scholarly journals Mitochondrial Sorting and Assembly Machinery Subunit Sam37 in Candida albicans: Insight into the Roles of Mitochondria in Fitness, Cell Wall Integrity, and Virulence

2012 ◽  
Vol 11 (4) ◽  
pp. 532-544 ◽  
Author(s):  
Yue Qu ◽  
Branka Jelicic ◽  
Filomena Pettolino ◽  
Andrew Perry ◽  
Tricia L. Lo ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Mitochondrial Function ◽  
Drug Tolerance ◽  
Cell Wall Integrity ◽  
Mitochondrial Outer Membrane ◽  
Wall Structure ◽  
Content Type ◽  
Mitochondrial Functions ◽  
Insight Into

ABSTRACT Recent studies indicate that mitochondrial functions impinge on cell wall integrity, drug tolerance, and virulence of human fungal pathogens. However, the mechanistic aspects of these processes are poorly understood. We focused on the mitochondrial outer membrane SAM ( S orting and A ssembly M achinery) complex subunit Sam37 in Candida albicans . Inactivation of SAM37 in C. albicans leads to a large reduction in fitness, a phenotype not conserved with the model yeast Saccharomyces cerevisiae . Our data indicate that slow growth of the sam37ΔΔ mutant results from mitochondrial DNA loss, a new function for Sam37 in C. albicans , and from reduced activity of the essential SAM complex subunit Sam35. The sam37ΔΔ mutant was hypersensitive to drugs that target the cell wall and displayed altered cell wall structure, supporting a role for Sam37 in cell wall integrity in C. albicans . The sensitivity of the mutant to membrane-targeting antifungals was not significantly altered. The sam37ΔΔ mutant was avirulent in the mouse model, and bioinformatics showed that the fungal Sam37 proteins are distant from their animal counterparts and could thus represent potential drug targets. Our study provides the first direct evidence for a link between mitochondrial function and cell wall integrity in C. albicans and is further relevant for understanding mitochondrial function in fitness, antifungal drug tolerance, and virulence of this major pathogen. Beyond the relevance to fungal pathogenesis, this work also provides new insight into the mitochondrial and cellular roles of the SAM complex in fungi.

scholarly journals Curcumin Targets Cell Wall Integrity via Calcineurin-Mediated Signaling in Candida albicans

2013 ◽  
Vol 58 (1) ◽  
pp. 167-175 ◽  
Author(s):  
Awanish Kumar ◽  
Sanjiveeni Dhamgaye ◽  
Indresh Kumar Maurya ◽  
Ashutosh Singh ◽  
Monika Sharma ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Critical Role ◽  
Pathogenic Fungi ◽  
Cell Wall Integrity ◽  
Ergosterol Biosynthesis ◽  
Ros Generation ◽  
Calcofluor White ◽  
Content Type ◽  
Cell Wall Damage

ABSTRACTCurcumin (CUR) shows antifungal activity against a range of pathogenic fungi, includingCandida albicans. The reported mechanisms of action of CUR include reactive oxygen species (ROS) generation, defects in the ergosterol biosynthesis pathway, decrease in hyphal development, and modulation of multidrug efflux pumps. Reportedly, each of these pathways is independently linked to the cell wall machinery inC. albicans, but surprisingly, CUR has not been previously implicated in cell wall damage. In the present study, we performed transcriptional profiling to identify the yet-unidentified targets of CUR inC. albicans. We found that, among 348 CUR-affected genes, 51 were upregulated and 297 were downregulated. Interestingly, most of the cell wall integrity pathway genes were downregulated. The possibility of the cell wall playing a critical role in the mechanism of CUR required further validation; therefore, we performed specific experiments to establish if there was any link between the two. The fractional inhibitory concentration index values of 0.24 to 0.37 show that CUR interacts synergistically with cell wall-perturbing (CWP) agents (caspofungin, calcofluor white, Congo red, and SDS). Furthermore, we could observe cell wall damage and membrane permeabilization by CUR alone, as well as synergistically with CWP agents. We also found hypersusceptibility in calcineurin and mitogen-activated protein (MAP) kinase pathway mutants against CUR, which confirmed that CUR also targets cell wall biosynthesis inC. albicans. Together, these data provide strong evidence that CUR disrupts cell wall integrity inC. albicans. This new information on the mechanistic action of CUR could be employed in improving treatment strategies and in combinatorial drug therapy.

