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Nature Reviews. Rheumatology Jul 2023
Topics: Humans; Rituximab; Pneumonia, Pneumocystis
PubMed: 37217611
DOI: 10.1038/s41584-023-00982-w -
JAMA Nov 2023
Topics: Humans; Pneumonia, Pneumocystis; Chemoprevention
PubMed: 37988090
DOI: 10.1001/jama.2023.18865 -
Frontiers in Immunology 2023With the extensive use of immunosuppressants, immunosuppression-associated pneumonitis including (PCP) has received increasing attention. Though aberrant adaptive...
INTRODUCTION
With the extensive use of immunosuppressants, immunosuppression-associated pneumonitis including (PCP) has received increasing attention. Though aberrant adaptive immunity has been considered as a key reason for opportunistic infections, the characteristics of innate immunity in these immunocompromised hosts remain unclear.
METHODS
In this study, wild type C57BL/6 mice or dexamethasone-treated mice were injected with or without . Bronchoalveolar lavage fluids (BALFs) were harvested for the multiplex cytokine and metabolomics analysis. The single-cell RNA sequencing (scRNA-seq) of indicated lung tissues or BALFs was performed to decipher the macrophages heterogeneity. Mice lung tissues were further analyzed via quantitative polymerase chain reaction (qPCR) or immunohistochemical staining.
RESULTS
We found that the secretion of both pro-inflammatory cytokines and metabolites in the -infected mice are impaired by glucocorticoids. By scRNA-seq, we identified seven subpopulations of macrophages in mice lung tissues. Among them, a group of Mmp12 macrophages is enriched in the immunocompetent mice with infection. Pseudotime trajectory showed that these Mmp12 macrophages are differentiated from Ly6c classical monocytes, and highly express pro-inflammatory cytokines elevated in BALFs of -infected mice. , we confirmed that dexamethasone impairs the expression of , , and , as well as the fungal killing capacity of alveolar macrophage (AM)-like cells. Moreover, in patients with PCP, we found a group of macrophages resembled the aforementioned Mmp12 macrophages, and these macrophages are inhibited in the patient receiving glucocorticoid treatment. Additionally, dexamethasone simultaneously impaired the functional integrity of resident AMs and downregulated the level of lysophosphatidylcholine, leading to the suppressed antifungal capacities.
CONCLUSION
We reported a group of Mmp12 macrophages conferring protection during infection, which can be dampened by glucocorticoids. This study provides multiple resources for understanding the heterogeneity and metabolic changes of innate immunity in immunocompromised hosts, and also suggests that the loss of Mmp12 macrophages population contributes to the pathogenesis of immunosuppression-associated pneumonitis.
Topics: Mice; Animals; Macrophages, Alveolar; Pneumonia, Pneumocystis; Transcriptome; Glucocorticoids; Matrix Metalloproteinase 12; Multiomics; Mice, Inbred C57BL; Pneumocystis; Cytokines; Immunocompromised Host; Dexamethasone
PubMed: 37359523
DOI: 10.3389/fimmu.2023.1179094 -
Frontiers in Cellular and Infection... 2020pneumonia (PCP) is an AIDS-defining illness. In patients with HIV, the benefit of PCP prophylaxis is well-defined when the CD4 T-cell count decreases below 200...
