Project SummaryCoccidioidomycosis (Valley Fever) is a serious public health problem for the Southwestern United States andall who visit there. A small proportion of infections result in progressive debilitating even life-threateningillness (disseminated coccidioidomycosis or DCM). All evidence suggests that this heightened susceptibility isdue to differences in immunologic responses of the patient clearly understood in overtly immunodeficientpersons (i.e. those with AIDS) but not understood for the large majority of otherwise healthy patients withDCM. The NIAID intramural PI (Dr. Steven Holland) has identified inheritable gene mutations in a few patientseach of which are associated with DCM. He has also found additional patients with DCM to have rare genevariants possibly producing deleterious consequences. These discoveries provide clues to the pathways thatmight be deregulated in other patients with DCM but who do not have such readily identifiable geneticalternations. This project builds on the ongoing collaboration between Dr. Holland and Dr. John GalgianiUniversity of Arizona (UA) Director of the Valley Fever Center for Excellence to maintain a referral path forsubjects living in Arizona to the existing program at the NIH Clinical Center. This work will better define thefunctional consequences of the Mendelian mutations that Dr. Holland has identified and how those differencespermit DCM to occur. A second aim is to analyze gene expression of peripheral blood mononuclear cells ofpatients with DCM not associated with Mendelian mutations in comparison to persons who control coccidioidalinfection without becoming ill. Such comparisons may identify dysregulated patterns of response and suggestwhich putatively deleterious variants in such patients might be responsible. A third aim is to geneticallyintroduce Mendelian mutations associated with human DCM (such as one found by Dr. Holland in STAT4) intoa mouse strain normally resistant to coccidioidal dissemination to determine if such mutations result inincreased DCM. If so we can also discover whether it is possible to prevent DCM in the transfected mice byimmunization. The murine studies will use containment facilities available at the UA and not currently availableat 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.