Characterization of a Distinct Host Response Profile to Pneumocystismurina Asci during Clearance of Pneumocystis Pneumonia

Linke, Michael J.; Ashbaugh, Alan; Collins, Margaret S.; Lynch, Keeley; Cushion, Melanie T.

doi:10.1128/iai.01181-12

Cited by 26 publications

(31 citation statements)

References 53 publications

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“…These data indicate that ␤-glucan-and Dectin-1-mediated signals contribute to hypoxemia during Pneumocystis IRIS, consistent with recent observations implicating the ␤-glucan-rich ascus in producing a proinflammatory response (56). Possible mechanisms of inflammatory exacerbation include induction of IL-8 secretion and activation of the IL-23/IL-17 axis by Pneumocystis ␤-glucan (59,60), as well as the effects of Dectin-1 signaling on Th1 and Th17 differentiation of CD4 ϩ T cells (33,56,61,62), which have been shown to contribute to the risk for IRIS (63,64). Although intracellular staining of PMA-and ionomycin-stimulated lung cells did not reveal a strong Th17 signature (see Fig.…”

Section: Discussionsupporting

confidence: 77%

“…Previous rodent studies have indicated that a purified Pneumocystis ascus preparation induces inflammation and a fulminant PCP infection (54), whereas echinocandin treatment can selectively ablate the cyst population and prevent transmission of infection (55). Another recent publication by Linke et al has shown that murine hosts mount unique immune responses to the different life forms of P. murina and that the ascus can contribute to the detrimental inflammatory response associated with infection and immune reconstitution syndrome (56). As ␤-glucan recognition is a critical component of fungal immunity, we have sought to test the effect of systemic expression of recombinant Dectin-1:Fc fusion proteins on host defense and inflammatory response in a murine model of P. murina infection.…”

Section: Discussionmentioning

confidence: 99%

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Dectin Immunoadhesins and Pneumocystis Pneumonia

et al. 2013

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The opportunistic pathogen Pneumocystis jirovecii is a significant cause of disease in HIV-infected patients and others with immunosuppressive conditions. Pneumocystis can also cause complications in treatment following antiretroviral therapy or reversal of immunosuppressive therapy, as the newly reconstituted immune system can develop a pathological inflammatory response to remaining antigens or a previously undetected infection. To target ␤-(1,3)-glucan, a structural component of the Pneumocystis cell wall with immune-stimulating properties, we have developed immunoadhesins consisting of the carbohydrate binding domain of Dectin-1 fused to the Fc regions of the 4 subtypes of murine IgG (mIgG). These immunoadhesins bind ␤-glucan with high affinity, and precoating the surface of zymosan with Dectin-1:Fc can reduce cytokine production by macrophages in an in vitro stimulation assay. All Dectin-1:Fc variants showed specificity of binding to the asci of Pneumocystis murina, but effector activity of the fusion molecules varied depending on Fc subtype. Dectin-1:mIgG2a Fc was able to reduce the viability of P. murina in culture through a complement-dependent mechanism, whereas previous studies have shown the mIgG1 Fc fusion to increase macrophage-dependent killing. In an in vivo challenge model, systemic expression of Dectin-1:mIgG1 Fc significantly reduced ascus burden in the lung. When administered postinfection in a model of immune reconstitution inflammatory syndrome (IRIS), both Dectin-1:mIgG1 and Dectin-1:mIgG2a Fc reduced hypoxemia despite minimal effects on fungal burden in the lung. Taken together, these data indicate that molecules targeting ␤-glucan may provide a mechanism for treatment of fungal infection and for modulation of the inflammatory response to Pneumocystis and other pathogens.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Dectin Immunoadhesins and Pneumocystis Pneumonia

et al. 2013

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“…Cysts drive the early recruitment of activated T cells into the alveolar spaces of neonatal mice. Based on previously published reports, we predicted that the absence of cysts in the inoculum of neonatal mice infected with trophic forms would yield a less robust response than infection with a normal mixture of trophic forms and cysts (22). Clearance of Pneumocystis organisms requires the generation of effective adaptive immune responses.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, it was reported that treatment of mice with the ␤-1,3-D-glucan synthase inhibitor anidulafungin resulted in depletion of P. murina cysts (22). The mice were able to control the remaining trophic burden in the absence of an excessive inflammatory response; however, the details of how trophic forms are recognized and cleared are not known.…”

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confidence: 99%

The Life Cycle Stages of Pneumocystis murina Have Opposing Effects on the Immune Response to This Opportunistic Fungal Pathogen