scholarly journals Interface of Candida albicans Biofilm Matrix-Associated Drug Resistance and Cell Wall Integrity Regulation

2011 ◽  
Vol 10 (12) ◽  
pp. 1660-1669 ◽  
Author(s):  
Jeniel E. Nett ◽  
Hiram Sanchez ◽  
Michael T. Cain ◽  
Kelly M. Ross ◽  
David R. Andes
Keyword(s):  
Drug Resistance ◽  
Cell Wall ◽  
Candida Albicans ◽  
Antifungal Drugs ◽  
Cell Wall Integrity ◽  
Candidate Gene Approach ◽  
Content Type ◽  
Resistant Phenotype ◽  
Cell Wall Integrity Pathway ◽  
Biofilm Matrix

ABSTRACTCandida albicansfrequently infects medical devices by growing as a biofilm, i.e., a community of adherent organisms entrenched in an extracellular matrix. During biofilm growth,Candidaspp. acquire the ability to resist high concentrations of antifungal drugs. One recently recognized biofilm resistance mechanism involves drug sequestration by matrix β-1,3 glucan. Using a candidate gene approach, we investigated potentialC. albicansβ-1,3-glucan regulators, based on their homology toSaccharomyces cerevisiae, includingSMI1and protein kinase C (PKC) pathway components. We identified a role for theSMI1in biofilm matrix glucan production and development of the associated drug resistance phenotype. This pathway appears to act through transcription factor Rlmp and glucan synthase Fks1p. The phenotypes of these mutant biofilms mimicked those of thesmi1Δ/smi1Δ biofilm, and overexpression ofFKS1in thesmi1Δ/smi1Δ mutant restored the biofilm resistant phenotype. However, control of this pathway is distinct from that of the upstream PKC pathway because thepkc1Δ/pkc1Δ,bck1Δ/bck1Δ,mkk2Δ/mkk2Δ, andmkc1Δ/mkc1Δ biofilms retained the resistant phenotype of the parent strain. In addition, resistance to cell-perturbing agents and gene expression data do not support a significant role for the cell wall integrity pathway during the biofilm formation. Here we show that Smi1p functions in conjunction with Rlm1p and Fks1p to produce drug-sequestering biofilm β-glucan. Our work provides new insight into how theC. albicansbiofilm matrix production and drug resistance pathways intersect with the planktonic cell wall integrity pathway. This novel connection helps explain how pathogens in a multicellular biofilm community are protected from anti-infective therapy.

scholarly journals Critical Roles for Lipomannan and Lipoarabinomannan in Cell Wall Integrity of Mycobacteria and Pathogenesis of Tuberculosis

mBio ◽  
2013 ◽  
Vol 4 (1) ◽  
Author(s):  
Takeshi Fukuda ◽  
Takayuki Matsumura ◽  
Manabu Ato ◽  
Maho Hamasaki ◽  
Yukiko Nishiuchi ◽  
...  
Keyword(s):  
Cell Wall ◽  
Mycobacterium Tuberculosis ◽  
Critical Role ◽  
Protective Role ◽  
Cell Wall Integrity ◽  
Structural Defects ◽  
Wall Structure ◽  
Content Type ◽  
Mycobacterial Cell ◽  
Mycobacterial Cell Wall

