Passive Immunization of Neonatal Mice against<i>Pneumocystis carinii</i>f. sp.<i>muris</i>Enhances Control of Infection without Stimulating Inflammation

Empey, Kerry M.; Hollifield, Melissa; Schuer, Kevin M.; Gigliotti, Francis; Garvy, Beth A.

doi:10.1128/iai.72.11.6211-6220.2004

Cited by 30 publications

(34 citation statements)

References 44 publications

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“…This delay in lung T cell infiltration is associated with delayed infiltration and activation of macrophages, delayed chemokine and cytokine production, and delayed adhesion molecule upregulation (12,13,(35)(36)(37). We also found that lung mRNA expression of transforming growth factor ␤2 (TGF-␤2) and TGF-␤3 isoforms was upregulated in the uninfected lungs of infant mice, and TGF-␤1 mRNA expression was similar in adult and infant mice (37).…”

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confidence: 51%

Alveolar Macrophages in Neonatal Mice Are Inherently Unresponsive to Pneumocystis murina Infection

et al. 2012

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dPneumocystis pneumonia was first diagnosed in malnourished children and has more recently been found in children with upper respiratory symptoms. We previously reported that there is a significant delay in the immune response in newborn mice infected with Pneumocystis compared to adults (Garvy BA, Harmsen AG, Infect. Immun. 64:3987-3992, 1996, and Garvy BA, Qureshi M, J. Immunol. 165:6480 -6486, 2000). This delay is characterized by the failure of neonatal lungs to upregulate proinflammatory cytokines and attract T cells into the alveoli. Here, we report that regardless of the age at which we infected the mice, they failed to mount an inflammatory response in the alveolar spaces until they were 21 days of age or older. Anti-inflammatory cytokines had some role in dampening inflammation, since interleukin-10 (IL-10)-deficient pups cleared Pneumocystis faster than wildtype pups and the neutralization of transforming growth factor beta (TGF-␤) with specific antibody enhanced T cell migration into the lungs at later time points. However, the clearance kinetics were similar to those of control pups, suggesting that there is an intrinsic deficiency in the ability of innate immunity to control Pneumocystis. We found, using an adoptive transfer strategy, that the lung environment contributes to association of Pneumocystis organisms with alveolar macrophages, implying no intrinsic deficiency in the binding of Pneumocystis by neonatal macrophages. Using both in vivo and in vitro assays, we found that Pneumocystis organisms were less able to stimulate translocation of NF-B to the nucleus of alveolar macrophages from neonatal mice. These data indicate that there is an early unresponsiveness of neonatal alveolar macrophages to Pneumocystis infection that is both intrinsic and related to the immunosuppressive environment found in neonatal lungs.

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confidence: 51%

Alveolar Macrophages in Neonatal Mice Are Inherently Unresponsive to Pneumocystis murina Infection

et al. 2012

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“…This may correspond to either activation of the alveolar macrophages or infiltration of monocytes. We and (10,29). However, we did not see differences in expression of major histocompatibility complex class II in alveolar macrophages from SRAKO compared to wild-type mice (data not shown).…”

Section: Resultsmentioning

confidence: 55%

“…Because we made the interesting observation that SRAKO mice may clear P. carinii faster than wild-type mice, we also examined clearance in neonatal SRAKO mice. We previously reported that neonatal mice clear P. carinii much more slowly than adult mice and were interested in whether the clearance could be expedited in the absence of SRA (10,15,16). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We have extensive data demonstrating that there is a significant delay in the ability of neonatal mice to clear P. carinii compared to adult mice, and this delay corresponds to delayed activation of alveolar macrophages, delayed entry of CD4 ϩ cells into the lungs, and delayed specific antibody responses to P. carinii (10,15,40). Consistent with our observations in adults, neonatally infected SRAKO mice had elevated numbers of CD4 ϩ cells in the lungs and draining lymph nodes compared to wild-type pups.…”

