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

Abstract

Vaccination strategies for rapid protection against multidrug-resistant bacterial infection are very important, especially for hospitalized patients who have high risk of exposure to these bacteria. However, few such vaccination strategies exist due to a shortage of knowledge supporting their rapid effect. Here, we demonstrated that a single intranasal immunization of inactivated whole cell of Acinetobacter baumannii elicits rapid protection against broad A. baumannii-infected pneumonia via training of innate immune response in Rag1-/- mice. Immunization-trained alveolar macrophages (AMs) showed enhanced TNF-α production upon restimulation. Adoptive transfer of immunization-trained AMs into naive mice mediated rapid protection against infection. Elevated TLR4 expression on vaccination-trained AMs contributed to rapid protection. Moreover, immunization-induced rapid protection was also seen in Pseudomonas aeruginosa and Klebsiella pneumoniae pneumonia models, but not in Staphylococcus aureus and Streptococcus pneumoniae model. Our data reveal that a single intranasal immunization induces rapid and efficient protection against certain Gram-negative bacterial pneumonia via training AMs response, which highlights the importance and the possibility of harnessing trained immunity of AMs to design rapid-effecting vaccine.

Neutrophil and Macrophage Response in Acinetobacter Baumannii Infection and Their Relationship to Lung Injury

“…After 24 h, the number of macrophages increased significantly at the site of infection ( Qiu et al., 2012 ; Harris et al., 2019 ; Zeng et al., 2019 ). At the same time, macrophages act as antigen-presenting cells and increase the expression of the costimulatory ligands, CD80 and CD86 on their surface, thus initiating and regulating T cell immunity ( Bhatia et al., 2006 ; Gu et al., 2021 ). Macrophages play direct and indirect roles in controlling AB infection and have an impact on subsequent immune responses.…”

“…Bacterial components of AB, including outer membrane protein A (OmpA), outer membrane vesicles (OMVs), and lipopolysaccharide (LPS), are involved in the pathogenesis and induction of the host immune response during infection. AB exhibits significant genetic plasticity and natural genetic transformation contributes to the acquisition of genetic elements, which causes antibiotic resistance in AB and causes it to evolve and pass it on from generation to generation ( Pires and Parker, 2019 ; Gu et al., 2021 ). Currently, the treatment of MDR ABs is mainly based on the combination of two or more antibiotics.…”

“…The current immunotherapy strategy is to induce immune memory by stimulating adaptive immunity to establish a rapid and specific immune response after real infection. This method requires multiple vaccine injections every few weeks or months ( Gu et al., 2021 ). However, the window of AB infection in hospitalized patients cannot meet the time required by the adaptive immunity strategy.…”

“…Therefore, the study of the early successful immune response after AB infection provides a key basis for timing and methods of artificial immune intervention. Innate immunity has, thus, become a target for new therapeutic measures ( Gu et al., 2021 ). This article reviews the changes and mechanisms of macrophages and neutrophils in response to AB infection, combined with the progress of lung injury in the interaction between infection and immunity, to take appropriate immune measures, control infection early, reduce lung injury, and improve prognosis.…”

Train the Trainer: Hematopoietic Stem Cell Control of Trained Immunity

“…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).…”