ABSTRACTLipomannan (LM) and lipoarabinomannan (LAM) are mycobacterial glycolipids containing a long mannose polymer. While they are implicated in immune modulations, the significance of LM and LAM as structural components of the mycobacterial cell wall remains unknown. We have previously reported that a branch-forming mannosyltransferase plays a critical role in controlling the sizes of LM and LAM and that deletion or overexpression of this enzyme results in gross changes in LM/LAM structures. Here, we show that such changes in LM/LAM structures have a significant impact on the cell wall integrity of mycobacteria. InMycobacterium smegmatis, structural defects in LM and LAM resulted in loss of acid-fast staining, increased sensitivity to β-lactam antibiotics, and faster killing by THP-1 macrophages. Furthermore, equivalentMycobacterium tuberculosismutants became more sensitive to β-lactams, and one mutant showed attenuated virulence in mice. Our results revealed previously unknown structural roles for LM and LAM and further demonstrated that they are important for the pathogenesis of tuberculosis.IMPORTANCETuberculosis (TB) is a global burden, affecting millions of people worldwide.Mycobacterium tuberculosisis a causative agent of TB, and understanding the biology ofM. tuberculosisis essential for tackling this devastating disease. The cell wall ofM. tuberculosisis highly impermeable and plays a protective role in establishing infection. Among the cell wall components, LM and LAM are major glycolipids found in allMycobacteriumspecies, show various immunomodulatory activities, and have been thought to play roles in TB pathogenesis. However, the roles of LM and LAM as integral parts of the cell wall structure have not been elucidated. Here we show that LM and LAM play critical roles in the integrity of mycobacterial cell wall and the pathogenesis of TB. These findings will now allow us to seek the possibility that the LM/LAM biosynthetic pathway is a chemotherapeutic target.

scholarly journals Hypoxia Promotes Immune Evasion by Triggering β-Glucan Masking on theCandida albicansCell Surface via Mitochondrial and cAMP-Protein Kinase A Signaling

mBio ◽  
2018 ◽  
Vol 9 (6) ◽  
Author(s):  
Arnab Pradhan ◽  
Gabriela M. Avelar ◽  
Judith M. Bain ◽  
Delma S. Childers ◽  
Daniel E. Larcombe ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Protein Kinase ◽  
Immune Evasion ◽  
Fungal Pathogen ◽  
Wall Structure ◽  
Adaptation To Hypoxia ◽  
Low Oxygen ◽  
Content Type ◽  
Kinase A

ABSTRACTOrganisms must adapt to changes in oxygen tension if they are to exploit the energetic benefits of reducing oxygen while minimizing the potentially damaging effects of oxidation. Consequently, organisms in all eukaryotic kingdoms display robust adaptation to hypoxia (low oxygen levels). This is particularly important for fungal pathogens that colonize hypoxic niches in the host. We show that adaptation to hypoxia in the major fungal pathogen of humansCandida albicansincludes changes in cell wall structure and reduced exposure, at the cell surface, of β-glucan, a key pathogen-associated molecular pattern (PAMP). This leads to reduced phagocytosis by murine bone marrow-derived macrophages and decreased production of IL-10, RANTES, and TNF-α by peripheral blood mononuclear cells, suggesting that hypoxia-induced β-glucan masking has a significant effect uponC. albicans-host interactions. We show that hypoxia-induced β-glucan masking is dependent upon both mitochondrial and cAMP-protein kinase A (PKA) signaling. The decrease in β-glucan exposure is blocked by mutations that affect mitochondrial functionality (goa1Δ andupc2Δ) or that decrease production of hydrogen peroxide in the inner membrane space (sod1Δ). Furthermore, β-glucan masking is enhanced by mutations that elevate mitochondrial reactive oxygen species (aox1Δ). The β-glucan masking defects displayed bygoa1Δ andupc2Δ cells are suppressed by exogenous dibutyryl-cAMP. Also, mutations that inactivate cAMP synthesis (cyr1Δ) or PKA (tpk1Δtpk2Δ) block the masking phenotype. Our data suggest thatC. albicansresponds to hypoxic niches by inducing β-glucan masking via a mitochondrial cAMP-PKA signaling pathway, thereby modulating local immune responses and promoting fungal colonization.IMPORTANCEAnimal, plant, and fungal cells occupy environments that impose changes in oxygen tension. Consequently, many species have evolved mechanisms that permit robust adaptation to these changes. The fungal pathogenCandida albicanscan colonize hypoxic (low oxygen) niches in its human host, such as the lower gastrointestinal tract and inflamed tissues, but to colonize its host, the fungus must also evade local immune defenses. We reveal, for the first time, a defined link between hypoxic adaptation and immune evasion inC. albicans. As this pathogen adapts to hypoxia, it undergoes changes in cell wall structure that include masking of β-glucan at its cell surface, and it becomes better able to evade phagocytosis by innate immune cells. We also define the signaling mechanisms that mediate hypoxia-induced β-glucan masking, showing that they are dependent on mitochondrial signaling and the cAMP-protein kinase pathway. Therefore, hypoxia appears to trigger immune evasion in this fungal pathogen.

