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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Blood Safety: Developing Methods to Reduce Infectious Agents in Blood and Related Products and Identifying Biomarkers of Stored Blood Cells

Principal Investigator: C. D. Atreya, PhD
Office / Division / Lab: OBRR / DH / LCH


General Overview

Platelets are cells in the blood that trigger blood clotting. Doctors use platelets to prevent or treat bleeding in individuals with dangerously low platelet counts, such as those undergoing chemotherapy for cancer, as well those who suffer major blood loss due to trauma or surgery, and individuals who do not produce adequate numbers of platelets.

However, donated, stored platelets contaminated with bacteria pose the risk of a life-threatening infection in patients who receive them. Therefore, platelets are stored for no more than five days and tested for contamination before being transfused into patients.

In response to this problem, first we are developing novel ways to reduce the levels of pathogenic bacteria and viruses in stored platelets. This work is important because growth of bacteria in room temperature-stored platelet concentrates (PCs) can cause sepsis ("blood infection," causing chills, fever, and other symptoms) and other complications in recipients of transfusions. Thus, reducing bacterial growth in platelets and other blood products, including bacteria that are resistant to conventional antibiotics, would significantly enhance blood and blood product safety. Our laboratory is studying the ability of certain molecules called anti-microbial peptides (AMPs) to reduce pathogens in PCs and other blood products. The initial goal of this project is to evaluate selected AMPs against a panel of bacteria that are potential threats to platelet safety. Subsequently, we will extend our studies to the protection of red blood cells.

We are also studying the potential usefulness of tiny pieces of genetic material called cellular micro-RNAs (miRs) in their value in identifying whole blood or blood products that are contaminated with infectious microorganisms. This will also contribute to biodefense efforts aimed at protecting the blood supply. In addition, screening for the cellular miRs might also help to predict whether these stored therapeutic products will function properly after being transfused into patients.


Scientific Overview

Pathogen reduction: A single, easy-to-use, and cost-effective pathogen inactivation approach would help to improve the safety of our nation's blood supply, including red blood cells, plasma, and platelets (PLTs). Several methods and technologies are currently being studied to help reduce bacterial contamination of blood components.

Our laboratory is introducing a novel proof of concept that uses known therapeutic antimicrobial peptides (AMPs) as bactericidal agents for platelet concentrates (PCs) stored at room temperature. We tested nine synthetic AMPs (four from PLT microbicidal protein-derived peptides (PD1-4) and five Arg-Trp (RW) repeat peptides containing one to five repeats) for bactericidal activity in plasma and PC samples spiked with Staphylococcus aureus, S. epidermidis, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Bacillus cereus. A 3-log reduction of viable bacteria was considered effective bactericidal activity for a given peptide.

In both plasma alone and PCs, RW3 peptide demonstrated bactericidal activity against S. aureus, S. epidermidis, E. coli, P. aeruginosa, and K. pneumoniae; PD4 and RW2 against P. aeruginosa; and RW4 against K. pneumoniae. The activity of each of these four peptides against the remaining bacterial species in the test panel resulted in less than a 3-log reduction in the number of viable bacteria and hence considered ineffective.

These findings suggest a new approach to improving the safety of blood components, demonstrating the potential usefulness of screening therapeutic AMPs against selected bacteria to identify suitable bactericidal agents for stored plasma, and blood cells.

Micro-RNAs as biomarkers of infection and stored blood and blood cells: In addition to the above described studies, we are also studying cellular micro-RNAs (miRs) to determine a) if they can be used as early indicators of infection when whole blood or cellular blood components are contaminated with pathogens--work that will also contribute to biodefense efforts aimed at protecting the blood supply and b) whether cellular miR profiles of stored blood cells (platelets and red blood cells) can be useful as markers of storage that are predictive of their function following transfusion into patients.


Publications

Transfusion 2014 Jun;54(6):1604-9
Leukoreduced whole blood-derived platelets treated with antimicrobial peptides maintain in vitro properties during storage.
Bosch-Marce M, Seetharaman S, Kurtz J, Mohan KV, Wagner SJ, Atreya CD

Transfusion 2014 Mar;54(3):569-76
Preclinical safety evaluation of human platelets treated with antimicrobial peptides in severe combined immunodeficient mice.
Bosch-Marcé M, Mohan KV, Gelderman MP, Ryan PL, Russek-Cohen E, Atreya CD

Clin Microbiol Infect 2014 Jan;20(1):O39-46
Enhanced antimicrobial activity of peptide-cocktails against common bacterial contaminants of ex vivo stored platelets.
Mohan KV, Rao SS, Gao Y, Atreya CD

Microbiol Res 2013 Feb 22;168(2):106-12
Identification and evaluation of a novel peptide binding to the cell surface of Staphylococcus aureus.
Rao SS, Mohan KV, Gao Y, Atreya CD

