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Early indicators of exposure to biological threat agents using host gene profiles in peripheral blood mononuclear cells.

Das R, Hammamieh R, Neill R, Ludwig GV, Eker S, Lincoln P, Ramamoorthy P, Dhokalia A, Mani S, Mendis C, Cummings C, Kearney B, Royaee A, Huang XZ, Paranavitana C, Smith L, Peel S, Kanesa-Thasan N, Hoover D, Lindler LE, Yang D, Henchal E, Jett M - BMC Infect. Dis. (2008)

Bottom Line: Most methods for identifying pathogens in body fluids and tissues require that the pathogen proliferate to detectable and dangerous levels, thereby delaying diagnosis and treatment, especially during the prelatent stages when symptoms for most BTA are indistinguishable flu-like signs.We found that certain gene expression patterns were unique to each pathogen and that other gene changes occurred in response to multiple agents, perhaps relating to the eventual course of illness.Nonhuman primates were exposed to some pathogens and the in vitro and in vivo findings were compared.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Pathology, Walter Reed Army Institute of Research, Silver Spring, MD, USA. dasr2@nhlbi.nih.gov

ABSTRACT

Background: Effective prophylaxis and treatment for infections caused by biological threat agents (BTA) rely upon early diagnosis and rapid initiation of therapy. Most methods for identifying pathogens in body fluids and tissues require that the pathogen proliferate to detectable and dangerous levels, thereby delaying diagnosis and treatment, especially during the prelatent stages when symptoms for most BTA are indistinguishable flu-like signs.

Methods: To detect exposures to the various pathogens more rapidly, especially during these early stages, we evaluated a suite of host responses to biological threat agents using global gene expression profiling on complementary DNA arrays.

Results: We found that certain gene expression patterns were unique to each pathogen and that other gene changes occurred in response to multiple agents, perhaps relating to the eventual course of illness. Nonhuman primates were exposed to some pathogens and the in vitro and in vivo findings were compared. We found major gene expression changes at the earliest times tested post exposure to aerosolized B. anthracis spores and 30 min post exposure to a bacterial toxin.

Conclusion: Host gene expression patterns have the potential to serve as diagnostic markers or predict the course of impending illness and may lead to new stage-appropriate therapeutic strategies to ameliorate the devastating effects of exposure to biothreat agents.

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Related in: MedlinePlus

Comparison of host gene responses in vivo and in vitro exposures to anthrax. Gene expression profiles in PBMC from healthy human donors exposed to anthrax spores in vitro were compared with gene expression patterns obtained in PBMC taken at 24, 48 and 72 hr after exposure of NHP to anthrax spores by aerosol challenge. (a) Gene cluster analysis of significantly altered genes in vivo. (b) comparison of gene expression profile between in vivo and in vitro exposures.
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Figure 4: Comparison of host gene responses in vivo and in vitro exposures to anthrax. Gene expression profiles in PBMC from healthy human donors exposed to anthrax spores in vitro were compared with gene expression patterns obtained in PBMC taken at 24, 48 and 72 hr after exposure of NHP to anthrax spores by aerosol challenge. (a) Gene cluster analysis of significantly altered genes in vivo. (b) comparison of gene expression profile between in vivo and in vitro exposures.

Mentions: To determine gene changes induced by BTAs in an animal model, NHP were exposed to B. anthracis spores by aerosol challenge. This model has been characterized previously to mimic inhalation anthrax in humans. Blood samples were collected 24 h, 48 h, and 72 h post exposure (by 72 h the NHP were beginning to show signs of the illness, which progresses very rapidly to lethality). The gene expression profiles for in vitro exposure of PBMC to anthrax spores were compared with those found in isolated PBMC at various time periods from NHP. Even by 24 h, a robust response was observed (Fig. 4a), showing up regulation of genes coding for proteases; proteosome components c2, c3, c5; various cytokines; pro-apoptotic genes; cyclic adenosine monophosphate (cAMP)-related kinases, cAMP regulated transcription factors; and hypoxia inducible factor-1 (HIF-1). Down regulated genes included tyrosine kinases, cytokine receptors, growth factors, and adenosine diphosphate (ADP) ribosylation factors. Comparison of the in vivo results with the in vitro changes induced by anthrax (Fig. 4b), showed remarkable similarities in gene patterns. Clearly many more changes were observed in vivo than in vitro. Certain surface antigens showed significant alteration that was unique to anthrax exposure. Diagrams were constructed to identify sets of genes that were up regulated (Fig. 5) at either 24 (blue) or 72 h (red); other gene sets showed up regulation at both time periods (center of graph, genes in both blue and red). Similarly, certain gene sets showed unique and common down-regulation patterns (far right, Fig. 5).


