In this proposed project, we seek to elucidate a mechanism by which Mucorales can establish devastating infection in hosts. Mucormycosis describes invasive fungal infections that are caused by fungi belonging to the family Mucorales, including genus Mucor and Rhizopus. Mucormycosis is considered to be one of the most lethal types of mycosis with an extremely high mortality rate ? more than 90% if disseminated. Diagnosis and treatment for mucormycosis are very difficult, and no standardized methods exist to handle mucormycosis. Nevertheless, mucormycosis has been under-studied, and it is largely elusive why hosts are extremely susceptible to the fungi. We have recently discovered that Mucorales secrete a protein, which blocks host detection by potently blocking TLR2 signaling. The result of the immune evasion is a failure of hosts to recruit phagocytes and allowing lethal dissemination by Mucorales. The objective of this proposed project is to identify molecular and cellular mechanisms by which Mucorales inhibit host immune responses. Our preliminary data strongly suggests that the inhibition is mediated by a TLR2 blockade by Mucormycosis. Thus, Aim 1 is to identify the TLR2 inhibitor (putatively termed ?MTIF? as Mucorales TLR2 Inhibitory Factor) secreted by Mucorales, to express recombinant MTIF (rMTIF) protein, and to generate an MTIF neutralization antibody.
Aim 2 is to elucidate molecular and cellular mechanisms by which TLR2 signaling is inhibited by MITF. Upon successful completion of this project, we expect to elucidate mechanisms by which the immune system fails to detect Mucorales and allows the fungi to be extremely virulent. Through the generation of rMITF and MITF antibodies, the following possibilities will be pursued in future ? First, MTIF antibody may be used to treat mucormycosis with current treatments using antifungal medications. Second, rMITF is a novel potent TLR2 inhibitor, which may be used to inhibit TLR2-mediated inflammation in other types of diseases, mainly autoimmune and autoinflammatory diseases.

Public Health Relevance

of the proposed research project to public health is in developing new therapeutics by targeting a novel Mucorales protein, which has been recently identified by our group. Mucormycosis (also known as zygomycosis) is an extremely lethal infectious disease. Despite the significant consequence of the disease, basic scientists, immunologists in particular, have paid little attention to mucormycosis, and a very limited number of research groups work on the host-microbial interaction of mucormycosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI135999-02
Application #
9620015
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Love, Dona
Project Start
2018-01-03
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Duke University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705