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Multi Drug Resistant Acinetobacter Baumannii Adapt to the Lung by Suppressing Inflammasome Activation
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A4702 - Multi Drug Resistant Acinetobacter Baumannii Adapt to the Lung by Suppressing Inflammasome Activation
Author Block: S. Gill, A. S. Prince, A. Uhlemann; Columbia University, New York, NY, United States.
Multi Drug Resistant Acinetobacter baumannii adapt to the lung by suppressing inflammasome activation.
Simren K. Gill1, Medini Annavajhal2, Phuc Vo1, Anne-Catrin Uhlemann2 and Alice Prince1.
1 Department of Pediatrics1 and Medicine2, Columbia University, New York, New York, USA.
Funding - NIH R35HL135800-01
The ESKAPE pathogens and particularly Acinetobacter baumannii are a major cause of morbidity and mortality in the ICU. Pneumonia due to these genetically flexible pathogens is complicated by their intrinsic and acquired resistance to antibiotics, as well as by the failure of innate immune clearance mechanisms. We postulated that genetic adaptation to the human airway by host-adapted A.baumannii results in failure to activate proinflammatory responses in the airway necessary to clear infection. We compared whole genome sequences, susceptibility to phagocytic killing, metabolic profiles and pulmonary clearance in a murine model of pneumonia of a typical MDR clinical isolate, NR0105 and a reference strain, ATCC 19606. Using a Seahorse analyzer, we found that that MDR A. baumannii NR0105 did not activate glycolysis in either airway epithelial and THP1 cells, a response that correlated with attenuated inflammasome activation and significantly decreased release of IL-1β. Uptake and killing of NR0105 by a THP-1 monocyte/macrophage cell line was also significantly impaired compared to the reference strain. In vivo, NR0105 was able to persist and replicate in the lungs by almost two logs more that the reference strain over the first 48 hours of infection. There was also a delay in the induction of proinflammatory cytokines including IL-1β over the initial stages of infection, a delayed response compared to ATCC 19606, which normalized after 48 hours. Our studies suggest that in addition to the acquisition of genetic elements that promote antimicrobial resistance, MDR A. baumannii also accrue a substantial number of genetic changes enabling them to adapt to the metabolic constraints of the airway and promoting evasion of inflammasome activation through multiple mechanisms.
Author Block: S. Gill, A. S. Prince, A. Uhlemann; Columbia University, New York, NY, United States.
Multi Drug Resistant Acinetobacter baumannii adapt to the lung by suppressing inflammasome activation.
Simren K. Gill1, Medini Annavajhal2, Phuc Vo1, Anne-Catrin Uhlemann2 and Alice Prince1.
1 Department of Pediatrics1 and Medicine2, Columbia University, New York, New York, USA.
Funding - NIH R35HL135800-01
The ESKAPE pathogens and particularly Acinetobacter baumannii are a major cause of morbidity and mortality in the ICU. Pneumonia due to these genetically flexible pathogens is complicated by their intrinsic and acquired resistance to antibiotics, as well as by the failure of innate immune clearance mechanisms. We postulated that genetic adaptation to the human airway by host-adapted A.baumannii results in failure to activate proinflammatory responses in the airway necessary to clear infection. We compared whole genome sequences, susceptibility to phagocytic killing, metabolic profiles and pulmonary clearance in a murine model of pneumonia of a typical MDR clinical isolate, NR0105 and a reference strain, ATCC 19606. Using a Seahorse analyzer, we found that that MDR A. baumannii NR0105 did not activate glycolysis in either airway epithelial and THP1 cells, a response that correlated with attenuated inflammasome activation and significantly decreased release of IL-1β. Uptake and killing of NR0105 by a THP-1 monocyte/macrophage cell line was also significantly impaired compared to the reference strain. In vivo, NR0105 was able to persist and replicate in the lungs by almost two logs more that the reference strain over the first 48 hours of infection. There was also a delay in the induction of proinflammatory cytokines including IL-1β over the initial stages of infection, a delayed response compared to ATCC 19606, which normalized after 48 hours. Our studies suggest that in addition to the acquisition of genetic elements that promote antimicrobial resistance, MDR A. baumannii also accrue a substantial number of genetic changes enabling them to adapt to the metabolic constraints of the airway and promoting evasion of inflammasome activation through multiple mechanisms.
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