Section: Discussionmentioning

confidence: 99%

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Scavenger Receptor A Dampens Induction of Inflammation in Response to the Fungal PathogenPneumocystis carinii

et al. 2007

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Alveolar macrophages are the effector cells largely responsible for clearance of Pneumocystis carinii from the lungs. Binding of organisms to ␤-glucan and mannose receptors has been shown to stimulate phagocytosis of the organisms. To further define the mechanisms used by alveolar macrophages for clearance of P. carinii, mice deficient in the expression of scavenger receptor A (SRA) were infected with P. carinii, and clearance of organisms was monitored over time. SRA-deficient (SRAKO) mice consistently cleared P. carinii faster than did wild-type control mice. Expedited clearance corresponded to elevated numbers of activated CD4 ؉ T cells in the alveolar spaces of SRAKO mice compared to wild-type mice. Alveolar macrophages from SRAKO mice had increased expression of CD11b on their surfaces, consistent with an activated phenotype. However, they were not more phagocytic than macrophages expressing SRA, as measured by an in vivo phagocytosis assay. SRAKO alveolar macrophages produced significantly more tumor necrosis factor alpha (TNF-␣) than wildtype macrophages when stimulated with lipopolysaccharide in vitro but less TNF-␣ in response to P. carinii in vitro. However, upon in vivo stimulation, SRAKO mice produced significantly more TNF-␣, interleukin 12 (IL-12), and IL-18 in response to P. carinii infection than did wild-type mice. Together, these data indicate that SRA controls inflammatory cytokines produced by alveolar macrophages in the context of P. carinii infection.

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“…Passive treatment with pools of anti-Pneumocystis monoclonal antibodies, including 4F11, has previously been shown to reduce both organism burden and inflammation (34)(35)(36). Therefore, in addition to the antimicrobial effects, the immunoregulatory effects of high-dose intravenous immunoglobulin (IVIG) may provide additional benefit in the treatment of a patient with PcP.…”

Section: Discussionmentioning

confidence: 99%

Immunization with Pneumocystis Cross-Reactive Antigen 1 (Pca1) Protects Mice against Pneumocystis Pneumonia and Generates Antibody to Pneumocystis jirovecii

et al. 2017

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Pneumocystis pneumonia (PcP) is a life-threatening infection that affects immunocompromised individuals. Nearly half of all PcP cases occur in those prescribed effective chemoprophylaxis, suggesting that additional preventive methods are needed. To this end, we have identified a unique mouse Pneumocystis surface protein, designated Pneumocystis cross-reactive antigen 1 (Pca1), as a potential vaccine candidate. Mice were immunized with a recombinant fusion protein containing Pca1. Subsequently, CD4 ϩ T cells were depleted, and the mice were exposed to Pneumocystis murina. Pca1 immunization completely protected nearly all mice, similar to immunization with whole Pneumocystis organisms. In contrast, all immunized negative-control mice developed PcP. Unexpectedly, Pca1 immunization generated cross-reactive antibody that recognized Pneumocystis jirovecii and Pneumocystis carinii. Potential orthologs of Pca1 have been identified in P. jirovecii. Such cross-reactivity is rare, and our findings suggest that Pca1 is a conserved antigen and potential vaccine target. The evaluation of Pca1-elicited antibodies in the prevention of PcP in humans deserves further investigation.

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Passive Immunization of Neonatal Mice againstPneumocystis cariniif. sp.murisEnhances Control of Infection without Stimulating Inflammation

Cited by 30 publications

References 44 publications

Alveolar Macrophages in Neonatal Mice Are Inherently Unresponsive to Pneumocystis murina Infection

Alveolar Macrophages in Neonatal Mice Are Inherently Unresponsive to Pneumocystis murina Infection

Scavenger Receptor A Dampens Induction of Inflammation in Response to the Fungal PathogenPneumocystis carinii

Immunization with Pneumocystis Cross-Reactive Antigen 1 (Pca1) Protects Mice against Pneumocystis Pneumonia and Generates Antibody to Pneumocystis jirovecii

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