Many diseases strike humans without obvious cause and, despite intense research, their etiology remains idiopathic. Thus, contesting current theories of pathogenesis for such conditions may result in unexpected progress and new lines of scientific inquiry. For example, it is likely that some idiopathic or autoimmune conditions or even cancers may be attributable to infectious agents even if conventional research avenues favor other mechanisms. Immune-mediated bone marrow failure syndromes (BMFS) and immune cytopenias, including aplastic anemia (AA), some forms of myelodysplasia, red cell aplasia and others, are all characterized by immune destruction of blood or blood-forming cells by various immunologic effector mechanisms, the target specificity determining the individual clinical presentations. Various pathogenetic mechanisms have been hypothesized to trigger an immune reaction, but no specific triggers have been identified. Clarification of the nature of causative events in these seemingly idiopathic diseases constitutes a major medical challenge. While at first glance the sporadic occurrence of these conditions, their seeming non-contagious nature and other signs of an infectious process may argue for other etiologies, we propose that infectious agents are responsible for triggering the subsequent immune pathophysiologic cascade. Our hypothesis that viral pathogens constitute the inciting events in AA or other immune-mediated cytopenias challenges the traditional understanding of autoimmunity in these specific conditions but if infectious agents, likely viruses, can be identified, such a discovery would change the paradigm not only for these diseases but also for many other autoimmune diseases. Most importantly, it would render them preventable. Recent descriptions of infectious pathogenesis in conditions not otherwise though to be caused by a virus demonstrate the viability of our application. We propose to apply high-density viral arrays as tools to screen and identify causative viruses. We stipulate that the offending pathogen will be present in blood cells or affected tissues even if in low quantities due to the persistent low productive or latent infection. We will apply 11k viral chip to establish DNA and RNA hybridization patterns in tissues for each disease entity in the earliest samples at presentation and during relapse and will narrow our search by design of custom arrays containing multiple copies of the most promising probes. Should results suggest a novel pathogen, we will clone and characterize its genome. Should a previously identified virus be detected we will apply serologic and PCR testing to establish incidence of viral nucleic acid detection in various tissues, seropositivity and titers. We believe that is a an important task of biomedical research to challenge the idiopathic primarily autoimmune nature of these disease as recognition of viral pathogen would render these disease avoidable and subject to prevention and improved diagnosis.

Public Health Relevance

Identification of unknown infectious causes for human diseases is an important goal of biomedical research as it opens avenues to prevention, diagnostics and effective treatments. Bone marrow failure syndromes are serious diseases of blood-forming tissues associated with deficient blood cell production that are thought to be mediated by autoimmunity, similar to rheumatoid arthritis or diabetes mellitus. Identification of viral pathogens that trigger aberrant reaction of immune system would have a major impact on the management and future research direction for not only bone marrow failure syndromes but also other autoimmune conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI085578-04
Application #
8310918
Study Section
Special Emphasis Panel (ZRG1-BCMB-A (51))
Program Officer
Johnson, David R
Project Start
2009-09-25
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$384,689
Indirect Cost
$139,664
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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