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Microbiology Spectrum Dec 2022The proposed life cycle of fungi in the genus Pneumocystis has typically included both an asexual cycle via binary fission and a sexual cycle. Until recently, the...
The proposed life cycle of fungi in the genus Pneumocystis has typically included both an asexual cycle via binary fission and a sexual cycle. Until recently, the strategy used for sexual replication was largely unknown, but genomic and functional assays now support a mode known as primary homothallism (self-fertilization). The question of whether an asexual cycle contributes to the growth of these fungi remains. Treatment of Pneumocystis pneumonia in immunosuppressed rodent models with the class of drugs known as echinocandins is challenging the historical concept of asexual replication. The echinocandins target 1,3-β-D-glucan (BG) synthesis resulting in death for most fungi. Because Pneumocystis species have both non-BG expressing life cycle stages (trophic forms) and BG-expressing asci, treatment with anidulafungin and caspofungin resulted in elimination of asci, with large numbers of non-BG expressing organisms remaining in the lungs. Transcriptional analyses of anidulafungin treated Pneumocystis murina-infected lungs indicated that these agents were blocking the sexual cycle. In the present study, we explored whether there was an asexual or alternative method of replication that could rescue P. murina survival and growth in the context of anidulafungin treatment. The effects of anidulafungin treatment on early events in the sexual cycle were investigated by RT-qPCR targeting specific mating genes, including , and . Results from the and gene expression studies clearly indicated there was no rescue by an asexual cycle, supporting these fungi's reliance on the sexual cycle for survival and growth. Dysregulation of mating-associated genes showed that anidulafungin induced effects early in the mating process. The concept of a sexually obligate fungus is unique among human fungal pathogens. This reliance can be exploited for drug development and here we show a proof of principle for this unusual target. Most human fungal pathogens eschew the mammalian environment with its battery of immune responses. Pneumocystis appear to have evolved to survive in such an environment, perhaps by using sexual replication to help in DNA repair and to introduce genetic variation in its major surface antigen family because the lung is the primary environment of these pathogens. The concept of primary homothallism fits well into its chosen ecosystem, with ready mating partners expressing both mating type receptors, and a sexual cycle that can introduce beneficial genetic variation without the need for outbreeding.
Topics: Animals; Anidulafungin; Echinocandins; Ecosystem; Pneumocystis; Pneumonia, Pneumocystis
PubMed: 36287071
DOI: 10.1128/spectrum.02906-22 -
Emerging Infectious Diseases Oct 2004Pneumocystis pneumonia (PCP) remains a major cause of illness and death in HIV-infected persons. Sulfa drugs, trimethoprim-sulfamethoxazole (TMP-SMX) and dapsone are... (Review)
Review
Pneumocystis pneumonia (PCP) remains a major cause of illness and death in HIV-infected persons. Sulfa drugs, trimethoprim-sulfamethoxazole (TMP-SMX) and dapsone are mainstays of PCP treatment and prophylaxis. While prophylaxis has reduced the incidence of PCP, its use has raised concerns about development of resistant organisms. The inability to culture human Pneumocystis, Pneumocystis jirovecii, in a standardized culture system prevents routine susceptibility testing and detection of drug resistance. In other microorganisms, sulfa drug resistance has resulted from specific point mutations in the dihydropteroate synthase (DHPS) gene. Similar mutations have been observed in P. jirovecii. Studies have consistently demonstrated a significant association between the use of sulfa drugs for PCP prophylaxis and DHPS gene mutations. Whether these mutations confer resistance to TMP-SMX or dapsone plus trimethoprim for PCP treatment remains unclear. We review studies of DHPS mutations in P. jirovecii and summarize the evidence for resistance to sulfamethoxazole and dapsone.
