HGT in the human and skin commensal Malassezia: A bacterially derived flavohemoglobin is required for NO resistance and host interaction.
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2020-06-23
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The skin of humans and animals is colonized by commensal and pathogenic fungi and bacteria that share this ecological niche and have established microbial interactions. Malassezia are the most abundant fungal skin inhabitant of warm-blooded animals and have been implicated in skin diseases and systemic disorders, including Crohn's disease and pancreatic cancer. Flavohemoglobin is a key enzyme involved in microbial nitrosative stress resistance and nitric oxide degradation. Comparative genomics and phylogenetic analyses within the Malassezia genus revealed that flavohemoglobin-encoding genes were acquired through independent horizontal gene transfer events from different donor bacteria that are part of the mammalian microbiome. Through targeted gene deletion and functional complementation in Malassezia sympodialis, we demonstrated that bacterially derived flavohemoglobins are cytoplasmic proteins required for nitric oxide detoxification and nitrosative stress resistance under aerobic conditions. RNA-sequencing analysis revealed that endogenous accumulation of nitric oxide resulted in up-regulation of genes involved in stress response and down-regulation of the MalaS7 allergen-encoding genes. Solution of the high-resolution X-ray crystal structure of Malassezia flavohemoglobin revealed features conserved with both bacterial and fungal flavohemoglobins. In vivo pathogenesis is independent of Malassezia flavohemoglobin. Lastly, we identified an additional 30 genus- and species-specific horizontal gene transfer candidates that might have contributed to the evolution of this genus as the most common inhabitants of animal skin.
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Ianiri, Giuseppe, Marco A Coelho, Fiorella Ruchti, Florian Sparber, Timothy J McMahon, Ci Fu, Madison Bolejack, Olivia Donovan, et al. (2020). HGT in the human and skin commensal Malassezia: A bacterially derived flavohemoglobin is required for NO resistance and host interaction. Proceedings of the National Academy of Sciences of the United States of America. pp. 202003473–202003473. 10.1073/pnas.2003473117 Retrieved from https://hdl.handle.net/10161/21122.
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Scholars@Duke
Timothy Joseph McMahon
The McMahon Lab at Duke University and Durham VA Medical Center is investigating novel roles of the red blood cell (RBC) in the circulation. The regulated release of the vasodilator SNO (a form of NO, nitric oxide) by RBCs within the respiratory cycle in mammals optimizes nutrient delivery at multiple levels, especially in the lung (gas exchange) and the peripheral microcirculation (O2 transport to tissues). Deficiency of RBC SNO bioactivity (as in human RBCs banked for transfusion), for example, appears to contribute to the serious lung and circulatory problems associated with RBC transfusion in some settings. We have also demonstrated benefit in the use of treatments that exploit RBCs as a vehicle for delivery of SNOs, in both human patients and in model animals.
RBCs also release ATP in response to stimuli including deformation and hypoxia, and the exported ATP also participates in the maintenance of a healthy circulation, according to mechanisms that we are now unraveling.
We use basic and translational approaches to understand the molecular mechanisms by which these RBC-derived signals effect circulatory changes in human health and disease, particularly in the lung. Disease states driving this research include acute and chronic lung diseases such as sepsis (severe infection, such as COVID-19), transfusion-related respiratory problems, sickle cell disease, and pulmonary hypertension of adults and newborns.
Funding: VA and NIH.
Fred Samuel Dietrich
My laboratory is interested in fungal genomics.
In particular we use genomic sequencing of fungal strains and species in comparative analysis. Starting with the sequencing of Saccharomyces cerevisiae strain S288C, I have been involved in the genome sequencing and annotation of Ashbya gossypii, Cryptococcus neoformans var. grubii and ~100 additional S. cerevisiae strains. We currently use Illumina paired end and mate paired sequencing, as this is at presently the most cost effective widely used technology capable of generating high accuracy, zero gap whole genome sequences. The 100-genomes S. cerevisiae data as well as the fully updated fully annotated A. gossypii sequence (Genbank numbers AE016814-AE016820), which spans all seven chromosomes from telomere to telomere, were generated using Illumina data. In my laboratory we strive to utilize comparative genomics data to understand aspects of basic fungal biology. Some of our specific areas of interest are filamentous growth, mapping of complex traits, horizontal gene transfer, and identification of RNA coding genes. This work involves a combination of experimental work and bioinformatics analysis. Research in S. cerevisiae has greatly benefitted from an accurate, annotated S. cerevisiae reference genome, and that research into the tremendous diversity in this organism will similarly benefit from the availability of a large number of accurate, fully annotated genome sequences. The use of genomic information to better understand the biology of these organisms, and this is what students in my laboratory generally work on.
What is the set of genes found in a pathogenic fungus such as Cryptococcus?
Our interest in this human pathogen is to expand beyond looking at one isolate and to investigate the diversity in the population. Are there genes found in some Cryptococcus neoformans isolates but not in others? Are there regions of the genome or individual genes which are highly diverged between Cryptococcus isolates? Efforts are now underway at Stanford University to sequence the genome of the JEC21 strain of Cryptococcus. This is a strain that has been agreed upon by the community of Cryptococcus researchers as a reference strain. Obtaining the DNA sequence of this strain is only the start however. From that sequence identifying the complete set of genes will be a considerable challenge requiring both bioinformatic as well as experimental tools. While this work on gene identification is going on we plan on addressing the question of how much do other Cryptococcus isolates differ from JEC21.
What is the set of genes in humans?
The complete DNA sequence of human and mouse will become available soon. This does not mean that we will know the complete set of human or mouse genes. Our current state of knowledge does not allow us to accurately predict human genes directly from DNA sequence. We are interested in applying to the human genome some of the experimental and bioinformatic tools we are developing and utilizing in fungal systems.
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