pneumonia (PCP) is an AIDS-defining illness. In patients with HIV, the benefit of PCP prophylaxis is well-defined when the CD4 T-cell count decreases below 200 cells/μL. In other immunocompromised patients, the value of PCP prophylaxis is not always as well-established. This study aimed to describe the epidemiology of PCP in recent years and assess how many patients with PCP did or did not receive prophylaxis in the month preceding the infection. A multicenter retrospective study was performed in 3 tertiary care hospital. A list of patients that underwent broncho-alveolar lavage sampling and (PJ) PCR testing was retrieved from the microbiology laboratories. An in-house PJ quantitative PCR (qPCR) was used in each center. A cycle threshold (Ct) value of ≤ 28.5-30 was considered a probable PCP. For patients with a positive PJ qPCR but above this threshold, a predefined case definition of possible PCP was defined as a qPCR Ct value ≤ 34-35 and both of the following criteria: 1. Clinical and radiological features compatible with PCP and 2. The patient died or received PCP therapy and survived. Patient files from those with a qPCR Ct value ≤ 35 were reviewed to determine whether the patient fulfilled the case definition and if PCP prophylaxis had been used in the weeks preceding the PCP. Disease-specific guidelines, as well as hospital-wide guidelines, were used to evaluate if prophylaxis could be considered indicated. From 2012 to 2018, 482 BAL samples were tested. Two hundred and four had a qPCR Ct value ≤ 35 and were further evaluated: 90 fulfilled the definition of probable and 63 of possible PCP while the remaining 51 were considered colonized. Seventy-four percentages of the patients with PCP were HIV-negative. Only 11 (7%) of the 153 patients had received prophylaxis, despite that in 133 (87%) cases prophylaxis was indicated according to guidelines. In regions where HIV testing and treatment is available without restrictions, PCP is mainly diagnosed in non-HIV immunocompromised patients. More than four out of five patients with PCP had not received prophylaxis. Strategies to improve awareness of antimicrobial prophylaxis guidelines in immunocompromised patients are urgently needed.
Topics: Humans; Immunocompromised Host; Pneumocystis carinii; Pneumonia, Pneumocystis; Real-Time Polymerase Chain Reaction; Retrospective Studies
PubMed: 32500040
DOI: 10.3389/fcimb.2020.00224 -
Frontiers in Cellular and Infection... 2020pneumonia (PCP) remains the most frequent AIDS-defining illness in developed countries. This infection also occurs in non-AIDS immunosuppressed patients, e.g., those... (Review)
Review
pneumonia (PCP) remains the most frequent AIDS-defining illness in developed countries. This infection also occurs in non-AIDS immunosuppressed patients, e.g., those who have undergone an organ transplantation. Moreover, mild infections related to low pulmonary fungal burden, frequently designated as pulmonary colonization, occurs in patients with chronic pulmonary diseases, e.g., cystic fibrosis (CF). Indeed, this autosomal recessive disorder alters mucociliary clearance leading to bacterial and fungal colonization of the airways. This mini-review compiles and discusses available information on and CF. It highlights significant differences in the prevalence of pulmonary colonization in European and Brazilian CF patients. It also describes the microbiota associated with in CF patients colonized by . Furthermore, we have described genomic diversity in colonized CF patients. In addition of pulmonary colonization, it appears that PCP can occur in CF patients specifically after lung transplantation, thus requiring preventive strategies. In other respects, primary infection is a worldwide phenomenon occurring in non-immunosuppressed infants within their first months. The primary infection is mostly asymptomatic but it can also present as a benign self-limiting infection. It probably occurs in the same manner in CF infants. Nonetheless, two cases of severe primary infection mimicking PCP in CF infants have been reported, the genetic disease appearing in these circumstances as a risk factor of PCP while the host-pathogen interaction in older children and adults with pulmonary colonization remains to be clarified.
Topics: Adult; Brazil; Child; Cystic Fibrosis; Humans; Infant; Lung; Pneumocystis carinii; Pneumonia, Pneumocystis
PubMed: 33117730
DOI: 10.3389/fcimb.2020.571253 -
Zhongguo Xue Xi Chong Bing Fang Zhi Za... Oct 2023, an important opportunistic fungal pathogen that parasitizes in multiple mammalian lungs, may cause life-threatening pneumonia (PCP) and even death among... (Review)
Review
, an important opportunistic fungal pathogen that parasitizes in multiple mammalian lungs, may cause life-threatening pneumonia (PCP) and even death among immunocompromised individuals. With the rapid development of high-throughput sequencing and multi-omics technologies, systematic comparative analyses of genome, transcriptome, and whole-genome sequencing results demonstrate that is a type of obligate biotrophic fungi, and requires obtaining nutrition from hosts. In addition, sexual reproduction is an essential process for survival, production and transmission, and asexual reproduction facilitates survival, which provides new insights into understanding of the whole developmental process of in the host lung and inter-host transmission of . This review summarizes the advances in the reproduction mode of and underlying mechanisms, which provides insights into prevention and treatment of PCP, notably for the prophylaxis against nosocomial transmission of PCP.