Topics: Anti-Infective Agents; Dapsone; Dihydropteroate Synthase; Drug Resistance, Fungal; Gene Expression; Humans; Mutation; Pneumocystis carinii; Pneumonia, Pneumocystis; Risk Factors; Sulfamethoxazole; Sulfones; Trimethoprim
PubMed: 15504256
DOI: 10.3201/eid1010.030994 -
Trends in Parasitology Oct 2021The clinical picture of the fungal disease, Pneumocystis pneumonia, resembles the course of coronavirus disease 2019 (COVID-19), presenting a diagnostic challenge in the...
The clinical picture of the fungal disease, Pneumocystis pneumonia, resembles the course of coronavirus disease 2019 (COVID-19), presenting a diagnostic challenge in the pandemic era. We discuss the concern of Pneumocystis jirovecii and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coinfection, their similarities, and the impact of immunosuppression, with a suggested diagnostic pathway for their suspected coinfection.
Topics: COVID-19; Coinfection; Humans; Immunosuppression Therapy; Pandemics; Pneumocystis carinii; Pneumonia, Pneumocystis
PubMed: 34364804
DOI: 10.1016/j.pt.2021.07.010 -
FEMS Microbiology Reviews Nov 2006The genus Pneumocystis comprises noncultivable, highly diversified fungal pathogens dwelling in the lungs of mammals. The genus includes numerous host-species-specific... (Review)
Review
Pneumocystis oryctolagi sp. nov., an uncultured fungus causing pneumonia in rabbits at weaning: review of current knowledge, and description of a new taxon on genotypic, phylogenetic and phenotypic bases.
The genus Pneumocystis comprises noncultivable, highly diversified fungal pathogens dwelling in the lungs of mammals. The genus includes numerous host-species-specific species that are able to induce severe pneumonitis, especially in severely immunocompromised hosts. Pneumocystis organisms attach specifically to type-1 epithelial alveolar cells, showing a high level of subtle and efficient adaptation to the alveolar microenvironment. Pneumocystis species show little difference at the light microscopy level but DNA sequences of Pneumocystis from humans, other primates, rodents, rabbits, insectivores and other mammals present a host-species-related marked divergence. Consistently, selective infectivity could be proven by cross-infection experiments. Furthermore, phylogeny among primate Pneumocystis species was correlated with the phylogeny of their hosts. This observation suggested that cophylogeny could explain both the current distribution of pathogens in their hosts and the speciation. Thus, molecular, ultrastructural and biological differences among organisms from different mammals strengthen the view of multiple species existing within the genus Pneumocystis. The following species were subsequently described: Pneumocystis jirovecii in humans, Pneumocystis carinii and Pneumocystis wakefieldiae in rats, and Pneumocystis murina in mice. The present work focuses on Pneumocystis oryctolagi sp. nov. from Old-World rabbits. This new species has been described on the basis of both biological and phylogenetic species concepts.
Topics: Animals; Animals, Wild; France; Fungal Proteins; Genes, Fungal; Lung; Microscopy, Electron; Molecular Sequence Data; Phylogeny; Pneumocystis; Pneumonia, Pneumocystis; Rabbits; Species Specificity
PubMed: 17064284
DOI: 10.1111/j.1574-6976.2006.00037.x -
COPD Feb 2008Chronic obstructive pulmonary disease (COPD) results in significant morbidity and mortality. Smoking has long been recognized as the primary risk factor for development... (Review)
Review
Chronic obstructive pulmonary disease (COPD) results in significant morbidity and mortality. Smoking has long been recognized as the primary risk factor for development of COPD, but factors determining the severity or pattern of disease in smokers are largely unknown. Recent interest has focused on the potential role of infectious agents and the associated host response in accelerating progression of airway obstruction or in perpetuating its progression following discontinuation of tobacco exposure. Pneumocystis jirovecii is a fungal pathogen that causes pneumonia in immunocompromised individuals. Recent evidence has linked this organism with COPD. Using sensitive molecular techniques, low levels of Pneumocystis have been detected in the respiratory tract of certain individuals and termed colonization. Several findings support the theory that colonization with Pneumocystis is involved in the "vicious circle" hypothesis of COPD in which colonization with organisms perpetuates an inflammatory and lung remodeling response. Pneumocystis colonization is more prevalent in smokers and in those with severe COPD. The presence of Pneumocystis in the lungs, even at low levels, produces inflammatory changes similar to those seen in COPD, with increases in numbers of neutrophils and CD8(+) lymphocytes. HIV-infected subjects who have had PCP develop permanent airway obstruction, and HIV-infected patients have a high prevalence of both emphysema and Pneumocystis colonization. In addition, a non-human primate model of colonization shows development of airway obstruction and radiographic emphysema. Additional studies are needed to confirm the role of Pneumocystis in the pathogenesis of COPD, given that this agent might be a treatable co-factor in disease progression.