scholarly journals Candida albicans ENT2 Contributes to Efficient Endocytosis, Cell Wall Integrity, Filamentation, and Virulence

mSphere ◽  
2021 ◽  
Author(s):  
Christiane Rollenhagen ◽  
Harrison Agyeman ◽  
Susan Eszterhas ◽  
Samuel A. Lee
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Fungal Pathogen ◽  
Clinical Importance ◽  
Hospitalized Patients ◽  
Cell Wall Integrity ◽  
Content Type ◽  
Invasive Infections ◽  
Opportunistic Fungal Pathogen ◽  
Considerable Morbidity

The opportunistic fungal pathogen Candida albicans is an important cause of invasive infections in hospitalized patients and a source of considerable morbidity and mortality. Despite its clinical importance, we still need to improve our ability to diagnose and treat this common pathogen.

scholarly journals Calcineurin Controls Drug Tolerance, Hyphal Growth, and Virulence in Candida dubliniensis

2011 ◽  
Vol 10 (6) ◽  
pp. 803-819 ◽  
Author(s):  
Ying-Lien Chen ◽  
Alexandra Brand ◽  
Emma L. Morrison ◽  
Fitz Gerald S. Silao ◽  
Ursela G. Bigol ◽  
...  
Keyword(s):  
Cell Wall ◽  
Combination Therapy ◽  
Calcineurin Inhibitors ◽  
Hyphal Growth ◽  
Drug Tolerance ◽  
Candida Dubliniensis ◽  
Cell Wall Integrity ◽  
Ocular Infection ◽  
Pathogenic Yeast ◽  
Content Type

ABSTRACTCandida dubliniensisis an emerging pathogenic yeast species closely related toCandida albicansand frequently found colonizing or infecting the oral cavities of HIV/AIDS patients. Drug resistance duringC. dubliniensisinfection is common and constitutes a significant therapeutic challenge. The calcineurin inhibitor FK506 exhibits synergistic fungicidal activity with azoles or echinocandins in the fungal pathogensC. albicans,Cryptococcus neoformans, andAspergillus fumigatus. In this study, we show that calcineurin is required for cell wall integrity and wild-type tolerance ofC. dubliniensisto azoles and echinocandins; hence, these drugs are candidates for combination therapy with calcineurin inhibitors. In contrast toC. albicans, in which the roles of calcineurin and Crz1 in hyphal growth are unclear, here we show that calcineurin and Crz1 play a clearly demonstrable role in hyphal growth in response to nutrient limitation inC. dubliniensis. We further demonstrate that thigmotropism is controlled by Crz1, but not calcineurin, inC. dubliniensis. Similar toC. albicans,C. dubliniensiscalcineurin enhances survival in serum.C. dubliniensiscalcineurin andcrz1/crz1mutants exhibit attenuated virulence in a murine systemic infection model, likely attributable to defects in cell wall integrity, hyphal growth, and serum survival. Furthermore, we show thatC. dubliniensiscalcineurin mutants are unable to establish murine ocular infection or form biofilms in a rat denture model. That calcineurin is required for drug tolerance and virulence makes fungus-specific calcineurin inhibitors attractive candidates for combination therapy with azoles or echinocandins against emergingC. dubliniensisinfections.

scholarly journals The Candida albicans Sur7 Protein Is Needed for Proper Synthesis of the Fibrillar Component of the Cell Wall That Confers Strength

2010 ◽  
Vol 10 (1) ◽  
pp. 72-80 ◽  
Author(s):  
Hong X. Wang ◽  
Lois M. Douglas ◽  
Vishukumar Aimanianda ◽  
Jean-Paul Latgé ◽  
James B. Konopka
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Plasma Membrane ◽  
Wall Structure ◽  
Cell Wall Synthesis ◽  
Calcofluor White ◽  
Content Type ◽  
Membrane Compartment ◽  
Fibrillar Component ◽  
And Function

