scholarly journals Host defense mechanisms induce genome instability in an opportunistic fungal pathogen

2021 ◽  
Author(s):  
Amanda C Smith ◽  
Meleah A Hickman
Keyword(s):  
Fungal Pathogen ◽  
Defense Mechanisms ◽  
Large Scale ◽  
Genome Instability ◽  
Innate Immune ◽  
Rapid Adaptation ◽  
Genomic Changes ◽  
Opportunistic Fungal Pathogen ◽  
Immunocompromised Hosts ◽  
Stressful Environments

The ability to generate genetic variation facilitates rapid adaptation in stressful environments. The opportunistic fungal pathogen Candida albicans frequently undergoes large-scale genomic changes, including aneuploidy and loss-of heterozygosity (LOH), following exposure to physiological stressors and host environments. However, the specific host factors that induce C. albicans genome instability remains largely unknown. Here, we leveraged genetically-tractable nematode hosts to specifically investigate the innate immune components driving host-associated C. albicans genome instability, which include host production of antimicrobial peptides (AMPs) and reactive oxygen species (ROS). C. albicans associated with wildtype, immunocompetent hosts carried multiple large-scale genomic changes including LOH, whole chromosome, and segmental aneuploidies. In contrast, C. albicans associated with immunocompromised hosts deficient in AMPs or ROS production had reduced LOH frequencies and fewer, if any, additional genomic changes. We also found that C. albicans cap1∆/∆ strains deficient in ROS detoxification, were more susceptible to host-produced ROS genome instability compared to wildtype C. albicans. Further, genomic perturbations resulting from host-produced ROS are mitigated by the addition of antioxidants. Taken together, this work suggests that host-produced ROS and AMPs induces genotypic plasticity in C. albicans which may facilitate rapid adaptation and lead to phenotypic changes.

Host defense mechanisms induce genome instability leading to rapid evolution in an opportunistic fungal pathogen

2021 ◽  
Author(s):  
Amanda Smith ◽  
Levi Morran ◽  
Meleah A. Hickman
Keyword(s):  
Fungal Pathogen ◽  
Defense Mechanisms ◽  
Large Scale ◽  
Genome Instability ◽  
Rapid Evolution ◽  
Genomic Changes ◽  
Opportunistic Fungal Pathogen ◽  
Immunocompromised Hosts ◽  
Stressful Environments

The ability to generate genetic variation facilitates rapid adaptation in stressful environments. The opportunistic fungal pathogen Candida albicans frequently undergoes large-scale genomic changes, including aneuploidy and loss-of heterozygosity (LOH), following exposure to host environments. However, the specific host factors inducing C. albicans genome instability remain largely unknown. Here, we leveraged the genetic tractability of nematode hosts to investigate whether innate immune components, including antimicrobial peptides (AMPs) and reactive oxygen species (ROS), induced host-associated C. albicans genome instability. C. albicans associated with immunocompetent hosts carried multiple large-scale genomic changes including LOH, whole chromosome, and segmental aneuploidies. In contrast, C. albicans associated with immunocompromised hosts deficient in AMPs or ROS production had reduced LOH frequencies and fewer, if any, additional genomic changes. To evaluate if extensive host-induced genomic changes had long-term consequences for C. albicans adaptation, we experimentally evolved C. albicans in either immunocompetent or immunocompromised hosts and selected for increased virulence. C. albicans evolved in immunocompetent hosts rapidly increased virulence, but not in immunocompromised hosts. Taken together, this work suggests that host-produced ROS and AMPs induces genotypic plasticity in C. albicans which facilitates rapid evolution.

scholarly journals The interplay of phenotype and genotype in Cryptococcus neoformans disease

2020 ◽  
Vol 40 (10) ◽  
Author(s):  
Sophie Altamirano ◽  
Katrina M. Jackson ◽  
Kirsten Nielsen
Keyword(s):  
Patient Outcome ◽  
Cryptococcus Neoformans ◽  
Fungal Pathogen ◽  
Proper Treatment ◽  
Rapid Adaptation ◽  
Complete Understanding ◽  
Phenotypic Changes ◽  
Life Threatening ◽  
Opportunistic Fungal Pathogen

