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Methods in Molecular Biology (Clifton,... 2023Pneumocystis jirovecii causes pneumonia in immunocompromised patients. A major challenge in drug susceptibility testing and in understanding host/pathogen interactions... (Review)
Review
Pneumocystis jirovecii causes pneumonia in immunocompromised patients. A major challenge in drug susceptibility testing and in understanding host/pathogen interactions is that Pneumocystis spp. are not viable in vitro. Continuous culture of the organism is not currently available, and therefore, developing new drug targets is very limited. Due to this limitation, mouse models of Pneumocystis pneumonia have proven to be an invaluable resource to researchers. In this chapter, we provide an overview of selected methods used in mouse models of infection including, in vivo Pneumocystis murina propagation, routes of transmission, genetic mouse models available, a P. murina life form-specific model, a mouse model of PCP immune reconstitution inflammatory syndrome (IRIS), and the experimental parameters associated with these models.
Topics: Animals; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pneumocystis carinii; Pneumonia, Pneumocystis
PubMed: 37145284
DOI: 10.1007/978-1-0716-3199-7_13 -
Advances in Experimental Medicine and... 2020Most fungal species are harmless to humans and some exist as commensals on mucocutaneous surfaces. Yet many fungi are opportunistic pathogens, causing life-threatening... (Review)
Review
Most fungal species are harmless to humans and some exist as commensals on mucocutaneous surfaces. Yet many fungi are opportunistic pathogens, causing life-threatening invasive infections when the immune system becomes compromised. The fungal cell wall contains conserved pathogen-associated molecular patterns (PAMPs), which allow the immune system to distinguish between self (endogenous molecular patterns) and foreign material. Sensing of invasive microbial pathogens is achieved through recognition of PAMPs by pattern recognition receptors (PRRs). One of the predominant fungal-sensing PRRs is the C-type lectin receptor (CLR) family. These receptors bind to structures present on the fungal cell wall, eliciting various innate immune responses as well as shaping adaptive immunity. In this chapter, we specifically focus on the four major human fungal pathogens, Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans and Pneumocystis jirovecii, reviewing our current understanding of the CLRs that are involved in their recognition and protection of the host.
Topics: Aspergillus fumigatus; Candida albicans; Cryptococcus neoformans; Fungi; Humans; Immunity, Innate; Lectins, C-Type; Pathogen-Associated Molecular Pattern Molecules; Pneumocystis carinii
PubMed: 32152941
DOI: 10.1007/978-981-15-1580-4_1 -
Respiratory Investigation Jul 2022While Pneumocystis jirovecii pneumonia (PCP) can occur in immunocompromised patients with HIV infection, the prognosis of non-HIV PCP is still poor, showing a high... (Review)
Review
While Pneumocystis jirovecii pneumonia (PCP) can occur in immunocompromised patients with HIV infection, the prognosis of non-HIV PCP is still poor, showing a high mortality rate of 30%-75%. The pathophysiological mechanism of non-HIV PCP is quite different from that of HIV-PCP. Aging, underlying disease, dysbiotic gut microbiome, and Th1 predominance, leads to macrophagic polarization shifting from M2 to M1. These cause dysregulation in the host immunity against P. jirovecii, resulting in severe lung injury and a high mortality rate among non-HIV PCP patients. This review describes poor prognostic factors, an issue of predictive values used for general pneumonia practice, and new aspects, including the dysbiosis of the gut microbiome and macrophagic polarization in the treatment of non-HIV PCP.
Topics: HIV Infections; Humans; Immunocompromised Host; Pneumocystis carinii; Pneumonia, Pneumocystis; Prognosis
PubMed: 35501264
DOI: 10.1016/j.resinv.2022.04.002 -
MBio Feb 2023Pneumocystis jirovecii kills hundreds of thousands of immunocompromised patients each year. Yet many aspects of the biology of this obligate pathogen remain obscure...
