Community-associated Staphylococcus aureus (CA-SA), such as USA300, the epidemic methicillin-resistant strain in the US, have led to a dramatic increase of skin and soft tissues infections over the past decade. Some of these infections are also invasive and often occur in otherwise healthy individuals. CA-SA appear to posses an enhanced capacity for both transmission and invasion, though we have limited understanding of how they spread and persist in the community. It is likely that strains adapt with minor genetic modifications to their environment and become more ecologically "fit". We have obtained proof of principle of discrete genetic adaptations over time by sequencing closely related USA300 strains, longitudinally collected from the same households. Concurrently, it appears that the originally zoonotic strain ST398 MSSA is emerging in the Northern Manhattan, without any animal contact. It is now amongst the most prevalent strains of our clinical infectious MSSA isolates, has a remarkable ability to spread from person-to-person, and shows enhanced survival on colonized environmental household surfaces. The overall goal of this study is to define the mechanisms of transmission and persistence of successful S. aureus strains as they adapt to their environmental niches, taking the examples of the well- established epidemic USA300 and the evolving zoonotic strain ST398, by using a combined epidemiologic and genetic approach. Specifically, the aims of this proposal are to (1) define the functional impact on S. aureus fitness and environmental adaptation of recent genetic changes in USA300, (2) define the reservoirs and modes of transmission of ST398 in Northern Manhattan, and (3) determine how the pig strain ST398 has evolved as a human pathogen. We will first study in vitro fitness, survival and cell adhesion properties of mutations of the sequenced later USA300, that we hypothesized have altered the fitness and survival of these strains. We will then extend our studies to the emerging ST398 to define the basis of its transmission in Northern Manhatten. Based on a cluster-based design we will interview and culture ST398 positive subjects, their contacts and contacts of contacts to determine factors associated with acquisition and spread of ST398. Critically, these studies will provide samples for comparative sequencing and will allow for comparison of human colonizing strains, infectious strains, as well as persisting and non-persisting strains. Sequence differences will be studied on isogenic mutants in functional assays implemented in studies on USA300. We anticipate that this work will lead to the identification of genetic traits accounting for the direct person-to-person transmission of ST398 and that contribute to enhanced fitness and ecological adaptation. This research is in direct line with my goal of becoming an independent Physician-investigator in the field of S. aureus pathogenesis. Bacteria such as Staphylococcus aureus can cause infections in otherwise healthy young people in the community. We have limited understanding of how these bacteria spread and why they persist. This research will help to find out how some of these strains survive and enable us to design interventions to limit their spread.

Public Health Relevance

Relevance: Bacteria such as Staphylococcus aureus can cause infections in otherwise healthy young people in the community. We have limited understanding of how these bacteria spread and why they persist. This research will help to find out how some of these strains survive and enable us to design interventions to limit their spread.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI090013-03
Application #
8288354
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Huntley, Clayton C
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$131,085
Indirect Cost
$9,710
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Knox, J; Van Rijen, M; Uhlemann, A-C et al. (2015) Community-associated methicillin-resistant Staphylococcus aureus transmission in households of infected cases: a pooled analysis of primary data from three studies across international settings. Epidemiol Infect 143:354-65
Sowash, Madeleine G; Uhlemann, Anne-Catrin (2014) Community-associated methicillin-resistant Staphylococcus aureus case studies. Methods Mol Biol 1085:25-69
Uhlemann, Anne-Catrin; Lowy, Franklin D (2014) Reply to Gandra et al. Clin Infect Dis 58:307-8
Benson, Meredith A; Ohneck, Elizabeth A; Ryan, Chanelle et al. (2014) Evolution of hypervirulence by a MRSA clone through acquisition of a transposable element. Mol Microbiol 93:664-81
Uhlemann, Anne-Catrin; Otto, Michael; Lowy, Franklin D et al. (2014) Evolution of community- and healthcare-associated methicillin-resistant Staphylococcus aureus. Infect Genet Evol 21:563-74
Uhlemann, Anne-Catrin; Dordel, Janina; Knox, Justin R et al. (2014) Molecular tracing of the emergence, diversification, and transmission of S. aureus sequence type 8 in a New York community. Proc Natl Acad Sci U S A 111:6738-43
Tanner, Joshua; Lin, Ying; Kornblum, John et al. (2014) Molecular characterization of methicillin-resistant Staphylococcus aureus clinical isolates obtained from the Rikers Island Jail System from 2009 to 2013. J Clin Microbiol 52:3091-4
Miko, Benjamin A; Herzig, Carolyn T A; Mukherjee, Dhritiman V et al. (2013) Is environmental contamination associated with Staphylococcus aureus clinical infection in maximum security prisons? Infect Control Hosp Epidemiol 34:540-2
Uhlemann, Anne-Catrin; Hafer, Cory; Miko, Benjamin A et al. (2013) Emergence of sequence type 398 as a community- and healthcare-associated methicillin-susceptible staphylococcus aureus in northern Manhattan. Clin Infect Dis 57:700-3
Uhlemann, A-C; Dumortier, C; Hafer, C et al. (2012) Molecular characterization of Staphylococcus aureus from outpatients in the Caribbean reveals the presence of pandemic clones. Eur J Clin Microbiol Infect Dis 31:505-11

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