Abstract Cryptococcus neoformans is an opportunistic fungal pathogen that causes life-threatening meningitis primarily in immunocompromised individuals. In order to survive and proliferate during infection, C. neoformans must adapt to a variety of stresses it encounters within the host. Patient outcome depends on the interaction between the pathogen and the host. Understanding the mechanisms that C. neoformans uses to facilitate adaptation to the host and promote pathogenesis is necessary to better predict disease severity and establish proper treatment. Several virulence phenotypes have been characterized in C. neoformans, but the field still lacks a complete understanding of how genotype and phenotype contribute to clinical outcome. Furthermore, while it is known that C. neoformans genotype impacts patient outcome, the mechanisms remain unknown. This lack of understanding may be due to the genetic heterogeneity of C. neoformans and the extensive phenotypic variation observed between and within isolates during infection. In this review, we summarize the current understanding of how the various genotypes and phenotypes observed in C. neoformans correlate with human disease progression in the context of patient outcome and recurrence. We also postulate the mechanisms underlying the genetic and phenotypic changes that occur in vivo to promote rapid adaptation in the host.

scholarly journals Proteinous Components of Neutrophil Extracellular Traps Are Arrested by the Cell Wall Proteins of Candida albicans during Fungal Infection, and Can Be Used in the Host Invasion

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2736
Author(s):  
Justyna Karkowska-Kuleta ◽  
Magdalena Smolarz ◽  
Karolina Seweryn-Ozog ◽  
Dorota Satala ◽  
Marcin Zawrotniak ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Fungal Pathogen ◽  
Defense Mechanisms ◽  
Triosephosphate Isomerase ◽  
Neutrophil Extracellular Traps ◽  
Phosphoglycerate Mutase ◽  
Human Immune System ◽  
Extracellular Traps ◽  
Human Proteins ◽  
Opportunistic Fungal Pathogen

One of defense mechanisms of the human immune system to counteract infection by the opportunistic fungal pathogen Candida albicans is the recruitment of neutrophils to the site of invasion, and the subsequent production of neutrophil extracellular traps (NETs) that efficiently capture and kill the invader cells. In the current study, we demonstrate that within these structures composed of chromatin and proteins, the latter play a pivotal role in the entrapment of the fungal pathogen. The proteinous components of NETs, such as the granular enzymes elastase, myeloperoxidase and lactotransferrin, as well as histones and cathelicidin-derived peptide LL-37, are involved in contact with the surface of C. albicans cells. The fungal partners in these interactions are a typical adhesin of the agglutinin-like sequence protein family Als3, and several atypical surface-exposed proteins of cytoplasmic origin, including enolase, triosephosphate isomerase and phosphoglycerate mutase. Importantly, the adhesion of both the elastase itself and the mixture of proteins originating from NETs on the C. albicans cell surface considerably increased the pathogen potency of human epithelial cell destruction compared with fungal cells without human proteins attached. Such an implementation of adsorbed NET-derived proteins by invading C. albicans cells might alter the effectiveness of the fungal pathogen entrapment and affect the further host colonization.

scholarly journals Host-Induced Genome Instability Rapidly Generates Phenotypic Variation across Candida albicans Strains and Ploidy States

mSphere ◽  
2020 ◽  
Vol 5 (3) ◽  
Author(s):  
Amanda C. Smith ◽  
Meleah A. Hickman
Keyword(s):  
Genetic Variation ◽  
Candida Albicans ◽  
Genome Size ◽  
Genetic Background ◽  
Genome Instability ◽  
Content Type ◽  
Host Environment ◽  
Genomic Changes ◽  
Opportunistic Fungal Pathogen

ABSTRACT Candida albicans is an opportunistic fungal pathogen of humans that is typically diploid yet has a highly labile genome tolerant of large-scale perturbations including chromosomal aneuploidy and loss-of-heterozygosity events. The ability to rapidly generate genetic variation is crucial for C. albicans to adapt to changing or stressful environments, like those encountered in the host. Genetic variation occurs via stress-induced mutagenesis or can be generated through its parasexual cycle, in which tetraploids arise via diploid mating or stress-induced mitotic defects and undergo nonmeiotic ploidy reduction. However, it remains largely unknown how genetic background contributes to C. albicans genome instability in vitro or in the host environment. Here, we tested how genetic background, ploidy, and the host environment impacts C. albicans genome stability. We found that host association induced both loss-of-heterozygosity events and genome size changes, regardless of genetic background or ploidy. However, the magnitude and types of genome changes varied across C. albicans strain background and ploidy state. We then assessed if host-induced genomic changes resulted in fitness consequences on growth rate and nonlethal virulence phenotypes and found that many host-derived isolates significantly changed relative to their parental strain. Interestingly, diploid host-associated C. albicans predominantly decreased host reproductive fitness, whereas tetraploid host-associated C. albicans increased host reproductive fitness. Together, these results are important for understanding how host-induced genomic changes in C. albicans alter its relationship with the host. IMPORTANCE Candida albicans is an opportunistic fungal pathogen of humans. The ability to generate genetic variation is essential for adaptation and is a strategy that C. albicans and other fungal pathogens use to change their genome size. Stressful environments, including the host, induce C. albicans genome instability. Here, we investigated how C. albicans genetic background and ploidy state impact genome instability, both in vitro and in a host environment. We show that the host environment induces genome instability, but the magnitude depends on C. albicans genetic background. Furthermore, we show that tetraploid C. albicans is highly unstable in host environments and rapidly reduces in genome size. These reductions in genome size often resulted in reduced virulence. In contrast, diploid C. albicans displayed modest host-induced genome size changes, yet these frequently resulted in increased virulence. Such studies are essential for understanding how opportunistic pathogens respond and potentially adapt to the host environment.