ABSTRACTTheCandida albicansplasma membrane plays important roles in interfacing with the environment, morphogenesis, and cell wall synthesis. The role of the Sur7 protein in cell wall structure and function was analyzed, since previous studies showed that this plasma membrane protein is needed to prevent abnormal intracellular growth of the cell wall. Sur7 localizes to stable patches in the plasma membrane, known as MCC (membrane compartment occupied by Can1), that are associated with eisosome proteins. Thesur7Δ mutant cells displayed increased sensitivity to factors that exacerbate cell wall defects, such as detergent (SDS) and the chitin-binding agents calcofluor white and Congo red. Thesur7Δ cells were also slightly more sensitive to inhibitors that block the synthesis of cell wall chitin (nikkomycin Z) and β-1,3-glucan (caspofungin). In contrast, Fmp45, a paralog of Sur7 that also localizes to punctate plasma membrane patches, did not have a detectable role in cell wall synthesis. Chemical analysis of cell wall composition demonstrated thatsur7Δ cells contain decreased levels of β-glucan, a glucose polymer that confers rigidity on the cell wall. Consistent with this,sur7Δ cells were more sensitive to lysis, which could be partially rescued by increasing the osmolarity of the medium. Interestingly, Sur7 is present in static patches, whereas β-1,3-glucan synthase is mobile in the plasma membrane and is often associated with actin patches. Thus, Sur7 may influence β-glucan synthesis indirectly, perhaps by altering the functions of the cell signaling components that localize to the MCC and eisosome domains.

scholarly journals Transcription Factor Efg1 Shows a Haploinsufficiency Phenotype in Modulating the Cell Wall Architecture and Immunogenicity of Candida albicans

2011 ◽  
Vol 11 (2) ◽  
pp. 129-140 ◽  
Author(s):  
Martin Zavrel ◽  
Olivia Majer ◽  
Karl Kuchler ◽  
Steffen Rupp
Keyword(s):  
Cell Wall ◽  
Transcription Factor ◽  
Candida Albicans ◽  
Structural Changes ◽  
Protein Composition ◽  
Surface Proteins ◽  
Wall Structure ◽  
Content Type ◽  
Cell Wall Biogenesis ◽  
General Metabolism

ABSTRACTTheCandida albicanstranscription factor Efg1 is known to be involved in many different cellular processes, including morphogenesis, general metabolism, and virulence. Here we show that besides its manifold roles, Efg1 also has a prominent effect on cell wall structure and composition, strongly affecting the structural glucan part. Deletion of only one allele ofEFG1already results in severe phenotypes for cell wall biogenesis, comparable to those with deletion of both alleles, indicative of a severe haploinsufficiency forEFG1. The observed defects in structural setup of the cell wall, together with previously reported alterations in expression of cell surface proteins, result in altered immunogenic properties of strains with compromised Efg1 function. This is shown by interaction studies with macrophages and primary dendritic cells. The structural changes in the cell wall carbohydrate meshwork presented here, together with the manifold changes in cell wall protein composition and metabolism reported in other studies, contribute to the altered immune response mounted by innate immune cells and to the altered virulence phenotypes observed for strains lackingEFG1.

scholarly journals Inhibition of Respiration of Candida albicans by Small Molecules Increases Phagocytosis Efficacy by Macrophages

mSphere ◽  
2020 ◽  
Vol 5 (2) ◽  
Author(s):  
Shuna Cui ◽  
Minghui Li ◽  
Rabeay Y. A. Hassan ◽  
Anna Heintz-Buschart ◽  
Junsong Wang ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Plasma Membrane ◽  
Energy Metabolism ◽  
Unsaturated Fatty Acids ◽  
Immune Defense ◽  
Host Cells ◽  
Wall Structure ◽  
Content Type ◽  
Metabolic Studies

