Transmission dynamics, pathogenicity, and immunological biomarkers of livestock-associated Staphylococcus aureus, North Carolina, USA.
Embargo until
2020-05-01
Date
2019-04-23
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Johns Hopkins University
Abstract
Introduction. In the past decade it has become evident that animal-adapted Staphylococcus aureus (S. aureus), including methicillin-resistant S. aureus (MRSA) and multidrug-resistant S. aureus (MDRSA), have emerged among pigs raised on industrial hog operations (IHOs) and among humans who have frequent contact with, or live near IHOs both globally and in the USA. IHO workers in the USA are at an increased risk of carrying livestock-associated (LA-) S. aureus, including LA-MRSA and LA-MDRSA, and developing LA-S. aureus skin and soft tissue infections (SSTI). The population structure, transmission dynamics, relative pathogenicity, and immunological biomarkers of LA-S. aureus commonly contracted by IHO workers and their family members in the USA remains poorly understood. Objectives. 1) Elucidate the population structure and transmission dynamics of LA-S. aureus clonal complex 9 (CC9) between pigs raised on IHOs (IHO pigs) and humans in North Carolina (NC), USA, a region with a particularly high density of IHOs, 2) Determine the degree to which LA-S. aureus strains contracted by IHO workers cause disease relative to a highly pathogenic epidemic community-associated (CA-) MRSA strain (i.e. USA300 clone, SF8300) in a mouse model of SSTI, and 3) Develop antigen-specific antibody-based oral fluid (OF) biomarkers and examine their associations with S. aureus nasal carriage and SSTI outcomes among a population of IHO workers and their household contacts. Methods. In Chapter 1, 81 LA-S. aureus CC9 isolates were subject to bioinformatic analysis, including core-genome SNP-based phylogenetic analysis and genotyping for antimicrobial resistance (AMR) and virulence factor (VF) genes. In Chapter 2, measures of pathogenicity, including lesion size, innate immune host response, and colony forming units (CFUs), were compared between mice infected with either LA-S. aureus CC9 or CC398 strains to mice infected with CA-MRSA clone, SF8300. In Chapter 3, the development of an OF multiplex S. aureus Luminex enzyme immunoassay (EIA) that can be employed in occupational and community settings is outlined. Associations between S. aureus nasal carriage and SSTI outcomes and S. aureus antigen-specific antibody levels in OF were examined among IHO workers and their family members. Results. In Chapter 1, high-resolution phylogenetic and genotyping analysis of LA-S. aureus CC9 isolates revealed two distinct transmission clusters which contained IHO pig and human isolates with a high degree of phylogenetic relatedness. Transmission cluster isolates were enriched with multiple acquired AMR genes and a MDRSA phenotype. In Chapter 2, mice infected with CC398 LA-S. aureus strains developed larger lesion sizes with higher bacterial burden than mice infected with CA-MRSA (USA300 clone, SF8300). The LA-S. aureus infected mice had decreased IL-1β protein levels compared with CA-MRSA-infected mice, suggesting a suboptimal host response to LA-S. aureus SSTIs. In Chapter 3, an OF multiplex S. aureus EIA was developed. Consistent with previous findings in serum, OF IgG antibody levels against SCIN, ClfA, and AT were elevated among adults (ages 18-49) compared to children (ages 7-17). OF IgG levels waned with aging (ages 50-82), whereas IgA levels remained elevated. Anti-ClfA IgA and IgG antibody levels were significantly elevated among IHO workers who carried S. aureus, multidrug-resistant S. aureus (MDRSA), and tetracycline-resistant S. aureus (tet[R]-S. aureus) intranasally. Anti-ClfA IgA levels were positively and anti-SCIN levels negatively associated with self-reported SSTI. Conclusions. 1) LA-S. aureus CC9 in the USA is distinct from lineages in Europe and Asia, and can be transmitted between IHO pigs and humans. A MDRSA phenotype, and a significantly increased number of acquired AMR genes, is associated with pig-human transmissions. 2) LA-S. aureus CC398 and CC9 display an equivalent or greater degree of pathogenicity compared to CA-MRSA USA300, SF8300, in a mouse model of SSTI. 3) OF antibodies against ClfA may serve as non-invasive biomarkers of S. aureus colonization and SSTI among IHO workers and their household contacts.
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Keywords
Staphylococcus aureus
Antimicrobial resistance
Concentrated animal feeding operations
Industrial hog operations
Transmission dynamics
Environmental health
Infectious disease
Immunology
Biomarker development