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Protection from pneumonic infection with burkholderia species by inhalational immunotherapy
Andrew Goodyear1, Lisa Kellihan, Helle Bielefeldt-Ohmann
1Department of Microbiology, Immunology and Pathology, Colorado State University, Ft. Collins, CO 80523, USA.
Abstract:
Burkholderia mallei and B. pseudomallei are important human pathogens and cause the diseases glanders and melioidosis, respectively. Both organisms are highly infectious when inhaled and are inherently resistant to many antimicrobials, thus making it difficult to treat pneumonic Burkholderia infections. We investigated whether it was possible to achieve rapid protection against inhaled Burkholderia infection by using inhaled immunotherapy. For this purpose, cationic liposome DNA complexes (CLDC), which are potent activators of innate immunity, were used to elicit the activation of pulmonary innate immune responses. We found that mucosal CLDC administration before or shortly after bacterial challenge could generate complete or nearly complete protection from inhalational challenge with 100% lethal doses of B. mallei and B. pseudomallei. Protection was found to be dependent on the CLDC-mediated induction of gamma interferon responses in lung tissues and was partially dependent on the activation of NK cells. However, CLDC-mediated protection was not dependent on the induction of inducible nitric oxide synthase, as assessed by depletion studies. We concluded that the potent local activation of innate immune responses in the lung could be used to elicit rapid and nonspecific protection from aerosol exposure to both B. mallei and B. pseudomallei.
Insights
Inhaled immunotherapy using cationic liposome DNA complexes (CLDC) rapidly protected against lethal Burkholderia infections. This approach activates innate immunity in the lungs, offering a novel strategy for preventing inhalational bacterial diseases.
Area of Science:
- Immunology
- Infectious Diseases
- Bacteriology
Background:
- Burkholderia mallei and B. pseudomallei cause glanders and melioidosis, respectively.
- These pathogens are highly infectious via inhalation and resistant to antimicrobials, complicating pneumonia treatment.
- Effective treatments for pneumonic Burkholderia infections are urgently needed.
Purpose of the Study:
- To investigate inhaled immunotherapy for rapid protection against inhaled Burkholderia species.
- To evaluate the efficacy of cationic liposome DNA complexes (CLDC) in activating pulmonary innate immunity.
- To determine the mechanisms underlying CLDC-mediated protection.
Main Methods:
- Administration of CLDC via mucosal inhalation before or after bacterial challenge.
- Inhalational challenge with 100% lethal doses of B. mallei and B. pseudomallei.
- Assessment of protection, gamma interferon induction, NK cell activation, and inducible nitric oxide synthase (iNOS) activity.
Main Results:
- Mucosal CLDC administration provided complete or near-complete protection against lethal inhalational B. mallei and B. pseudomallei.
- Protection was dependent on CLDC-induced gamma interferon and partially on NK cell activation.
- CLDC-mediated protection was independent of inducible nitric oxide synthase.
Conclusions:
- Inhaled immunotherapy with CLDC can rapidly induce nonspecific protection against B. mallei and B. pseudomallei.
- Potent local activation of innate immune responses in the lung is key to this protection.
- This strategy offers a promising approach for preventing infections from aerosolized Burkholderia pathogens.
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