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Principal Investigator: JOHN N GALGIANI
Organization: UNIVERSITY OF ARIZONA
Fiscal Year: 2019
Award: $579,122
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Coccidioidomycosis (Valley Fever) is a serious public health problem for the Southwestern United States and
all who visit there. A small proportion of infections result in progressive, debilitating, even life-threatening
illness (disseminated coccidioidomycosis or DCM). All evidence suggests that this heightened susceptibility is
due to differences in immunologic responses of the patient, clearly understood in overtly immunodeficient
persons (i.e., those with AIDS) but not understood for the large majority of otherwise healthy patients with
DCM. The NIAID intramural PI (Dr. Steven Holland) has identified inheritable gene mutations in a few patients
each of which are associated with DCM. He has also found additional patients with DCM to have rare gene
variants possibly producing deleterious consequences. These discoveries provide clues to the pathways that
might be deregulated in other patients with DCM but who do not have such readily identifiable genetic
alternations. This project builds on the ongoing collaboration between Dr. Holland and Dr. John Galgiani,
University of Arizona (UA) Director of the Valley Fever Center for Excellence, to maintain a referral path for
subjects living in Arizona to the existing program at the NIH Clinical Center. This work will better define the
functional consequences of the Mendelian mutations that Dr. Holland has identified and how those differences
permit DCM to occur. A second aim is to analyze gene expression of peripheral blood mononuclear cells of
patients with DCM not associated with Mendelian mutations in comparison to persons who control coccidioidal
infection without becoming ill. Such comparisons may identify dysregulated patterns of response and suggest
which putatively deleterious variants in such patients might be responsible. A third aim is to genetically
introduce Mendelian mutations associated with human DCM (such as one found by Dr. Holland in STAT4) into
a mouse strain normally resistant to coccidioidal dissemination to determine if such mutations result in
increased DCM. If so, we can also discover whether it is possible to prevent DCM in the transfected mice by
immunization. The murine studies will use containment facilities available at the UA and not currently available
at the NIH. As a result of this work, it may be possible to identify persons who, if infected, will develop DCM.
Also, our findings may suggest new approaches to therapy or preventative vaccines.
Terms: <AIDS><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immuno-Deficiency Syndrome><Acquired Immunodeficiency Syndrome><Acquired Immunologic Deficiency Syndrome><Arizona><BSL-3 facility><BSL3 facility><Blood monocyte><Body Tissues><Body part><CDC><CNS Nervous System><Category C pathogen><Category C priority pathogen><Centers for Disease Control><Centers for Disease Control and Prevention><Centers for Disease Control and Prevention (U.S.)><Central Nervous System><Clinical><Coccidioides><Coccidioidomycosis><Collaborations><Communities><Complex><Containment><Contracting Opportunities><Contracts><DNA Alteration><DNA Sequence Alteration><DNA mutation><Defect><Desert rheumatism><Development><Disease><Disorder><Fungus Diseases><Gene Alteration><Gene Expression><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Gene Mutation><Gene variant><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genetic mutation><Hereditary><Host Factor><Host Factor Protein><Human><Immune response><Immunization><Immunochemical Immunologic><Immunocompetent><Immunodeficiency Disorder><Immunodeficiency Syndrome><Immunologic><Immunologic Deficiency Syndromes><Immunologic Sensitization><Immunologic Stimulation><Immunological><Immunological Deficiency Syndromes><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunologically><Immunologics><Immunostimulation><In Vitro><Infection><Inherited><Institution><Integration Host Factors><Investigators><Joints><Laboratories><Life><Lung><Lung Respiratory System><Marrow monocyte><Messenger RNA><Mice><Mice Mammals><Modern Man><Mouse Strains><Murine><Mus><Mutation><Mycoses><NIAID><NIH><National Institute of Allergy and Infectious Disease><National Institutes of Health><Neuraxis><Other Genetics><Outcome><PBMC><Pathway interactions><Patients><Pattern><Peripheral Blood Lymphocyte><Peripheral Blood Mononuclear Cell><Persons><Pneumonia><Predisposition><Preventative vaccine><Preventive vaccine><Procedures><Prophylactic vaccine><Protocol><Protocols documentation><Public Health><Reporting><Research Personnel><Research Resources><Research Specimen><Researchers><Resistance><Resources><Risk><STAT4><STAT4 gene><San Joaquin Valley fever><Sequence Alteration><Severities><Skin><Southwest U.S.><Southwest US><Southwestern United States><Specimen><Study models><Susceptibility><Syndrome><Testing><Time><Tissues><Transcript Expression Analyses><Transcript Expression Analysis><United States><United States Centers for Disease Control><United States Centers for Disease Control and Prevention><United States National Institutes of Health><Universities><Vaccination><Valley Fever><Variant><Variation><Virulence><Visit><Work><accurate diagnosis><adaptive immunity><allele variant><allelic variant><biosafety level 3 facility><bone><desert fever><developmental><experience><fungal infection><fungus infection><gene expression analysis><gene expression assay><genetic variant><genome mutation><genomic alteration><genomic variant><host response><hypoimmunity><immune deficiency disorder><immunodeficiency><immunoresponse><in vivo><mRNA><medical attention><monocyte><mouse model><murine model><new approaches><novel approaches><novel strategies><novel strategy><pathway><patient response><prevent><preventing><programs><pulmonary><resistant><response><responsive patient><screening><transcriptional profiling>