Pneumocystis jirovecii kills hundreds of thousands of immunocompromised patients each year. Yet many aspects of the biology of this obligate pathogen remain obscure because it is not possible to culture the fungus independently of its host. Consequently, our understanding of Pneumocystis pathobiology is heavily reliant upon bioinformatic inferences. We have exploited a powerful combination of genomic and phylogenetic approaches to examine the evolution of transcription factors in Pneumocystis species. We selected protein families (Pfam families) that correspond to transcriptional regulators and used bioinformatic approaches to compare these families in the seven Pneumocystis species that have been sequenced to date with those from other yeasts, other human and plant pathogens, and other obligate parasites. Some Pfam families of transcription factors have undergone significant reduction during their evolution in the Pneumocystis genus, and other Pfam families have been lost or appear to be in the process of being lost. Meanwhile, other transcription factor families have been retained in Pneumocystis species, and some even appear to have undergone expansion. On this basis, Pneumocystis species seem to have retained transcriptional regulators that control chromosome maintenance, ribosomal gene regulation, RNA processing and modification, and respiration. Meanwhile, regulators that promote the assimilation of alternative carbon sources, amino acid, lipid, and sterol biosynthesis, and iron sensing and homeostasis appear to have been lost. Our analyses of transcription factor retention, loss, and gain provide important insights into the biology and lifestyle of Pneumocystis. Pneumocystis jirovecii is a major fungal pathogen of humans that infects healthy individuals, colonizing the lungs of infants. In immunocompromised and transplant patients, this fungus causes life-threatening pneumonia, and these Pneumocystis infections remain among the most common and serious infections in HIV/AIDS patients. Yet we remain remarkably ignorant about the biology and epidemiology of Pneumocystis due to the inability to culture this fungus . Our analyses of transcription factor retentions, losses, and gains in sequenced Pneumocystis species provide valuable new views of their specialized biology, suggesting the retention of many metabolic and stress regulators and the loss of others that are essential in free-living fungi. Given the lack of culture methods for Pneumocystis, this powerful bioinformatic approach has advanced our understanding of the lifestyle of and the nature of its dependence on the host for survival.
Topics: Humans; Pneumocystis; Phylogeny; Transcription Factors; Pneumonia, Pneumocystis; Pneumocystis carinii; Genomics; Life Style
PubMed: 36651897
DOI: 10.1128/mbio.02711-22 -
Rheumatology (Oxford, England) Oct 2023To identify potential risk factors and prognostic factors of Pneumocystis jirovecii pneumonia (PJP) infection in anti-melanoma differentiation-associated gene 5...
OBJECTIVES
To identify potential risk factors and prognostic factors of Pneumocystis jirovecii pneumonia (PJP) infection in anti-melanoma differentiation-associated gene 5 antibody-positive DM (anti-MDA5+ DM) patients, and to evaluate the diagnostic performance of metagenomic next-generation sequencing (mNGS).
METHODS
Anti-MDA5+ DM patients who underwent mNGS or real-time PCR for PJP detection were recruited. The potential risk factors for PJP occurrence and death were analysed via Logistic regression and Cox proportional hazards regression, respectively. The diagnostic efficacy of mNGS was compared with the conventional methods.
RESULTS
91 patients were enrolled and 44 were assigned to PJP+ group. The PJP detection rate was 48.4%. PJP often occurred in the first 3 months (68.2%) of the disease; this period also showed the highest mortality rate (20.5%). Fever and increased lactate dehydrogenase (LDH) were independent risk factors for PJP occurrence, while trimethoprim-sulfamethoxazole (TMP/SMZ) prophylaxis was an independent protective factor (all P < 0.05). Older age and increased LDH were predictors for mortality in patients with anti-MDA5+ DM and PJP (all P < 0.05). In addition, we found that mNGS had a sensitivity of 100.0% and specificity of 90.0% in diagnosing PJP, with the highest area under the curve of 0.95 (P < 0.001).
CONCLUSION
PJP has high prevalence and mortality in anti-MDA5+ DM. It is crucial for clinicians to identify high-risk patients and promptly institute TMP/SMZ to prevent PJP. mNGS is the preferred approach for pathogen detection in anti-MDA5+ DM when PJP is suspected.
Topics: Humans; Pneumonia, Pneumocystis; Pneumocystis carinii; Prevalence; Dermatomyositis; Retrospective Studies; Trimethoprim, Sulfamethoxazole Drug Combination
PubMed: 36734589
DOI: 10.1093/rheumatology/kead063 -
Infectious Disease Clinics of North... Sep 2023Pneumocystis infection manifests predominantly as an interstitial pneumonia in immunocompromised patients. Diagnostic testing in the appropriate clinical context can be... (Review)
Review
Pneumocystis infection manifests predominantly as an interstitial pneumonia in immunocompromised patients. Diagnostic testing in the appropriate clinical context can be highly sensitive and specific and involves radiographic imaging, fungal biomarkers, nucleic acid amplification, histopathology, and lung fluid or tissue sampling. Trimethoprim-sulfamethoxazole remains the first-choice agent for treatment and prophylaxis. Investigation continues to promote a deeper understanding of the pathogen's ecology, epidemiology, host susceptibility, and optimal treatment and prevention strategies in solid organ transplant recipients.
Topics: Humans; Pneumonia, Pneumocystis; Pneumocystis carinii; Organ Transplantation; Trimethoprim, Sulfamethoxazole Drug Combination; Immunocompromised Host
PubMed: 37142510
DOI: 10.1016/j.idc.2023.03.005 -
BMC Immunology Jun 2021Pneumocystis pneumonia (PcP), which is caused by Pneumocystis carinii, is a life-threatening infection that affects immunocompromised individuals. Unfortunately,...
