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Title: Direct detection of bacteremia by exploiting host-pathogen interactions of lipoteichoic acid and lipopolysaccharide

Abstract

Bacteremia is a leading cause of death in sub-Saharan Africa where childhood mortality rates are the highest in the world. The early diagnosis of bacteremia and initiation of treatment saves lives, especially in high-disease burden areas. However, diagnosing bacteremia is challenging for clinicians, especially in children presenting with co-infections such as malaria and HIV. There is an urgent need for a rapid method for detecting bacteremia in pediatric patients with co-morbidities to inform treatment. In this manuscript, we have developed and clinically validated a novel method for the direct detection of amphiphilic pathogen biomarkers indicative of bacteremia, directly in aqueous blood, by mimicking innate immune recognition. Specifically, we have exploited the interaction of amphiphilic pathogen biomarkers such as lipopolysaccharides (LPS) from Gram-negative bacteria and lipoteichoic acids (LTA) from Gram-positive bacteria with host lipoprotein carriers in blood, in order to develop two tailored assays – lipoprotein capture and membrane insertion – for their direct detection. Our assays demonstrate a sensitivity of detection of 4 ng/mL for LPS and 2 ng/mL for LTA using a waveguide-based optical biosensor platform that was developed at LANL. In this manuscript, we also demonstrate the application of these methods for the detection of LPS in serummore » from pediatric patients with invasive Salmonella Typhimurium bacteremia (n = 7) and those with Staphylococcal bacteremia (n = 7) with 100% correlation with confirmatory culture. Taken together, these results demonstrate the significance of biochemistry in both our understanding of host-pathogen biology, and development of assay methodology, as well as demonstrate a potential new approach for the rapid, sensitive and accurate diagnosis of bacteremia at the point of need.« less

Authors:
ORCiD logo [1];  [1]; ORCiD logo [1];  [2];  [3];  [1];  [1];  [1];  [1];  [4];  [5];  [6];  [7];  [8];  [9];  [1]; ORCiD logo [1]
  1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  2. Univ. of New Mexico, Albuquerque, NM (United States). Dept. of Biomedical Engineering
  3. Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Univ. of New Mexico, Albuquerque, NM (United States). Dept. of Biomedical Engineering
  4. Kenya Medical Research Inst., Kisumu (Kenya). Univ. of New Mexico/KEMRI Lab. of Parasitic and Viral Diseases. Centre for Global Health Research
  5. Univ. of New Mexico, Albuquerque, NM (United States). Health Sciences Center. Center for Global Health. Dept. of Internal Medicine
  6. Kenya Medical Research Inst., Kisumu (Kenya). Univ. of New Mexico/KEMRI Lab. of Parasitic and Viral Diseases. Centre for Global Health Research; Maseno Univ. (Kenya). Dept. of Medical Biochemistry. School of Medicine
  7. Kenya Medical Research Inst., Kisumu (Kenya). Univ. of New Mexico/KEMRI Lab. of Parasitic and Viral Diseases. Centre for Global Health Research; Maseno Univ. (Kenya). Dept. of Biomedical Sciences and Technology. School of Public Health and Community Development
  8. Kenya Medical Research Inst., Kisumu (Kenya). Univ. of New Mexico/KEMRI Lab. of Parasitic and Viral Diseases. Centre for Global Health Research; Masinde Muliro Univ. of Science and Technology, Kakamega (Kenya). Dept. of Medical Laboratory Science. School of Public Health, Biomedical Sciences and Technology
  9. Kenya Medical Research Inst., Kisumu (Kenya). Univ. of New Mexico/KEMRI Lab. of Parasitic and Viral Diseases. Centre for Global Health Research; Univ. of New Mexico, Albuquerque, NM (United States). Health Sciences Center. Center for Global Health. Dept. of Internal Medicine
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Univ. of New Mexico, Albuquerque, NM (United States)
Sponsoring Org.:
USDOE; LANL Laboratory Directed Research and Development (LDRD) Program; National Inst. of Health (NIH) (United States)
OSTI Identifier:
1511232
Report Number(s):
LA-UR-18-22478
Journal ID: ISSN 2045-2322
Grant/Contract Number:  
89233218CNA000001; AI51305-01; D43 TW05884
Resource Type:
Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 9; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
applied microbiology; microbiology

