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Review 1: "Pneumocystis Murina Promotes Inflammasome Formation and NETosis during Pneumocystis Pneumonia"

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).

Published onMar 30, 2024
Review 1: "Pneumocystis Murina Promotes Inflammasome Formation and NETosis during Pneumocystis Pneumonia"
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Pneumocystis murina Promotes Inflammasome Formation and NETosis during Pneumocystis Pneumonia
Pneumocystis murina Promotes Inflammasome Formation and NETosis during Pneumocystis Pneumonia
Description

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.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.

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Review: The authors utilize a mouse in vivo model and a neutrophil cell culture model to examine the response of neutrophils to the opportunistic pathogen, Pneumocystis murina. The mouse model is a well characterized model in which mice are treated with the steroid dexamethasone to make them immunodeficient and susceptible to growth of P. murina. They examined the lungs and found by RNAseq that some genes related to neutrophil NET formation are upregulated as are some inflammasome genes. They also did some assays to determine that proteins related to NETosis are expressed in the lungs of infected mice. However, no uninfected controls are shown with their immunofluorescence of lungs. Using neutrophils isolated from bone marrow, the authors show that P. murina causes NET formation but there is no effect on viability of the fungi. A control using pentamidine also had no significant effect, so this makes it hard to interpret the data. The authors conclude that the upregulated NETosis and inflammasome genes “bear the risk of uncontrolled activation leading to excessive tissue damage and persistent inflammation”. Though the data is interesting, it is descriptive and the data is somewhat inconsistent with published data in mouse models that show that deletion of neutrophils has no effect on clearance of P. murina, nor in lung injury induced by infection. Published work has shown that dexamethasone has effects on NETosis, not mentioned in this paper. Also, extracellular traps have recently been shown to be formed by macrophages, also not mentioned in this manuscript.

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