Many infectious diseases exhibit differential severity between the sexes yet the mechanisms driving such innate biases are incompletely understood. Staphylococcus aureus (SA), including methicillin-resistant (MRSA), is the most common cause of skin and soft tissue infection (SSTI) in the US, and males have a greater than 2-fold higher incidence of infection versus females. Neutrophils are essential for clearance of SA skin infections, and we found that, consistent with murine infection outcomes, neutrophils from female mice are better able to clear SA ex vivo compared to neutrophils from male mice. Major contributors to neutrophil killing of SA include oxidative burst, antimicrobial factors in neutrophil granules, and neutrophil extracellular traps (NET). Therefore, in this exploratory proposal, we aim to align the efficacy of neutrophil phagocytosis and killing of SA ex vivo with measurements of reactive oxygen species (ROS) and nitric oxide (NO) production, NET formation, and changes in gene and protein expression and activation, to define the mechanism(s) of sex-specific phagocyte efficacy against SA. Furthermore, we have identified sex-specific modulators which enhance phagocyte efficacy and will determine the mechanisms by which these modulators augment innate defense. Upon the successful completion of these aims, we will have gained significant insight into the mechanisms of sex-specific phagocyte efficacy against SA, as well as mechanisms and/or targets for augmenting host innate defense.

Public Health Relevance

Females are innately resistant to many infectious diseases, including skin infections caused by Staphylococcus aureus (SA). Neutrophils are essential for clearing SA infections, and, in animal models, neutrophils from females are more effective killers of SA compared to those from males. We aim to determine the molecular mechanism(s) driving this difference in neutrophil efficacy, and, in the process, to identify targets for immunomodulation to promote host innate defense.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI128159-01
Application #
9225366
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Huntley, Clayton C
Project Start
2016-11-22
Project End
2018-10-31
Budget Start
2016-11-22
Budget End
2017-10-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of New Mexico Health Sciences Center
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
829868723
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Castleman, Moriah J; Pokhrel, Srijana; Triplett, Kathleen D et al. (2018) Innate Sex Bias of Staphylococcus aureus Skin Infection Is Driven by ?-Hemolysin. J Immunol 200:657-668