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Reviews of "Pneumocystis Murina Promotes Inflammasome Formation and NETosis during Pneumocystis Pneumonia"

Reviewers: B Garvy (University of Kentucky) | 📒📒📒 ◻️◻️ • T W Wright (University of Rochester) | 📗📗📗📗◻️

Published onMar 30, 2024
Reviews of "Pneumocystis Murina Promotes Inflammasome Formation and NETosis during Pneumocystis Pneumonia"
key-enterThis Pub is a Review of
Pneumocystis murina Promotes Inflammasome Formation and NETosis during Pneumocystis Pneumonia
Pneumocystis murina Promotes Inflammasome Formation and NETosis during Pneumocystis Pneumonia

ABSTRACT Pneumocystis jirovecii pneumonia (PjP) poses a serious risk to individuals with compromised immune systems, such as individuals with HIV/AIDS or undergoing immunosuppressive therapies for cancer or solid organ transplants. Severe PjP triggers excessive lung inflammation, resulting in lung function decline and consequential alveolar damage, potentially culminating in acute respiratory distress syndrome. Non-HIV patients face a 30-60%mortality rate, emphasizing the need for a deeper understanding of inflammatory responses in PjP.Prior research emphasized macrophages in Pneumocystis infections, neglecting neutrophils’ role in tissue damage. Consequently, the overemphasis on macrophages led to an incomplete understanding of the role of neutrophils and inflammatory responses. In the current investigation, our RNAseq studies on a murine surrogate model of PjP revealed heightened activation of the NLRP3 inflammasome and NETosis cell death pathways in their lungs. Immunofluorescence staining confirmed Neutrophil Extracellular Trap (NET) presence in the lungs of the P. murina-infected mice, validating our findings. Moreover, isolated neutrophils exhibited NETosis when directly stimulated with P. murina. While isolated NETs did not compromise P. murina viability, our data highlight the potential role of neutrophils in promoting inflammation during P. murina pneumonia through NLRP3 inflammasome assembly and NETosis. These pathways, essential for inflammation and pathogen elimination, bear the risk of uncontrolled activation leading to excessive tissue damage and persistent inflammation.This pioneering study is the first to identify the formation of NETs and inflammasomes during Pneumocystis infection, paving the way for comprehensive investigations into treatments aimed at mitigating lung damage and augmenting survival rates for individuals with PjP.IMPORTANCE Pneumocystis jirovecii pneumonia (PjP) affects individuals with weakened immunity, such as HIV/AIDS, cancer, and organ transplant patients. Severe PjP triggers lung inflammation, impairing function and potentially causing acute respiratory distress syndrome. Non-HIV individuals face a 30-60% mortality rate, underscoring the need for deeper insight into PjP’s inflammatory responses.Past research focused on macrophages in managing Pneumocystis infection and its inflammation, while the role of neutrophils was generally overlooked. In contrast, our findings in P. murina-infected mouse lungs showed neutrophil involvement during inflammation and increased expression of NLRP3 inflammasome and NETosis pathways. Detection of neutrophil extracellular traps further indicated their involvement in the inflammatory process. Although beneficial in combating infection, unregulated neutrophil activation poses a potential threat to lung tissues.Understanding the behavior of neutrophils in Pneumocystis infections is crucial for controlling detrimental reactions and formulating treatments to reduce lung damage, ultimately improving the survival rates of individuals with PjP.

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Summary of Reviews: The reviewers find that this study provides interesting initial observations on the involvement of neutrophil extracellular traps (NETs) and inflammasome activation in a mouse model of Pneumocystis pneumonia (PJP). The authors demonstrate that some genes related to NETosis and inflammasomes are upregulated in infected lungs, and in vitro studies show Pneumocystis induces NET formation in bone marrow neutrophils. However, the reviewers point out limitations, including the lack of direct evidence for NET formation and NETosis in vivo, the absence of quantification of the percentage of neutrophils undergoing NETosis in vitro, and the inconsistency with some published data. They suggest further studies are needed to establish the biological relevance and potential implications of NETosis in PJP pathogenesis and treatment.

Reviewer 1 (Beth G…) | 📒📒📒 ◻️◻️

Reviewer 2 (Terry W W…) | 📗📗📗📗◻️

RR:C19 Strength of Evidence Scale Key

📕 ◻️◻️◻️◻️ = Misleading

📙📙 ◻️◻️◻️ = Not Informative

📒📒📒 ◻️◻️ = Potentially Informative

📗📗📗📗◻️ = Reliable

📘📘📘📘📘 = Strong

To read the reviews, click the links below. 

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