The Novel J-Domain Protein Mrj1 Is Required for Mitochondrial Respiration and Virulence in Cryptococcus neoformans
This week we profile a recent publication in mBio from the laboratory of Dr. Jim
Kronstad (pictured, back row fifth from left) at the Michael Smith Laboratories.
Can you provide a brief overview of your lab’s current research focus?
Fungi threaten human health in a number of ways such as causing infectious diseases, reducing crop production and contaminating harvested foods with mycotoxins. The research program in the Kronstad laboratory focuses on identifying the molecular mechanisms required for disease development by pathogenic fungi that attack animals or plants. Our recent publication arises from a project on Cryptococcus neoformans, the causative agent of cryptococcal meningitis, a disease that is estimated to result in ~ 15% of all HIV/AIDS-related deaths. In this context, cryptococosis is one of the most common causes of mortality in people with HIV/AIDS. Unfortunately, very few antifungal drugs are available to treat cryptococcal meningitis. The studies in the Kronstad laboratory are based on the premise that understanding mechanisms of pathogenesis for C. neoformans will lead to new therapeutic avenues. We are particularly interested in identifying fungal-specific targets for the development of new drugs, and in repurposing existing drugs to ablate fungal growth or virulence factor-deployment during infection.
What is the significance of the findings in this publication?
Invasive diseases caused by Cryptococcus neoformans and other life-threatening fungal pathogens such as Candida albicans and Aspergillus fumigatus are a major and underappreciated health problem, particularly for people with compromised immune systems. The development of antifungal drugs is difficult because potential targets are conserved between humans and fungi such as C. neoformans. In this context, our recent study characterized a unique J-domain protein, Mrj1, which lacks orthologs in humans. We discovered that Mrj1 was required for normal mitochondrial respiration and that mutants lacking Mrj1 were deficient in growth and virulence. Interestingly, the mutant was also defective in production of the polysaccharide capsule that is the major virulence factor of the fungus. We were able to reproduce the defects in growth and capsule elaboration by inhibiting respiration. This finding suggests that the role of Mrj1 in mitochondrial function is responsible for the observed virulence defects and reinforces the importance of mitochondria for fungal pathogenesis. The study presented in the publication benefited from interactions with strong collaborators in Germany and at UBC.
What are the next steps for this research?
Mrj1 is just one of 24 J-domain proteins in C. neoformans, and mutations is several of the others cause interesting phenotypes related to virulence. One protein in particular is being investigated for its role as a histone chaperone that participates in DNA damage repair.
This work was funded by:
This work was supported by grants from the Canadian Institutes of Health Research (MOP13234, to JWK) and the National Institutes of Health (RO1AI053721, to JWK), as well as the PRoTECT program, an NSERC CREATE-funded collaboration with a DFG IRTG training program in Goettingen, Germany.