Early indicators of exposure to biological threat agents using host gene profiles in peripheral blood mononuclear cells.

Das R, Hammamieh R, Neill R, Ludwig GV, Eker S, Lincoln P, Ramamoorthy P, Dhokalia A, Mani S, Mendis C, Cummings C, Kearney B, Royaee A, Huang XZ, Paranavitana C, Smith L, Peel S, Kanesa-Thasan N, Hoover D, Lindler LE, Yang D, Henchal E, Jett M - BMC Infect. Dis. (2008)

Comparison of host gene responses in vivo and in vitro exposures to anthrax. Gene expression profiles in PBMC from healthy human donors exposed to anthrax spores in vitro were compared with gene expression patterns obtained in PBMC taken at 24, 48 and 72 hr after exposure of NHP to anthrax spores by aerosol challenge. (a) Gene cluster analysis of significantly altered genes in vivo. (b) comparison of gene expression profile between in vivo and in vitro exposures.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2542375&req=5

Figure 4: Comparison of host gene responses in vivo and in vitro exposures to anthrax. Gene expression profiles in PBMC from healthy human donors exposed to anthrax spores in vitro were compared with gene expression patterns obtained in PBMC taken at 24, 48 and 72 hr after exposure of NHP to anthrax spores by aerosol challenge. (a) Gene cluster analysis of significantly altered genes in vivo. (b) comparison of gene expression profile between in vivo and in vitro exposures.
Mentions: To determine gene changes induced by BTAs in an animal model, NHP were exposed to B. anthracis spores by aerosol challenge. This model has been characterized previously to mimic inhalation anthrax in humans. Blood samples were collected 24 h, 48 h, and 72 h post exposure (by 72 h the NHP were beginning to show signs of the illness, which progresses very rapidly to lethality). The gene expression profiles for in vitro exposure of PBMC to anthrax spores were compared with those found in isolated PBMC at various time periods from NHP. Even by 24 h, a robust response was observed (Fig. 4a), showing up regulation of genes coding for proteases; proteosome components c2, c3, c5; various cytokines; pro-apoptotic genes; cyclic adenosine monophosphate (cAMP)-related kinases, cAMP regulated transcription factors; and hypoxia inducible factor-1 (HIF-1). Down regulated genes included tyrosine kinases, cytokine receptors, growth factors, and adenosine diphosphate (ADP) ribosylation factors. Comparison of the in vivo results with the in vitro changes induced by anthrax (Fig. 4b), showed remarkable similarities in gene patterns. Clearly many more changes were observed in vivo than in vitro. Certain surface antigens showed significant alteration that was unique to anthrax exposure. Diagrams were constructed to identify sets of genes that were up regulated (Fig. 5) at either 24 (blue) or 72 h (red); other gene sets showed up regulation at both time periods (center of graph, genes in both blue and red). Similarly, certain gene sets showed unique and common down-regulation patterns (far right, Fig. 5).

Bottom Line: Most methods for identifying pathogens in body fluids and tissues require that the pathogen proliferate to detectable and dangerous levels, thereby delaying diagnosis and treatment, especially during the prelatent stages when symptoms for most BTA are indistinguishable flu-like signs.We found that certain gene expression patterns were unique to each pathogen and that other gene changes occurred in response to multiple agents, perhaps relating to the eventual course of illness.Nonhuman primates were exposed to some pathogens and the in vitro and in vivo findings were compared.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Pathology, Walter Reed Army Institute of Research, Silver Spring, MD, USA. dasr2@nhlbi.nih.gov

ABSTRACT

Background: Effective prophylaxis and treatment for infections caused by biological threat agents (BTA) rely upon early diagnosis and rapid initiation of therapy. Most methods for identifying pathogens in body fluids and tissues require that the pathogen proliferate to detectable and dangerous levels, thereby delaying diagnosis and treatment, especially during the prelatent stages when symptoms for most BTA are indistinguishable flu-like signs.

Methods: To detect exposures to the various pathogens more rapidly, especially during these early stages, we evaluated a suite of host responses to biological threat agents using global gene expression profiling on complementary DNA arrays.

Results: We found that certain gene expression patterns were unique to each pathogen and that other gene changes occurred in response to multiple agents, perhaps relating to the eventual course of illness. Nonhuman primates were exposed to some pathogens and the in vitro and in vivo findings were compared. We found major gene expression changes at the earliest times tested post exposure to aerosolized B. anthracis spores and 30 min post exposure to a bacterial toxin.

Conclusion: Host gene expression patterns have the potential to serve as diagnostic markers or predict the course of impending illness and may lead to new stage-appropriate therapeutic strategies to ameliorate the devastating effects of exposure to biothreat agents.

Show MeSH
Related in: MedlinePlus