Nonredundant Roles of Interleukin-17A (IL-17A) and IL-22 in Murine Host Defense against Cutaneous and Hematogenous Infection Due to Methicillin-Resistant Staphylococcus aureus.
Staphylococcus aureus is the leading cause of skin and skin structure infections (SSSI) in humans. Moreover, the high frequency of recurring SSSI due to S. aureus, particularly methicillin-resistant S. aureus (MRSA) strains, suggests that infection induces suboptimal anamnestic defenses. The present study addresses the hypothesis that interleukin-17A (IL-17A) and IL-22 play distinct roles in immunity to cutaneous and invasive MRSA infection in a mouse model of SSSI. Mice were treated with specific neutralizing antibodies against IL-17A and/or IL-22 and infected with MRSA, after which the severity of infection and host immune response were determined. Neutralization of either IL-17A or IL-22 reduced T cell and neutrophil infiltration and host defense peptide elaboration in lesions. These events corresponded with increased abscess severity, MRSA viability, and CFU density in skin. Interestingly, combined inhibition of IL-17A and IL-22 did not worsen abscesses but did increase gamma interferon (IFN-γ) expression at these sites. The inhibition of IL-22 led to a reduction in IL-17A expression, but not vice versa. These results suggest that the expression of IL-17A is at least partially dependent on IL-22 in this model. Inhibition of IL-17A but not IL-22 led to hematogenous dissemination to kidneys, which correlated with decreased T cell infiltration in renal tissue. Collectively, these findings indicate that IL-17A and IL-22 have complementary but nonredundant roles in host defense against cutaneous versus hematogenous infection. These insights may support targeted immune enhancement or other novel approaches to address the challenge of MRSA infection.
Division of Molecular Medicine, Harbor-UCLA Medical Center, Torrance, California, USA St. John's Cardiovascular Research Center, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA.
Liana C
LC
Chan
Division of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, California, USA St. John's Cardiovascular Research Center, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA.
Siyang
S
Chaili
Division of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, California, USA St. John's Cardiovascular Research Center, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Scott G
SG
Filler
Division of Molecular Medicine, Harbor-UCLA Medical Center, Torrance, California, USA.
Kevin
K
Barr
Division of Molecular Medicine, Harbor-UCLA Medical Center, Torrance, California, USA.
Huiyuan
H
Wang
Division of Molecular Medicine, Harbor-UCLA Medical Center, Torrance, California, USA.
Deborah
D
Kupferwasser
Division of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, California, USA St. John's Cardiovascular Research Center, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
John E
JE
Edwards
Division of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, California, USA St. John's Cardiovascular Research Center, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Yan Q
YQ
Xiong
Division of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, California, USA St. John's Cardiovascular Research Center, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Ashraf S
AS
Ibrahim
Department of Dermatology, Johns Hopkins University, Baltimore, Maryland, USA.
Lloyd S
LS
Miller
NovaDigm Therapeutics, Inc., Grand Forks, North Dakota, USA.
Clint S
CS
Schmidt
NovaDigm Therapeutics, Inc., Grand Forks, North Dakota, USA.
John P
JP
Hennessey
Division of Molecular Medicine, Harbor-UCLA Medical Center, Torrance, California, USA Division of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, California, USA St. John's Cardiovascular Research Center, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA MRYeaman@ucla.edu.
Michael R
MR
Yeaman
D000818:Animals; D006402:Hematologic Diseases / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology*; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000276:immunology* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013207:Staphylococcal Skin Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D000097043:Interleukin-22
D020381:Interleukin-17; D007378:Interleukins; D000097043:Interleukin-22