PLoS One 2013;8(2):e56081
A Peptide Derived from Phage Display Library Exhibits Antibacterial Activity against E. coli and Pseudomonas aeruginosa.
Sainath Rao S, Mohan KV, Atreya CD

PLoS One 2012;7(3):e32853
Identification of XMRV infection-associated microRNAs in four cell types in culture.
Mohan KV, Devadas K, Sainath Rao S, Hewlett I, Atreya C

Transfusion 2011 Aug;51(8):1855-71
FDA workshop on emerging infectious diseases: evaluating emerging infectious diseases (EIDs) for transfusion safety.
Atreya C, Nakhasi H, Mied P, Epstein J, Hughes J, Gwinn M, Kleinman S, Dodd R, Stramer S, Walderhaug M, Ganz P, Goodrich R, Tibbetts C, Asher D

Transfus Med Rev 2011 Jul;25(3):247-51
Blood cell microRNAs: what are they and what future do they hold?
Ryan P, Atreya C

Transfusion 2010 Jul;50(7):1581-8
Differential profiling of human red blood cells during storage for 52 selected microRNAs.
Kannan M, Atreya C

Transfus Med Rev 2010 Jul;24(3):211-7
Omic approaches to quality biomarkers for stored platelets: are we there yet?
Kulkarni S, Kannan M, Atreya CD

J Microbiol Methods 2010 Jul;82(1):1-10
Detection technologies for Bacillus anthracis: prospects and challenges.
Rao SS, Mohan KV, Atreya CD

Antiviral Res 2010 Jun;86(3):306-11
Antiviral activity of selected antimicrobial peptides against vaccinia virus.
Mohan KV, Rao SS, Atreya CD

Biochem Biophys Res Commun 2010 Apr 23;395(1):93-8
Peptides panned from a phage-displayed random peptide library are useful for the detection of Bacillus anthracis surrogates B. cereus 4342 and B. anthracis Sterne.
Sainath Rao S, Mohan KV, Nguyen N, Abraham B, Abdouleva G, Zhang P, Atreya CD

Transfusion 2010 Jan;50(1):166-73
Evaluation of antimicrobial peptides as novel bactericidal agents for room temperature-stored platelets.
Mohan KV, Rao SS, Atreya CD

Transfusion 2009 Jul;49(7):1443-50
Membrane array-based differential profiling of platelets during storage for 52 miRNAs associated with apoptosis.
Kannan M, Mohan KV, Kulkarni S, Atreya C

BMC Biotechnol 2009 Jul 22;9:67
Gamma-phage lysin PlyG sequence-based synthetic peptides coupled with Qdot-nanocrystals are useful for developing detection methods for Bacillus anthracis by using its surrogates, B. anthracis-Sterne and B. cereus-4342.
Sainathrao S, Mohan KV, Atreya C

J Neurovirol 2009 Jun;15(3):229-37
The proteoglycan bamacan is a host cellular ligand of vaccinia virus neurovirulence factor N1L.
Mohan KV, Zhang CX, Atreya CD

Semin Thromb Hemost 2009 Apr;35(3):337-43
An update on the prevalence and characterization of H-PF4 antibodies in Asian-Indian patients.
Kannan M, Saxena R, Adiguzel C, Fareed J

Arch Virol 2008;153(12):2283-90
Defective rotavirus particle assembly in lovastatin-treated MA104 cells.
Mohan KV, Muller J, Atreya CD

BMC Cell Biol 2008 Apr 28;9(1):22
Application of Bioinformatics-Coupled Experimental Analysis reveals a new Transport-Competent Nuclear Localization Signal in the Nucleoprotein of an Influenza A Virus strain.
Ketha KM, Atreya CD

Biologicals 2006 Dec;34(4):265-72
Comparative molecular characterization of gene segment 11-derived NSP6 from lamb rotavirus LLR strain used as a human vaccine in China.
Mohan KV, Glass RI, Atreya CD

Arch Virol 2006 Sep;151(9):1841-51
The rubella virus nonstructural protease recognizes itself via an internal sequence present upstream of the cleavage site for trans-activity.
Chen HH, Stark CJ, Atreya CD

Virol J 2005 Apr 15;2(1):35
Molecular advances in the cell biology of SARS-CoV and current disease prevention strategies.
Stark CJ, Atreya C

Birth Defects Res A Clin Mol Teratol 2004 Jul;70(7):431-7
Rubella Virus and Birth Defects: Molecular Insights into the Viral Teratogenesis at the Cellular Level
Atreya CD, Mohan KV, Kulkarni S.

Arch Virol 2004 Apr;149(4):779-89
Rubella virus P90 associates with the cytokinesis regulatory protein Citron-K kinase and the viral infection and constitutive expression of P90 protein both induce cell cycle arrest following S phase in cell culture.
Atreya CD, Kulkarni S, Mohan KV

     
 

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