2016

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P neumocystis species are opportunistic fungal pathogens that cause severe pneumonia in immunocompromised hosts, including AIDS patients. Clearance of Pneumocystis organisms is dependent on effective CD4ϩ T and B cell and macrophage responses (1-4). Failure to clear Pneumocystis organisms leads to severe alveolar damage due to the exaggerated inflammatory immune response (5). In spite of a reduced incidence of Pneumocystis pneumonia (PcP) in HIV-infected individuals due to improved antiviral therapies, the mortality rate for patients with PcP has not improved with the implementation of highly active antiretroviral therapy (HAART) (6). Additional studies are required to inform novel approaches to reduce morbidity and mortality due to Pneumocystis pneumonia.Outbreaks of PcP were first described in malnourished or premature infants in orphanages following the Second World War (7). Evidence suggests that immunocompetent individuals of all ages are capable of mounting protective immune responses to Pneumocystis jirovecii that prevent progression to pneumonia. Most children encounter this opportunistic fungus at a young age, as indicated by the presence of specific antibodies in the sera of 85% of individuals by the age of 3 years (8). Previous work from our lab has shown that the neonatal mouse immune response to Pneumocystis is delayed, due in part to an anti-inflammatory lung environment (9-12). The neonatal lung environment is characterized by anti-inflammatory mediators, including transforming growth factor ␤1 (TGF-␤1) and interleukin 10 (IL-10), and immature immune cells (9-12). Neonatal alveolar macrophages and T cells adoptively transferred to an adult lung environment are competent at resolving Pneumocystis murina pneumonia in mice (9, 12). In addition, neonatal alveolar macrophages are deficient in NF-B translocation following stimulation with Pneumocystis organisms (9). Neonatal alveolar CD11c ϩ cells demonstrate delayed trafficking to the draining lymph nodes (11). Together, these data indicate that both the neonatal lung environment and intrinsic immune cell deficits contribute to the delayed clearance of P. murina in neonatal mice.Pneumocystis species have a biphasic life cycle. Trophic forms are proposed to represent the asexual stage of the life cycle, whereas cysts are the ascus-like sexual stage (13). Trophic forms are single-nucleated organisms that are typically found in clusters surrounded by a biofilm-like substance consisting of a conglomeration of DNA, ␤-glucan, and other sugars (14). Cysts are ascuslike structures that consist of multiple nuclei surrounded by a fungal cell wall. ␤-1,3-Glucan and ␤-1,6-glucan serve as the structural components of the cyst wall (15, 16). Trophic forms do not express ␤-glucan (15). Both stages express surface glycoproteins and mannoproteins, which may serve as pathogen-associated molecular patterns (PAMPs) that could interact with receptors on phagocytic cells (17)(18)(19). Neither life form expresses chitin or ␣-glucans (20).Dendritic cells are the principal ant...

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“…Therefore, caspofungin and TMP/SMZ used in combination may inhibit the entire life cycle of Pneumocystis jirovecii. Alternatively, caspofungin may decrease β-glucan induced excessive inflammatory responses by inhibiting β-glucan synthesis (20), thus alleviating PCP. Finally, TMP/SMZ acts slowly, requiring 5-8 days to induce a curative effect (1), whereas caspofungin has a rapid onset, therefore it may be inferred that combinational treatment with TMP/SMZ and caspofungin may compensate the TMP/SMZ deficiency that occurs in patients receiving delayed PCP treatment.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of caspofungin combined with trimethoprim/sulfamethoxazole as first‑line therapy to treat non‑HIV patients with severe pneumocystis pneumonia

et al. 2017

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Abstract. Combined treatment with caspofungin and trimethoprim/sulfamethoxazole (TMP/SMZ) as salvage therapy in non-HIV positive patients with severe pneumocystis pneumonia (PCP) yields poor outcomes. It remains unknown whether the use of this combination strategy as a first-line therapy would improve patient outcomes. The present study aimed to assess the efficacy of caspofungin combined with TMP/SMZ as a first-line therapy in non-HIV positive patients with severe PCP. A retrospective cohort study was conducted between March 2016 and February 2017. Patient clinical characteristics and outcomes were compared between two groups receiving first-line and second-line therapy respectively. In addition, similar cases from previous studies were assessed. A total of 14 patients were included in the present study (mean age, 58.79±14.41 years); including 9 patients receiving caspofungin and TMP/SMZ as a first-line therapy and 5 that received it as a second-line therapy. The overall positive response rate was 71.43% (10/14), with 88.89 (8/9) and 40.00% (2/5) in the first-line and second-line therapy groups, respectively (P=0.095). The positive response rates of patients requiring invasive mechanical ventilation differed significantly between the first-line (5/6, 83.33%) and the second-line (0/3, 0%) therapy groups (P=0.048). All-cause hospital mortality was 42.86% (6/14), with mortality rates of 33.33 (3/9) and 60.00% (3/5) in the first-line and second-line therapy groups, respectively (P=0.580). Combined with previously reported cases (n=27), the positive response rate was significantly greater in the first-line therapy group (11/12, 91.67%) than in the second-line therapy group (8/15, 53.33%, P= 0.043). No significant differences were in all-cause mortality rates between the two groups (25.00 vs. 46.67%, P=0.424) were identified, despite the fact that all-course mortality in the first-line therapy group was ~50% that of the second-line therapy group. Therefore, the results of the present study indicate that combined caspofungin and TMP/SMZ as first-line therapy may be a promising and effective strategy to treat non-HIV positive patients with severe PCP, particularly for those requiring invasive mechanical ventilation.

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Characterization of a Distinct Host Response Profile to Pneumocystismurina Asci during Clearance of Pneumocystis Pneumonia

Cited by 26 publications

References 53 publications

Dectin Immunoadhesins and Pneumocystis Pneumonia

Dectin Immunoadhesins and Pneumocystis Pneumonia

The Life Cycle Stages of Pneumocystis murina Have Opposing Effects on the Immune Response to This Opportunistic Fungal Pathogen

Efficacy of caspofungin combined with trimethoprim/sulfamethoxazole as first‑line therapy to treat non‑HIV patients with severe pneumocystis pneumonia

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