Staphylococcus aureus is the leading cause of skin infections that presents to the emergency department. With the advent of methicillin resistant strains, outbreaks of community-acquired methicillin- resistant S. aureus (CA-MRSA) pneumonia have emerged as a very possible threat. The incidence of CA- MRSA has been increasing and presently at about 20 per 100,000 pneumonia cases. Although many factors of S. aureus virulence have been extensively studied, the mechanisms of human host defense against this pathogen have yet to be fully characterized. However alcohol abuse leads to susceptibility to multiple pulmonary bacterial infections. We have found that administration of alcohol 30 minutes lead to decreased pulmonary clearance of MRSA at 20 hours in mice. With acute alcohol, proinflammatory cytokine interleukin 22 (IL-22) was increased however, IL-22 inducible antimicrobial protein Reg3y was not increased proportionally. Acute alcohol intoxication has been shown to increase expression of Suppressor of Cytokine Signaling (SOCS) 1 and 3, which ultimately inhibit Signal Transducer and Activator of Transcription 3 (STAT3) signaling. Therefore we hypothesize that acute alcohol intoxication suppresses STAT3 signaling needed for IL-22 induction of Reg3y leading to increased pulmonary MRSA susceptibility. In support of this hypothesis, Reg3y inhibits MRSA growth in vitro and Hyper IgE Syndrome (HIES) patients are susceptible to recurrent S. aureus skin and pulmonary infections as a result of mutations in STAT3. To test our hypothesis that alcohol inhibits IL-22/STAT3 induction of Reg3y that is critical for MRSA pneumonia, we will observe bacterial burden, STAT3 activation and signaling, within cell cultures and after MRSA oropharyngeal aspiration in an acute alcohol mouse model.

Public Health Relevance

With the advent of methicillin resistant strains, outbreaks of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) pneumonia in young previously healthy individuals have increased. Although many factors of S. aureus virulence have been extensively studied, the mechanisms of human host defense against this pathogen have yet to be fully characterized. Acute alcohol intoxication seems to impede lung epithelial production of antimicrobial protein, Reg3y, by IL-22 and STAT3 signaling in mice. In order to enhance immune-based therapies for the future treatment of alcohol-related MRSA pneumonia patients, it has become essential to more comprehensively describe the host immune response to Staphylococcus pneumonia.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AA021061-03
Application #
8520122
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Jung, Kathy
Project Start
2011-09-12
Project End
2014-09-11
Budget Start
2013-09-12
Budget End
2014-09-11
Support Year
3
Fiscal Year
2013
Total Cost
$47,232
Indirect Cost
Name
Louisiana State Univ Hsc New Orleans
Department
Genetics
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112