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Updated: Mar 19, 2026
A Non-invasive and Technically Non-intensive Method for Induction and Phenotyping of Experimental Bacterial Pneumonia in Mice
Published on: September 28, 2016
Inducible epithelial resistance protects mice against leukemia-associated pneumonia
Miguel M Leiva-Juárez1, Hayden H Ware1, Vikram V Kulkarni1
1Division of Internal Medicine, Department of Pulmonary Medicine, and.
Abstract:
Despite widespread infection prevention efforts, pneumonia remains the leading cause of death among patients with acute leukemia, due to complex disease- and treatment-dependent immune defects. We have reported that a single inhaled treatment with a synergistic combination of Toll-like receptor 2/6 (TLR 2/6) and TLR9 agonists (Pam2-ODN) induces protective mucosal defenses in mice against a broad range of pathogens. As Pam2-ODN-induced protection persists despite depletion of several leukocyte populations, we tested whether it could prevent pneumonia in a mouse model of acute myeloid leukemia (AML) remission induction therapy. Pam2-ODN prevented death due to pneumonia caused by Pseudomonas aeruginosa, Streptococcus pneumoniae, and Aspergillus fumigatus when mice were heavily engrafted with leukemia cells, had severe chemotherapy-induced neutropenia or both. Pam2-ODN also extended survival of pneumonia in NSG mice engrafted with primary human AML cells. Protection was associated with rapid pathogen killing in the lungs at the time of infection and with reduced pathogen burdens at distant sites at the end of observation. Pathogen killing was inducible directly from isolated lung epithelial cells and was not abrogated by the presence of leukemia cells or cytotoxic agents. Pam2-ODN had no discernible effect on replication rate, total tumor population, or killing by chemotherapy of mouse or human leukemia cells, either in vitro or in vivo. Taken together, we report that therapeutic stimulation of lung epithelial defenses robustly protects against otherwise lethal pneumonias despite the profound immune dysfunction associated with acute leukemia and its treatment. These findings may suggest an opportunity to protect this population during periods of peak vulnerability.
Insights
A novel inhaled therapy, Pam2-ODN, stimulates lung defenses to prevent lethal pneumonia in acute myeloid leukemia (AML) patients undergoing chemotherapy. This approach offers protection against diverse pathogens despite immune suppression.
Area of Science:
- Immunology
- Infectious Diseases
- Hematology
Background:
- Pneumonia is the leading cause of death in acute leukemia patients due to immune defects from disease and treatment.
- Existing infection prevention strategies are insufficient for this vulnerable population.
- Toll-like receptor (TLR) agonists can induce protective mucosal immunity.
Purpose of the Study:
- To evaluate the efficacy of inhaled Pam2-ODN (TLR 2/6 and TLR9 agonists) in preventing pneumonia in a mouse model of acute myeloid leukemia (AML).
- To determine if Pam2-ODN protects against common pneumonia-causing pathogens (Pseudomonas aeruginosa, Streptococcus pneumoniae, Aspergillus fumigatus) during chemotherapy-induced immunosuppression.
Main Methods:
- Mice with AML were treated with inhaled Pam2-ODN during remission induction therapy.
- Protection was assessed against lethal challenge with P. aeruginosa, S. pneumoniae, and A. fumigatus.
- Pam2-ODN's effect on pathogen burden, lung epithelial cell function, and leukemia cell viability was analyzed in vitro and in vivo.
Main Results:
- Inhaled Pam2-ODN significantly prevented death from pneumonia in AML mice, even with severe neutropenia or high leukemia burden.
- Protection was associated with rapid pathogen killing in the lungs and reduced pathogen loads at distant sites.
- Pam2-ODN-induced pathogen killing was mediated by lung epithelial cells and was independent of leukemia cells or chemotherapy.
Conclusions:
- Therapeutic stimulation of lung epithelial defenses with Pam2-ODN provides robust protection against lethal pneumonias in the context of acute leukemia and its treatment.
- This approach may offer a novel strategy to protect immunocompromised leukemia patients during periods of high vulnerability.
- Pam2-ODN did not negatively impact leukemia cell replication or chemotherapy efficacy.