Citation Formats

Kubicek-Sutherland, Jessica Z., Vu, Dung M., Noormohamed, Aneesa, Mendez, Heather M., Stromberg, Loreen R., Pedersen, Christine A., Hengartner, Astrid C., Klosterman, Katja E., Bridgewater, Haley A., Otieno, Vincent, Cheng, Qiuying, Anyona, Samuel B., Ouma, Collins, Raballah, Evans, Perkins, Douglas J., McMahon, Benjamin H., and Mukundan, Harshini. Direct detection of bacteremia by exploiting host-pathogen interactions of lipoteichoic acid and lipopolysaccharide. United States: N. p., 2019. Web. doi:10.1038/s41598-019-42502-5.
Kubicek-Sutherland, Jessica Z., Vu, Dung M., Noormohamed, Aneesa, Mendez, Heather M., Stromberg, Loreen R., Pedersen, Christine A., Hengartner, Astrid C., Klosterman, Katja E., Bridgewater, Haley A., Otieno, Vincent, Cheng, Qiuying, Anyona, Samuel B., Ouma, Collins, Raballah, Evans, Perkins, Douglas J., McMahon, Benjamin H., & Mukundan, Harshini. Direct detection of bacteremia by exploiting host-pathogen interactions of lipoteichoic acid and lipopolysaccharide. United States. doi:10.1038/s41598-019-42502-5.
Kubicek-Sutherland, Jessica Z., Vu, Dung M., Noormohamed, Aneesa, Mendez, Heather M., Stromberg, Loreen R., Pedersen, Christine A., Hengartner, Astrid C., Klosterman, Katja E., Bridgewater, Haley A., Otieno, Vincent, Cheng, Qiuying, Anyona, Samuel B., Ouma, Collins, Raballah, Evans, Perkins, Douglas J., McMahon, Benjamin H., and Mukundan, Harshini. Wed . "Direct detection of bacteremia by exploiting host-pathogen interactions of lipoteichoic acid and lipopolysaccharide". United States. doi:10.1038/s41598-019-42502-5. https://www.osti.gov/servlets/purl/1511232.
@article{osti_1511232,
title = {Direct detection of bacteremia by exploiting host-pathogen interactions of lipoteichoic acid and lipopolysaccharide},
author = {Kubicek-Sutherland, Jessica Z. and Vu, Dung M. and Noormohamed, Aneesa and Mendez, Heather M. and Stromberg, Loreen R. and Pedersen, Christine A. and Hengartner, Astrid C. and Klosterman, Katja E. and Bridgewater, Haley A. and Otieno, Vincent and Cheng, Qiuying and Anyona, Samuel B. and Ouma, Collins and Raballah, Evans and Perkins, Douglas J. and McMahon, Benjamin H. and Mukundan, Harshini},
abstractNote = {Bacteremia is a leading cause of death in sub-Saharan Africa where childhood mortality rates are the highest in the world. The early diagnosis of bacteremia and initiation of treatment saves lives, especially in high-disease burden areas. However, diagnosing bacteremia is challenging for clinicians, especially in children presenting with co-infections such as malaria and HIV. There is an urgent need for a rapid method for detecting bacteremia in pediatric patients with co-morbidities to inform treatment. In this manuscript, we have developed and clinically validated a novel method for the direct detection of amphiphilic pathogen biomarkers indicative of bacteremia, directly in aqueous blood, by mimicking innate immune recognition. Specifically, we have exploited the interaction of amphiphilic pathogen biomarkers such as lipopolysaccharides (LPS) from Gram-negative bacteria and lipoteichoic acids (LTA) from Gram-positive bacteria with host lipoprotein carriers in blood, in order to develop two tailored assays – lipoprotein capture and membrane insertion – for their direct detection. Our assays demonstrate a sensitivity of detection of 4 ng/mL for LPS and 2 ng/mL for LTA using a waveguide-based optical biosensor platform that was developed at LANL. In this manuscript, we also demonstrate the application of these methods for the detection of LPS in serum from pediatric patients with invasive Salmonella Typhimurium bacteremia (n = 7) and those with Staphylococcal bacteremia (n = 7) with 100% correlation with confirmatory culture. Taken together, these results demonstrate the significance of biochemistry in both our understanding of host-pathogen biology, and development of assay methodology, as well as demonstrate a potential new approach for the rapid, sensitive and accurate diagnosis of bacteremia at the point of need.},
doi = {10.1038/s41598-019-42502-5},
journal = {Scientific Reports},
number = ,
volume = 9,
place = {United States},
year = {2019},
month = {4}
}

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