Acute lower respiratory tract (LRT) infections are a leading cause of global mortality and morbidity. Currently, pneumonia accounts for the largest number of Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) patients. Successful clearance of pathogens from the LRT is dependent on effective innate immune responses. Understanding the innate defense mechanisms in the LRT is critical for the development of novel immunotherapeutics or vaccines to reduce this burden of disease. The signaling cascades triggering innate immune responses consist of a delicate balance between pro- inflammatory responses that facilitate pathogen clearance, and counteracting anti-inflammatory responses that control excessive systemic inflammation. It is poorly understood how these signaling cascades converge to control host defense while minimizing inflammatory tissue injury. As a model to elucidate the basic host defense mechanisms, we have focused on a primary pathogen, Klebsiella pneumoniae because this extracellular Gram-negative bacterium causes severe pneumonia; and multiple drug-resistant and hypervirulent variants have emerged. Our new preliminary data support a novel role for neutrophil-derived IL-1? as a major regulator of immunity to Klebsiella pneumonia. We show that: (1) human lungs with bacterial pneumonia display higher IL-1? expression by neutrophils; (2) human and mouse neutrophils show elevated IL-1? production following K. pneumoniae infection; (3) both caspase-1 and -11 activation by K. pneumoniae are essential for IL-1? production by neutrophils; (4) human and mouse neutrophils produce IL-17A during bacterial infection in an IL-1? dependent manner; (5) IL-1? but not IL-1? or IL-18 is important for survival in response to K. pneumoniae infection; and (6) neutrophil depletion greatly reduces IL-1? but not IL-18 or IL-1?ni the lungs after K. pneumoniae challenge. These observations have led us to hypothesize that neutrophil-derived IL-1? is a key defense mechanism that regulates immunity via modulating IL-17 production. Little is known regarding the role of neutrophil- derived IL-1? in bacterial pneumonia.
The Aims are: (1) Delineate the in vivo mechanisms that modulate IL-1? production and neutrophil function during Klebsiella pneumonia; (2) Determine the effects of neutrophil-derived IL-1? on IL-17A and IL-17F responses to bacterial pneumonia; and (3) Determine if manipulation of neutrophil-derived IL-1? expression can alter host resistance during Klebsiella pneumonia. A unique combination of in vivo and in vitro systems, including KO mice, lentiviral transduction and adoptive transfer strategies will be employed to address these aims. This is a conceptually, technically and translationally innovative proposal that will establish a paradigm shift in the way researchers and clinicians think about bacterial pneumonia and ultimately lead to improved therapeutic and prevention strategies of the treatment of bacterial pneumonia.
Lower respiratory tract infections (LRTIs) remain a major cause of mortality and morbidity worldwide. As projected by the WHO, LRTIs, mainly pneumonia, should be in 2030 one of the four leading causes of death in adults. Pneumonia is the single largest cause of death in children worldwide. Pneumonia accounts for the largest number of Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) patients. LRTIs are also an important cause of sepsis and acute exacerbations of COPD. How the innate immune system senses pathogens and induces protective responses is a prerequisite for the design of novel immunotherapeutics and vaccines. The long-term goal of this research is to understand how multiple innate immune events are integrated into effective antimicrobial resistance while minimizing excessive tissue damage. The objective of the translational investigation is to dissect molecular mechanisms that augment host defense while minimizing extensive tissue/organ damage during infectious inflammation.