Topics: Disease Progression; Humans; Lung; Morbidity; Pneumocystis; Pneumonia, Pneumocystis; Pulmonary Disease, Chronic Obstructive; Survival Rate; United States
PubMed: 18259974
DOI: 10.1080/15412550701817656 -
Journal of Medical Microbiology Dec 2021Pathogen-associated molecular patterns' (PAMPs) are microbial signatures that are recognized by host myeloid C-type lectin receptors (CLRs). These CLRs interact with...
Pathogen-associated molecular patterns' (PAMPs) are microbial signatures that are recognized by host myeloid C-type lectin receptors (CLRs). These CLRs interact with micro-organisms via their carbohydrate recognition domains (CRDs) and engage signalling pathways within the cell resulting in pro-inflammatory and microbicidal responses. In this article, we extend our laboratory study of additional CLRs that recognize fungal ligands against and and their purified major surface glycoproteins (Msgs). To study the potential of newly synthesized hFc-CLR fusions on binding to and its Msg. A library of new synthesized hFc-CLR fusions was screened against and organisms and their purified major surface glycoproteins (Msgs) found on the respective fungi via modified ELISA. Immunofluorescence assay (IFA) was implemented and quantified to verify results. mRNA expression analysis by quantitative PCR (q-PCR) was employed to detect respective CLRs found to bind fungal organisms in the ELISA and determine their expression levels in the mouse immunosuppressed Pneumocystis pneumonia (PCP) model. We detected a number of the CLR hFc-fusions displayed significant binding with and organisms, and similarly to their respective Msgs. Significant organism and Msg binding was observed for CLR members C-type lectin domain family 12 member A (CLEC12A), Langerin, macrophage galactose-type lectin-1 (MGL-1), and specific intracellular adhesion molecule-3 grabbing non-integrin homologue-related 3 (SIGNR3). Immunofluorescence assay (IFA) with the respective CLR hFc-fusions against whole life forms corroborated these findings. Lastly, we surveyed the mRNA expression profiles of the respective CLRs tested above in the mouse immunosuppressed Pneumocystis pneumonia (PCP) model and determined that macrophage galactose type C-type lectin (), implicated in recognizing terminal N-acetylgalactosamine (GalNAc) found in the glycoproteins of microbial pathogens was significantly up-regulated during infection. The data herein add to the growing list of CLRs recognizing and provide insights for further study of organism/host immune cell interactions.