Topics: Humans; Lung; Pneumocystis; Pneumonia, Pneumocystis
PubMed: 38148544
DOI: 10.16250/j.32.1374.2022289 -
American Journal of Transplantation :... Apr 2024Solid organ transplant recipients (SOTRs) frequently receive adjunctive glucocorticoid therapy (AGT) for Pneumocystis jirovecii pneumonia (PJP). This multicenter cohort...
Solid organ transplant recipients (SOTRs) frequently receive adjunctive glucocorticoid therapy (AGT) for Pneumocystis jirovecii pneumonia (PJP). This multicenter cohort of SOTRs with PJP admitted to 20 transplant centers in Canada, the United States, Europe, and Australia, was examined for whether AGT was associated with a lower rate of all-cause intensive care unit (ICU) admission, 90-day death, or a composite outcome (ICU admission or death). Of 172 SOTRs with PJP (median [IQR] age: 60 (51.5-67.0) years; 58 female [33.7%]), the ICU admission and death rates were 43.4%, and 20.8%, respectively. AGT was not associated with a reduced risk of ICU admission (adjusted odds ratio [aOR] [95% CI]: 0.49 [0.21-1.12]), death (aOR [95% CI]: 0.80 [0.30-2.17]), or the composite outcome (aOR [95% CI]: 0.97 [0.71-1.31]) in the propensity score-adjusted analysis. AGT was not significantly associated with at least 1 unit of the respiratory portion of the Sequential Organ Failure Assessment score improvement by day 5 (12/37 [32.4%] vs 39/111 [35.1%]; P = .78). We did not observe significant associations between AGT and ICU admission or death in SOTRs with PJP. Our findings should prompt a reevaluation of routine AGT administration in posttransplant PJP treatment and highlight the need for interventional studies.
Topics: Female; Humans; Middle Aged; Europe; Glucocorticoids; Organ Transplantation; Pneumocystis carinii; Pneumonia, Pneumocystis; Retrospective Studies; Transplant Recipients; Male; Aged
PubMed: 37977229
DOI: 10.1016/j.ajt.2023.11.003 -
The Journal of Infectious Diseases Jul 2019Glucan is the major cell wall component of Pneumocystis cysts. In the current study, we have characterized Pneumocystis Bgl2 (EC 3.2.1.58), an enzyme with...
Glucan is the major cell wall component of Pneumocystis cysts. In the current study, we have characterized Pneumocystis Bgl2 (EC 3.2.1.58), an enzyme with glucanosyltransferase and β-1,3 endoglucanase activity in other fungi. Pneumocystis murina, Pneumocystis carinii, and Pneumocystis jirovecii bgl2 complementary DNA sequences encode proteins of 437, 447, and 408 amino acids, respectively. Recombinant P. murina Bgl2 expressed in COS-1 cells demonstrated β-glucanase activity, as shown by degradation of the cell wall of Pneumocystis cysts. It also cleaved reduced laminaripentaose and transferred oligosaccharides, resulting in polymers of 6 and 7 glucan residues, demonstrating glucanosyltransferase activity. Surprisingly, confocal immunofluorescence analysis of P. murina-infected mouse lung sections using an antibody against recombinant Bgl2 showed that the native protein is localized primarily to the trophic form of Pneumocystis in both untreated mice and mice treated with caspofungin, an antifungal drug that inhibits β-1,3-glucan synthase. Thus, like other fungi, Bgl2 of Pneumocystis has both endoglucanase and glucanosyltransferase activities. Given that it is expressed primarily in trophic forms, further studies are needed to better understand its role in the biology of Pneumocystis.
Topics: Amino Acid Sequence; Animals; Antifungal Agents; CD40 Ligand; COS Cells; Caspofungin; Cell Wall; Chlorocebus aethiops; Glucan Endo-1,3-beta-D-Glucosidase; Glucans; Lung; Mice; Mice, Inbred C57BL; Mice, Knockout; Pneumocystis; Pneumonia, Pneumocystis; Recombinant Proteins; Sequence Alignment
PubMed: 31100118
DOI: 10.1093/infdis/jiz172 -
Antimicrobial Agents and Chemotherapy Mar 2024cyst life forms contain abundant β-glucan carbohydrates, synthesized using β-1,3 and β-1,6 glucan synthase enzymes and the donor uridine diphosphate (UDP)-glucose....
