Cessation from Smoking Improves Innate Host Defense and Clearance of Experimentally Inoculated Nasal Staphylococcus aureus

Abstract

nasal carriage is transient in most humans and usually benign, but dissemination of to extranasal sites causes the majority of clinical infections, and is a major cause of serious infections in the United States. A better understanding of innate nasal decolonization mechanisms is urgently needed, as are relevant models for studying clearance. Here, we screened a population of healthy smokers for nasal carriage and compared the participants' abilities to clear experimentally applied nasal before and after completion of a smoking cessation program. We determined that cigarette smoking increases the mean nasal load (2.6 × 10 CFU/swab) compared to the load observed in healthy nonsmokers (1.7 × 10 CFU/swab) and might increase the rate of nasal carriage in otherwise-healthy adults: 22 of 99 smokers carried at the screening visit, while only 4 of 30 nonsmokers screened positive during the same time period. Only 6 of 19 experimental inoculation studies in active smokers resulted in clearance within the month of follow-up, while in the cessation group, 6 of 9 subjects cleared nasal and carriage duration averaged 21 ± 4 days. Smoking cessation associated with enhanced expression of -associated interleukin-1β (IL-1β) and granulocyte colony-stimulating factor (G-CSF) in nasal fluids. Participants who failed to clear exhibited a higher nasal load and elevated nasal interleukin-1 receptor antagonist (IL-1RA) expression at the preexperiment study visits. We conclude that smokers exhibit higher loads than nonsmokers and that innate immune pathways, including G-CSF expression and signaling through the IL-1 axis, are important mediators of nasal clearance.

Evaluation of the Pig-Tailed Macaque (Macaca nemestrina) as a Model of Human Staphylococcus aureus Nasal Carriage

“…Increased expression of MIP-1␤ was observed in S. aureus-positive nostrils compared to negative nostrils, regardless of whether clearance was achieved (data not shown). The levels of TNF-␣ and IL-17A were low (Ͻ10 pg/ml) in most samples and near the lower limit of detection in the utilized assay, similar to other observations in human subjects (11,12,37). The serum levels of all 10 analytes were unchanged by experimental nasal S. aureus inoculation (data not shown).…”

“…An important finding of this study is that all macaques were successfully decolonized using a 5-day course of topical nasal mupirocin. Consistent with the human SANC condition (2,11,12,31,32), nasal mupirocin application eradicated S. aureus not only in the nostrils but also in the axillae, hands, and vagina, with pharyngeal S. aureus being cleared in 21 of 24 tests ( Fig. 2A).…”

“…Macaque nasal secretions averaged 9.9 Ϯ 3. inflammatory protein 1␣ (MIP-1␤), MCP-1, granulocyte colony-stimulating factor (G-CSF), IL-6, tumor necrosis factor alpha (TNF-␣), IL-17A, and vascular endothelial growth factor (VEGF) using nonhuman primate-specific antibody sets. These analytes were chosen on the basis of the findings of previous experiments in human subjects that showed associations between increased IL-1␤, IL-8, MIP-1␤, MCP-1, and G-CSF expression and nasal S. aureus clearance (11,12). IL-6 and TNF-␣ are hallmark inflammatory cytokines, IL-17A is associated with S. aureus host defense in mice (33,34), and VEGF is important for mucosal barrier homeostasis and remodeling and is highly expressed in mucosal fluids (11,35,36).…”

“…Our laboratory (A. M. Cole) has conducted 43 experimental nasal S. aureus inoculations in which healthy human subjects self-applied their previously isolated S. aureus strains and then returned for swab and nasal fluid collections for a month of follow-up to evaluate S. aureus carriage duration and mucosal host defense characteristics (11,12). Both human subjects and macaques presented a trend that a rapid innate nasal inflammatory response, typified by peak IL-1␤ and IL-8 expression within 7 days of S. aureus inoculation, was associated with shortened carriage duration (Fig.…”

“…Some European studies which used experimental inoculation of human noses with diverse S. aureus strains were conducted (2,9,10). However, institutional review board approval for experimental inoculation of human subjects in the United States has been limited to strains isolated from the subject's own nostrils (11,12), without the possibility of testing potentially virulent or antibiotic-resistant strains. Rodent models have been useful for studying S. aureus-induced cutaneous infections, lung injury, sepsis, endocarditis, and more (13), and the cotton rat (Sigmodon hispidus) model was used for identifying bacterial determinants of SANC (14)(15)(16).…”