scholarly journals Telomeric DNA sequences in beetle taxa vary with species richness

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Daniela Prušáková ◽  
Vratislav Peska ◽  
Stano Pekár ◽  
Michal Bubeník ◽  
Lukáš Čížek ◽  
...  
Keyword(s):  
Species Richness ◽  
Dna Sequences ◽  
Genome Instability ◽  
Telomeric Sequence ◽  
Dna Repeats ◽  
Telomeric Dna ◽  
Common Pattern ◽  
Telomeric Sequences ◽  
Genomic Changes ◽  
Protective Structures

AbstractTelomeres are protective structures at the ends of eukaryotic chromosomes, and disruption of their nucleoprotein composition usually results in genome instability and cell death. Telomeric DNA sequences have generally been found to be exceptionally conserved in evolution, and the most common pattern of telomeric sequences across eukaryotes is (TxAyGz)n maintained by telomerase. However, telomerase-added DNA repeats in some insect taxa frequently vary, show unusual features, and can even be absent. It has been speculated about factors that might allow frequent changes in telomere composition in Insecta. Coleoptera (beetles) is the largest of all insect orders and based on previously available data, it seemed that the telomeric sequence of beetles varies to a great extent. We performed an extensive mapping of the (TTAGG)n sequence, the ancestral telomeric sequence in Insects, across the main branches of Coleoptera. Our study indicates that the (TTAGG)n sequence has been repeatedly or completely lost in more than half of the tested beetle superfamilies. Although the exact telomeric motif in most of the (TTAGG)n-negative beetles is unknown, we found that the (TTAGG)n sequence has been replaced by two alternative telomeric motifs, the (TCAGG)n and (TTAGGG)n, in at least three superfamilies of Coleoptera. The diversity of the telomeric motifs was positively related to the species richness of taxa, regardless of the age of the taxa. The presence/absence of the (TTAGG)n sequence highly varied within the Curculionoidea, Chrysomeloidea, and Staphylinoidea, which are the three most diverse superfamilies within Metazoa. Our data supports the hypothesis that telomere dysfunctions can initiate rapid genomic changes that lead to reproductive isolation and speciation.

scholarly journals Pneumocystis Melanins Confer Enhanced Organism Viability

2006 ◽  
Vol 5 (6) ◽  
pp. 916-923 ◽  
Author(s):  
Crystal R. Icenhour ◽  
Theodore J. Kottom ◽  
Andrew H. Limper
Keyword(s):  
Fungal Pathogen ◽  
Pneumocystis Carinii ◽  
Environmental Stressors ◽  
Resonance Spectroscopy ◽  
Reverse Transcription Pcr ◽  
Spin Resonance ◽  
Opportunistic Fungal Pathogen ◽  
Adverse Environmental Conditions ◽  
Previous Identification

ABSTRACT Pneumocystis continues to represent an important opportunistic fungal pathogen of those with compromised immunity. Thus, it is crucial to identify factors that affect its viability and pathogenicity. We previously reported the first identification of melanins in Pneumocystis. In the present study, we sought to further characterize these components and define the function for these melanins. Melanins extracted from Pneumocystis and melanized Pneumocystis cells were analyzed by electron spin resonance spectroscopy, revealing spectra consistent with melanins from other fungi. Immunofluorescence assays using anti-melanin monoclonal antibodies showed that melanins are widely present across Pneumocystis host species, including mouse-, ferret-, and human-derived Pneumocystis organisms, as well as Pneumocystis carinii derived from rat. Using immunoelectron microscopy, melanins were found to localize to the cell wall and cytoplasm of P. carinii cysts, as well as to intracystic bodies within mature cysts. Next, the role of melanins on the maintenance of Pneumocystis viability was determined by using quantitative reverse transcription-PCR measurement of the heat shock protein mRNA under adverse environmental conditions. Using a new method to promote the melanization of Pneumocystis, we observed that strongly melanized Pneumocystis retained viability to a greater degree when exposed to UV irradiation or desiccation compared to less-pigmented organisms. These studies support our previous identification of Pneumocystis melanins across the genus, further characterize these Pneumocystis components, and demonstrate that melanins protect Pneumocystis from environmental stressors.

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