肺孢子虫肺炎(PjP)对免疫系统受损的个体构成了严重的风险,例如患有HIV/AIDS或接受癌症或实体器官移植的免疫抑制治疗的个体。严重的PjP会引发过度的肺部炎症,导致肺功能下降和相应的肺泡损伤,可能导致急性呼吸窘迫综合征。非HIV患者面临30%-60%的死亡率,强调需要更深入地了解PjP中的炎症反应。先前的研究强调肺孢子虫感染中的巨噬细胞,忽视中性粒细胞在组织损伤中的作用。因此,对巨噬细胞的过分强调导致对中性粒细胞和炎症反应的作用的不完全理解.在目前的调查中,我们对PjP的鼠替代模型的RNAseq研究揭示了NLRP3炎性体和NETosis细胞死亡途径在其肺中的激活增强。免疫荧光染色证实嗜中性粒细胞胞外诱捕网(NET)存在于小鼠的肺中。验证我们的发现。此外,当直接用P.murina刺激时,分离的嗜中性粒细胞表现出NETosis。分离的NETs在体外损害了P.murina活力,强调中性粒细胞在通过NLRP3炎性体组装和NETosis控制真菌生长和促进P.murina肺炎期间的炎症中的潜在作用。这些途径,对于炎症和病原体消除至关重要,承担不受控制的激活导致过度组织损伤和持续炎症的风险。这项开创性研究首次确定了肺孢子虫感染过程中NETs和炎性体的形成,为全面研究旨在减轻肺损伤和提高PjP患者生存率的治疗方法铺平了道路。IMPORTANCEPkirovecii肺炎(PjP)影响免疫力减弱的个体,如艾滋病毒/艾滋病,癌症,器官移植患者。严重的PjP引发肺部炎症,功能受损并可能导致急性呼吸窘迫综合征。非艾滋病毒个体面临30%-60%的死亡率,强调需要更深入地了解PjP的炎症反应。过去的研究集中在巨噬细胞管理肺孢子虫感染及其炎症,而中性粒细胞的作用普遍被忽视。相比之下,我们在小鼠肺部感染P.murina的发现显示,炎症过程中中性粒细胞受累,NLRP3炎症小体和NETosis通路表达增加.中性粒细胞胞外诱捕网的检测进一步表明它们参与了炎症过程。虽然有益于对抗感染,中性粒细胞活化失调对肺组织构成潜在威胁.了解嗜中性粒细胞在肺孢子虫感染中的行为对于控制有害反应和制定减少肺损伤的治疗方法至关重要。最终提高PjP患者的生存率。
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. Isolated NETs compromised P. murina viability in vitro, highlighting the potential role of neutrophils in controlling fungal growth and 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.IMPORTANCEPneumocystis 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.