BACKGROUND
Pneumocystis pneumonia (PcP), which is caused by Pneumocystis carinii, is a life-threatening infection that affects immunocompromised individuals. Unfortunately, chemoprophylaxis and dapsone are only effective for half of the patients with PcP, indicating that additional preventive methods are needed. We predicated the pneumocystis surface protein A12 sequence 1-85 by DNAStar software and BepiPred, and identified it as a potential vaccine candidate by bioresearch.
METHODS
We used recombinant A12 as antigen to immunized mice and detected serum titer of IgG, expression of inflammatory factors by EILSA, qRT-PCR and flow cytometry.
RESULTS
Our results showed that immunization with recombinant A12 increased the serum titer of IgG, promoted the secretion of T lymphocytes, increased the expression of inflammatory factors, and elevated lung inflammatory injury in mice.
CONCLUSIONS
Our findings suggest that A12 is a potential vaccine target for preventing Pneumocystis carinii. The evaluation of A12-elicited antibodies in the prevention of PcP in humans deserves further investigation.
Topics: Animals; Antibodies, Fungal; Antigens, Fungal; Cells, Cultured; Disease Models, Animal; Female; Fungal Vaccines; Humans; Immunization; Immunocompromised Host; Immunoglobulin G; Lung; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Peptides; Pneumocystis carinii; Pneumonia, Pneumocystis; Recombinant Proteins; T-Lymphocytes
PubMed: 34174820
DOI: 10.1186/s12865-021-00436-6 -
Frontiers in Cellular and Infection... 2022can result in a serious pulmonary infection, pneumonia, in immunocompetent hosts. The diagnosis of pneumonia has long been a major clinical concern, and there are...
BACKGROUND
can result in a serious pulmonary infection, pneumonia, in immunocompetent hosts. The diagnosis of pneumonia has long been a major clinical concern, and there are limitations with the currently utilized immunostaining and polymerase chain reaction diagnosis/detection technologies (, insufficient sensitivity and accuracy). Hence, we sought to establish a rapid and RNA-specific transcription mediated amplification and CRISPR/Cas13a-based diagnostics targeted -mitochondrial large subunit ribosomal RNA.
METHODS
The procedure of the diagnostics included amplification of the extracted RNA samples by transcription mediated amplification, followed by CRISPR/Cas13 detection, and ultimately, the judgment of the results after 30 minutes of fluorescence signal. Later, the diagnostic performance of the CRISPR/Cas13-based diagnostics were tested on the 62 surplus clinical samples.
RESULTS
This CRISPR/Cas13-based diagnostics achieved limits of detection of approximately 2 copies/µL transcribed RNA templates, with no cross reaction to other respiratory pathogens, including bacteria and fungi. Similar to in-house quantitative real-time polymerase chain reaction, CRISPR/Cas13-based diagnostics was still positive in 243-fold diluted bronchial alveolar lavage fluid. A preliminary evaluation of 62 surplus bronchial alveolar lavage fluid samples from patients suspected of pneumonia showed that CRISPR/Cas13-based diagnostics achieved a 78.9% sensitivity and a 97.7% specificity in the diagnosis of pneumonia.
CONCLUSION
Our study demonstrates that the CRISPR/Cas13-based diagnostics technique has good performance for the accurate and specific diagnosis of pneumonia.
Topics: CRISPR-Cas Systems; Humans; Pneumocystis carinii; Pneumonia, Pneumocystis; RNA; Real-Time Polymerase Chain Reaction
PubMed: 35782118
DOI: 10.3389/fcimb.2022.904485 -
Journal of Hospital Medicine Aug 2019
Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Antigens, Viral; Capsid Proteins; Ceftriaxone; Chills; Diagnosis, Differential; Dyspnea; Fatal Outcome; Fever; Humans; Male; Middle Aged; Pneumocystis carinii; Pneumonia, Bacterial; Prednisolone; Shock, Hemorrhagic
PubMed: 31251159
DOI: 10.12788/jhm.3224 -
Pharmaceutical Patent Analyst Jul 2023Repurposing of approved drugs in a new strategy to combat cancer that leads to savings in time and investment. Atovaquone is a US FDA-approved drug for treatment of...
Repurposing of approved drugs in a new strategy to combat cancer that leads to savings in time and investment. Atovaquone is a US FDA-approved drug for treatment of pneumonia and malaria. Patent US2023017373 describe the use of mito-atovaquone for the treatment of several types of cancer. Mito-atovaquone demonstrated antiproliferative activity in cell lines of pancreatic cancer, lung cancer and brain cancer and inhibited tumor growth in syngeneic mouse models and in animals genetically prone to breast cancer. Mito-atovaquone has the potential to be used successfully in the treatment of various types of tumors.
Topics: Mice; Animals; Atovaquone; Drug Repositioning; Antifungal Agents; Naphthoquinones; Pneumonia, Pneumocystis; Neoplasms; Mitomycin
PubMed: 37801038
DOI: 10.4155/ppa-2023-0015