ABSTRACT Candida albicans adapts to various conditions in different body niches by regulating gene expression, protein synthesis, and metabolic pathways. These adaptive reactions not only allow survival but also influence the interaction with host cells, which is governed by the composition and structure of the fungal cell wall. Numerous studies had shown linkages between mitochondrial functionality, cell wall integrity and structure, and pathogenicity. Thus, we decided to inhibit single complexes of the respiratory chain of C. albicans and to analyze the resultant interaction with macrophages via their phagocytic activity. Remarkably, inhibition of the fungal bc1 complex by antimycin A increased phagocytosis, which correlated with an increased accessibility of β-glucans. To contribute to mechanistic insights, we performed metabolic studies, which highlighted significant changes in the abundance of constituents of the plasma membrane. Collectively, our results reinforce the strong linkage between fungal energy metabolism and other components of fungal physiology, which also determine the vulnerability to immune defense reactions. IMPORTANCE The yeast Candida albicans is one of the major fungal human pathogens, for which new therapeutic approaches are required. We aimed at enhancements of the phagocytosis efficacy of macrophages by targeting the cell wall structure of C. albicans, as the coverage of the β-glucan layer by mannans is one of the immune escape mechanisms of the fungus. We unambiguously show that inhibition of the fungal bc1 complex correlates with increased accessibilities of β-glucans and improved phagocytosis efficiency. Metabolic studies proved not only the known direct effects on reactive oxygen species (ROS) production and fermentative pathways but also the clear downregulation of the ergosterol pathway and upregulation of unsaturated fatty acids. The changed composition of the plasma membrane could also influence the interaction with the overlying cell wall. Thus, our work highlights the far-reaching relevance of energy metabolism, indirectly also for host-pathogen interactions, without affecting viability.

scholarly journals The Novel J-Domain Protein Mrj1 Is Required for Mitochondrial Respiration and Virulence in Cryptococcus neoformans

mBio ◽  
2020 ◽  
Vol 11 (3) ◽  
Author(s):  
Linda C. Horianopoulos ◽  
Guanggan Hu ◽  
Mélissa Caza ◽  
Kerstin Schmitt ◽  
Peter Overby ◽  
...  
Keyword(s):  
Cell Wall ◽  
Cryptococcus Neoformans ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Antifungal Drugs ◽  
Complex Iii ◽  
Content Type ◽  
Mitochondrial Functions ◽  
J Domain ◽  
Domain Protein

ABSTRACT The opportunistic fungal pathogen Cryptococcus neoformans must adapt to the mammalian environment to establish an infection. Proteins facilitating adaptation to novel environments, such as chaperones, may be required for virulence. In this study, we identified a novel mitochondrial co-chaperone, Mrj1 (mitochondrial respiration J-domain protein 1), necessary for virulence in C. neoformans. The mrj1Δ and J-domain-inactivated mutants had general growth defects at both routine laboratory and human body temperatures and were deficient in the major virulence factor of capsule elaboration. The latter phenotype was associated with cell wall changes and increased capsular polysaccharide shedding. Accordingly, the mrj1Δ mutant was avirulent in a murine model of cryptococcosis. Mrj1 has a mitochondrial localization and co-immunoprecipitated with Qcr2, a core component of complex III of the electron transport chain. The mrj1 mutants were deficient in mitochondrial functions, including growth on alternative carbon sources, growth without iron, and mitochondrial polarization. They were also insensitive to complex III inhibitors and hypersensitive to an alternative oxidase (AOX) inhibitor, suggesting that Mrj1 functions in respiration. In support of this conclusion, mrj1 mutants also had elevated basal oxygen consumption rates which were completely abolished by the addition of the AOX inhibitor, confirming that Mrj1 is required for mitochondrial respiration through complexes III and IV. Furthermore, inhibition of complex III phenocopied the capsule and cell wall defects of the mrj1 mutants. Taken together, these results indicate that Mrj1 is required for normal mitochondrial respiration, a key aspect of adaptation to the host environment and virulence. IMPORTANCE Cryptococcus neoformans is the causative agent of cryptococcal meningitis, a disease responsible for ∼15% of all HIV-related deaths. Unfortunately, development of antifungal drugs is challenging because potential targets are conserved between humans and C. neoformans. In this context, we characterized a unique J-domain protein, Mrj1, which lacks orthologs in humans. We showed that Mrj1 was required for normal mitochondrial respiration and that mutants lacking Mrj1 were deficient in growth, capsule elaboration, and virulence. Furthermore, we were able to phenocopy the defects in growth and capsule elaboration by inhibiting respiration. This result suggests that the role of Mrj1 in mitochondrial function was responsible for the observed virulence defects and reinforces the importance of mitochondria to fungal pathogenesis. Mitochondria are difficult to target, as their function is also key to human cells; however, Mrj1 presents an opportunity to target a unique fungal protein required for mitochondrial function and virulence in C. neoformans.

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