pneumoniae respiratory infection.

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“…Their immune status is difficult to assess with current diagnostic methods but it predisposes for infections and antibiotic therapy. A study on A. baumannii pneumonia in aged mice illustrates that mortality increases with age, while efficacies of treatment, both antibiotics and vaccination, decrease because both rely on functional immune responses (79). Similarly, the human vaccine response is compromised by the immunodeficiencies caused by aging of the immune system [reviewed in (80,81)].…”

Section: Consequences For Design Of Efficacy Studiesmentioning

confidence: 99%

Challenges for Clinical Development of Vaccines for Prevention of Hospital-Acquired Bacterial Infections

Bekeredjian‐Ding

2020

Front. Immunol.

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Increasing antibiotic resistance in bacteria causing endogenous infections has entailed a need for innovative approaches to therapy and prophylaxis of these infections and raised a new interest in vaccines for prevention of colonization and infection by typically antibiotic resistant pathogens. Nevertheless, there has been a long history of failures in late stage clinical development of this type of vaccines, which remains not fully understood. This article provides an overview on present and past vaccine developments targeting nosocomial bacterial pathogens; it further highlights the specific challenges associated with demonstrating clinical efficacy of these vaccines and the facts to be considered in future study designs. Notably, these vaccines are mainly applied to subjects with preexistent immunity to the target pathogen, transient or chronic immunosuppression and ill-defined microbiome status. Unpredictable attack rates and changing epidemiology as well as highly variable genetic and immunological strain characteristics complicate the development. In views of the clinical need, rethinking of the study designs and expectations seems warranted: first of all, vaccine development needs to be footed on a clear rationale for choosing the immunological mechanism of action and the optimal time point for vaccination, e.g., (1) prevention (or reduction) of colonization vs. prevention of infection and (2) boosting of a preexistent immune response vs. altering the quality of the immune response. Furthermore, there are different, probably redundant, immunological and microbiological defense mechanisms that provide protection from infection. Their interplay is not well-understood but as a consequence their effect might superimpose vaccine-mediated resolution of infection and lead to failure to demonstrate efficacy. This implies that improved characterization of patient subpopulations within the trial population should be obtained by pro-and retrospective analyses of trial data on subject level. Statistical and systems biology approaches could help to define immune and microbiological biomarkers that discern populations that benefit from vaccination from those where vaccines might not be effective.

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Aging exacerbates mortality of Acinetobacter baumannii pneumonia and reduces the efficacies of antibiotics and vaccine

Cited by 17 publications

References 38 publications

Transcriptome Profiling of Lung Innate Immune Responses Potentially Associated With the Pathogenesis of Acinetobacter baumannii Acute Lethal Pneumonia

Transcriptome Profiling of Lung Innate Immune Responses Potentially Associated With the Pathogenesis of Acinetobacter baumannii Acute Lethal Pneumonia

Innate Immune Effectors Play Essential Roles in Acute Respiratory Infection Caused by Klebsiella pneumoniae

Challenges for Clinical Development of Vaccines for Prevention of Hospital-Acquired Bacterial Infections

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