cyst life forms contain abundant β-glucan carbohydrates, synthesized using β-1,3 and β-1,6 glucan synthase enzymes and the donor uridine diphosphate (UDP)-glucose. In yeast, phosphoglucomutase (PGM) plays a crucial role in carbohydrate metabolism by interconverting glucose 1-phosphate and glucose 6-phosphate, a vital step in UDP pools for β-glucan cell wall formation. This pathway has not yet been defined in . Herein, we surveyed the and genomes, which predicted a homolog of the major PGM enzyme. Furthermore, we show that PjPgm2p and PmPgm2p function similarly to the yeast counterpart. When both homologs are heterologously expressed in cells, both genes can restore growth and sedimentation rates to wild-type levels. Additionally, we demonstrate that yeast cell lysates expressing the two transcripts individually can restore PGM activities significantly altered in the yeast strain. The addition of lithium, a competitive inhibitor of yeast PGM activity, significantly reduces PGM activity. Next, we tested the effects of lithium on viability and found the compound displays significant anti- activity. Finally, we demonstrate that a para-aryl derivative (ISFP10) with known inhibitory activity against the PGM protein and exhibiting 50-fold selectivity over the human PGM enzyme homolog can also significantly reduce Pmpgm2 activity . Collectively, our data genetically and functionally validate phosphoglucomutases in both and and suggest the potential of this protein as a selective therapeutic target for individuals with pneumonia.
Topics: Humans; Pneumocystis carinii; Pneumonia, Pneumocystis; Phosphoglucomutase; Saccharomyces cerevisiae; Lithium; Pneumocystis; beta-Glucans; Phosphates; Glucose; Uridine Diphosphate
PubMed: 38259086
DOI: 10.1128/aac.00756-23 -
Medical Mycology Dec 2023Bronchoalveolar lavage fluid (BALF) is a standard respiratory sample for diagnosing invasive fungal diseases like Pneumocystis pneumonia (PCP) and invasive pulmonary... (Observational Study)
Observational Study
Bronchial aspirate obtained during bronchoscopy yields increased fungal load compared to bronchoalveolar lavage fluid in patients at risk of invasive aspergillosis and Pneumocystis pneumonia.
Bronchoalveolar lavage fluid (BALF) is a standard respiratory sample for diagnosing invasive fungal diseases like Pneumocystis pneumonia (PCP) and invasive pulmonary aspergillosis (IPA). However, procedural variations exist across medical centers and wards. This study aimed to compare the diagnostic potential of BALF and bronchial aspirate (BA) obtained during bronchoscopy in 173 patients suspected of fungal infections. A prospective observational study was conducted from April 2020 to November 2021. BALF and BA were collected during bronchoscopy and subjected to direct examination, fungal culture, Aspergillus fumigatus qPCR (AfqPCR), and Pneumocystis jirovecii qPCR (PjqPCR). Galactomannan detection was performed on BALF. Patients were classified based on established European Organization for Research and Treatment of Cancer (EORTC) criteria. Out of 173 patients, 75 tested positive for at least one test in BA or BALF. For Aspergillus, proportion of positive AfqPCR (14.5% vs. 9.2%; P < 0.0001) and fungal loads (Cq of 31.3 vs. 32.8; P = 0.0018) were significantly higher in BA compared to BALF. For Pneumocystis, fungal loads by PjqPCR was also higher in BA compared to BALF (Cq of 34.2 vs. 35.7; P = 0.003). BA only detected A. fumigatus and P. jirovecii in 12 (42.9%) and 8 (19.5%) patients, respectively. BA obtained during a BAL procedure can be a suitable sample type for increased detection of P. jirovecii and A. fumigatus by qPCR. The use of BA in diagnostic algorithms requires further investigation in prospective studies.
Topics: Humans; Bronchoalveolar Lavage Fluid; Pneumonia, Pneumocystis; Bronchoscopy; Prospective Studies; Sensitivity and Specificity; Aspergillosis; Invasive Pulmonary Aspergillosis; Pneumocystis carinii; Mannans
PubMed: 37996394
DOI: 10.1093/mmy/myad120