Fungal infections claim an estimated 1.5 million lives every year and constitute a severe health threat, especially to people with an impaired immune status. HIV infection, immune suppression, and certain types of primary immune deficiencies are instances of compromised immunity.
Candida species are the second-most numerous agents of fungal infections worldwide, and Candida albicans is the most frequent fungal pathogen in patients suffering from severe forms of fungal infections. Despite the availability of several anti-fungal drugs, invasive candidiasis still has a high mortality rate ranging from 45% to 75%. High morbidity and mortality are primarily due to lack of early and accurate diagnostic tools, limited anti-fungal drugs and fungal drug resistance.
It is imperative to further understand host-pathogen interactions and the mechanisms of immune resistance to fungal spread, and to develop alternative immune-based strategies to combat candidemia. Numerous studies have shed light on the cellular and molecular basis of fungal immunity, but have thus far failed to provide targets for increasing the potency of the immune system to eliminate fungal pathogens.
Dr. Jian Zhang, MD, received a $1,872,080 R01 grant from the National Institute of Allergy and Infectious Diseases to study how Cbl-b controls invasive fungal infection. Dr. Zhang’s group identified how an E3 ubiquitin ligase called Cbl-b as a potential target in the host in fungal diseases. His study, "Regulation of innate immune system sensing of C. albicans infection,” explores how Cbl-b controls fungal recognition. His ultimate goal is to develop a host-derived immune therapy to invasive fungal infection.
His research is applied via two aims, to study how Cbl-b regulates fungal recognition via controlling the expression of a set of the surface receptors called C-Type lectin receptors such as Dectin-1 and Dectin-2 in macrophages, and whether and how Cbl-b controls the immune responses against systemic Candida albicans infection. The proposed study will provide the first highly efficacious in vivo inhibition of Cbl-b function that protects mice from dying of Candida albicans induced sepsis.
Dr. Zhang has noticed success in his mouse models. When mice are deficient for the molecule Cbl-b, they are protected from systematic fungal infections. Dr. Zhang knows that manipulating the molecule can be translated to humans because silencing Cbl-b in human macrophages mimic a similar phenomenon.
His line of research targets manipulation of the immune system without the use of drugs. There are a lot of drugs to treat fungal infection on the market. However, drug resistance is proving to be a sweeping dilemma in pharmaceutical treatment.
“Mice with decreased expression of Cbl-b will be able to show us whether or not we can protect them from fungal infections,” says Dr. Zhang