Topics: Animals; Mice; Fungal Proteins; Galactose; Host-Pathogen Interactions; Lectins, C-Type; Membrane Glycoproteins; Pneumocystis; Pneumocystis carinii; Pneumonia, Pneumocystis; RNA, Messenger
PubMed: 34889727
DOI: 10.1099/jmm.0.001470 -
Antimicrobial Agents and Chemotherapy Oct 2019
Topics: Caspofungin; Catalytic Domain; Echinocandins; Glucosyltransferases; Humans; Mutagenesis, Site-Directed; Pneumocystis carinii; Pneumonia, Pneumocystis
PubMed: 31548210
DOI: 10.1128/AAC.01296-19 -
Frontiers in Immunology 2021is one of the most common fungal pathogens in immunocompromised individuals. Pneumocystis jirovecii pneumonia (PJP) causes a significant host immune response that is... (Review)
Review
is one of the most common fungal pathogens in immunocompromised individuals. Pneumocystis jirovecii pneumonia (PJP) causes a significant host immune response that is driven greatly by the organism's cell wall components including β-glucans and major surface glycoprotein (Msg). These ligands interact with a number of C-type lectin receptors (CLRs) leading to downstream activation of proinflammatory signaling pathways. This minireview provides a brief overview summarizing known CLR/ interactions.
Topics: Animals; Fungal Proteins; Host-Pathogen Interactions; Humans; Immunity, Innate; Inflammation Mediators; Lectins, C-Type; Ligands; Membrane Glycoproteins; Pneumocystis carinii; Pneumonia, Pneumocystis; Signal Transduction; beta-Glucans
PubMed: 34975910
DOI: 10.3389/fimmu.2021.798214 -
PLoS Neglected Tropical Diseases Dec 2021Pneumocystis pneumonia (PCP) and pulmonary toxoplasmosis (PT) are caused by Pneumocystis jirovecii and Toxoplasma gondii. The clinical symptoms and imaging of PCP and PT...
Pneumocystis pneumonia (PCP) and pulmonary toxoplasmosis (PT) are caused by Pneumocystis jirovecii and Toxoplasma gondii. The clinical symptoms and imaging of PCP and PT are indistinguishable. A duplex qPCR was developed to differentiate between these two pathogens. In testing 92 clinical samples to validate the performance of this method for P. jirovecii detection, it identified 31 positive samples for P. jirovecii infection, consistent with clinical diagnosis. Among the remainder of the 61 clinical samples with suspected PCP, yet showing as negative by the conventional PCR diagnosis approach, 6 of them proved positive using our new assay. Our new approach also produced similar results in identification of T. gondii infections, giving a result of 2 positive and 20 negative in clinical samples. An investigation was undertaken on the prevalence of P. jirovecii and T. gondii infections using 113 samples from lung infection patients. 9% (10/113) were shown to be positive with infections of P. jirovecii, 2% with T. gondii (2/113) and 5% (6/113) were co-infected with both pathogens. Although this duplex qPCR can detect individual P. jirovecii and T. gondii infection, and co-infection of both pathogens, further large-scale investigations are needed to validate its performance, especially in T. gondii detection. Our assay provides a rapid and accurate tool for PCP and PT diagnosis in immunocompromised population and clinical surveillance of these infections in patients with no immune defects.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Female; Humans; Immunocompromised Host; Infant; Lung; Lung Diseases; Male; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Polymerase Chain Reaction; Toxoplasma; Toxoplasmosis; Young Adult
PubMed: 34919557
DOI: 10.1371/journal.pntd.0010025 -
Parasite (Paris, France) Aug 2011Pneumocystis pneumonia (PcP) is a serious fungal infection among immunocompromised patients. In developed countries, the epidemiology and clinical spectrum of PcP have... (Review)
Review
Pneumocystis pneumonia (PcP) is a serious fungal infection among immunocompromised patients. In developed countries, the epidemiology and clinical spectrum of PcP have been clearly defined and well documented. However, in most developing countries, relatively little is known about the prevalence of pneumocystosis. Several articles covering African, Asian and American countries were reviewed in the present study. PcP was identified as a frequent opportunistic infection in AIDS patients from different geographic regions. A trend to an increasing rate of PcP was apparent in developing countries from 2002 to 2010.
Topics: Africa; Americas; Asia; Developing Countries; Immunocompromised Host; Pneumocystis carinii; Pneumonia, Pneumocystis; Prevalence
PubMed: 21894262
DOI: 10.1051/parasite/2011183219