Vaccination induces rapid protection against bacterial pneumonia via training alveolar macrophage in mice

Zhang, Yiqiang; Zeng, Xi; Peng, Liu-sheng; Xiang, Chuanying; Zhou, Yangyang; Zhang, Xiaomin; Zhang, Jixin; Wang, Ning; Guo, Gang; Li, Yan; Liu, Kaiyun; Gu, Jiang; Zeng, Hao; Zhuang, Yuan; Li, Haibo; Zhang, Jinyong; Zhang, Wei; Zou, Quanming; Shi, Yun Q.

doi:10.7554/elife.69951

Cited by 10 publications

(3 citation statements)

References 34 publications

(43 reference statements)

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“…A number of recent studies investigated how prior viral infection alters AM function, uncovering either enhanced AM antimicrobial phenotypes 9, 10, 11 or impaired responses 48, 49 following exposure. Other studies have discovered long-lasting changes to AMs following intranasal immunization of either adenoviral-based or inactivated whole cell vaccines 20, 50, 51 . Several reports have identified T cell-derived IFNγ as critical for altering AM function, although the immunological outcome varies substantially based on the context.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterial exposure remodels alveolar macrophages and the early innate response to Mycobacterium tuberculosis infection

Mai

Jahn

Murray

et al. 2022

Preprint

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As innate sentinels in the lung, alveolar macrophages (AMs) play a critical role during Mycobacterium tuberculosis (Mtb) infection as the first cells to encounter bacteria. We previously showed that AMs initially respond to Mtb infection in vivo by mounting a cell-protective, rather than pro-inflammatory response, yet whether the AM response could be modified by environmental factors was unknown. Here, we characterize how previous exposure to mycobacteria, either through subcutaneous vaccination with Mycobacterium bovis (scBCG) or through a contained Mtb infection (coMtb), impacts the initial response by AMs and early innate response in the lung. We find that both scBCG and coMtb accelerate early innate cell activation and recruitment and generate a stronger pro-inflammatory AM response to Mtb in vivo. AMs from scBCG vaccinated mice mount a robust interferon response, while AMs from coMtb mice produce a broader and more diverse inflammatory response. Using single-cell RNA-sequencing, we identify exposure-induced changes to airway-resident cells, with scBCG and coMtb enriching for different AM subpopulations. Ex vivo stimulation assays reveal that AMs from scBCG and coMtb mice switch on an interferon-dependent response, which is absent in AMs from unexposed mice. Overall, our studies reveal significant, durable, and cell-intrinsic modifications to AMs following exposure to mycobacterium, and comparison of scBCG and coMtb models reveals that AMs can be reprogrammed into more than one state. These findings highlight the plasticity of innate responses in the airway and underscore the unexplored potential of targeting AMs through vaccination or host-directed therapy to augment host responses.

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Section: Discussionmentioning

confidence: 99%

Mycobacterial exposure remodels alveolar macrophages and the early innate response to Mycobacterium tuberculosis infection

Mai

Jahn

Murray

et al. 2022

Preprint

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“…Several reports have established the critical role of AMs during A. baumannii respiratory infections (Gu et al, 2021;H. Qiu et al, 2012;Tsay et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

ReplicativeAcinetobacter baumanniistrains interfere with phagosomal maturation by modulating the vacuolar pH

Distel

Venanzio

Mackel

et al. 2023

Preprint

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Bacterial pneumonia is a common infection of the lower respiratory tract that can afflict patients of all ages. Multidrug-resistant strains of Acinetobacter baumannii are increasingly responsible for causing nosocomial pneumonias, thus posing an urgent threat. Alveolar macrophages play a critical role in overcoming respiratory infections caused by this pathogen. Recently, we and others have shown that new clinical isolates of A. baumannii, but not the common lab strain ATCC 19606 (19606), can persist and replicate in macrophages within spacious vacuoles that we called Acinetobacter Containing Vacuoles (ACV). In this work, we demonstrate that the modern A. baumannii clinical isolate 398, but not the lab strain 19606, can infect alveolar macrophages and produce ACVs in vivo in a murine pneumonia model. Both strains initially interact with the alveolar macrophage endocytic pathway, as indicated by EEA1 and LAMP1 markers; however, the fate of these strains diverges at a later stage. While 19606 is eliminated in an autophagy pathway, 398 replicates in ACVs and are not degraded. We show that 398 reverts the natural acidification of the phagosome by secreting large amounts of ammonia, a by-product of amino acid catabolism. We propose that this ability to survive within macrophages may be critical for the persistence of clinical A. baumannii isolates in the lung during a respiratory infection.

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“…Recent studies demonstrated that long-lived, self-renewing cells are involved in the onset of trained immunity and, indeed, participate in long-lasting protection against pathogens. For example, alveolar macrophages are able to replenish populations of tissue-resident macrophages in the lungs independently of bone marrow (BM)-derived monocytes and were shown to offer cross-protection against lung pathogens after an initial intranasal challenge with Acinetobacter baumannii (23,24). However, the duration and extent of the unspecific peripheral protection in vivo (which is measured in years) is poorly compatible with the average lifespan of human monocytes (5 to 7 days), suggesting that other long-lived cells, such as hematopoietic stem and progenitor cells (HSPCs, with lifespans ranging from 10 to 60 months), might be involved in this phenomenon (25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

Train the Trainer: Hematopoietic Stem Cell Control of Trained Immunity

Zuani

Fric

2022

Front. Immunol.

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Recent evidence shows that innate immune cells, in addition to B and T cells, can retain immunological memory of their encounters and afford long-term resistance against infections in a process known as ‘trained immunity’. However, the duration of the unspecific protection observed in vivo is poorly compatible with the average lifespan of innate immune cells, suggesting the involvement of long-lived cells. Accordingly, recent studies demonstrate that hematopoietic stem and progenitor cells (HSPCs) lay at the foundation of trained immunity, retaining immunological memory of infections and giving rise to a “trained” myeloid progeny for a long time. In this review, we discuss the research demonstrating the involvement of HSPCs in the onset of long-lasting trained immunity. We highlight the roles of specific cytokines and Toll-like receptor ligands in influencing HSPC memory phenotypes and the molecular mechanisms underlying trained immunity HSPCs. Finally, we discuss the potential benefits and drawbacks of the long-lasting trained immune responses, and describe the challenges that the field is facing.

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Vaccination induces rapid protection against bacterial pneumonia via training alveolar macrophage in mice

Cited by 10 publications

References 34 publications

Mycobacterial exposure remodels alveolar macrophages and the early innate response to Mycobacterium tuberculosis infection

Mycobacterial exposure remodels alveolar macrophages and the early innate response to Mycobacterium tuberculosis infection

ReplicativeAcinetobacter baumanniistrains interfere with phagosomal maturation by modulating the vacuolar pH

Train the Trainer: Hematopoietic Stem Cell Control of Trained Immunity

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