Immune reconstitution during Pneumocystis lung infection

Disruption of surfactant component expression and function by S-nitrosylation

Elena N. Atochina-Vasserman, Andrew J. Gow, Helen Abramova, Chang Jiang Guo, Yaniv Tomer, Angela M. Preston, James M. Beck, Michael F. Beers

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Pneumocystis pneumonia (PCP), the most common opportunistic pulmonary infection associated with HIV infection, is marked by impaired gas exchange and significant hypoxemia. Immune reconstitution disease (IRD) represents a syndrome of paradoxical respiratory failure in patients with active or recently treated PCP subjected to immune reconstitution. To model IRD, C57BL/6 mice were selectively depleted of CD4+ T cells using mAb GK1.5. Following inoculation with Pneumocystis murina cysts, infection was allowed to progress for 2 wk, GK1.5 was withdrawn, and mice were followed for another 2 or 4 wk. Flow cytometry of spleen cells demonstrated recovery of CD4+ cells to >65% of nondepleted controls. Lung tissue and bronchoalveolar lavage fluid harvested from IRD mice were analyzed in tandem with samples from CD4-depleted mice that manifested progressive PCP for 6 wks. Despite significantly decreased pathogen burdens, IRD mice had persistent parenchymal lung inflammation, increased bronchoalveolar lavage fluid cellularity, markedly impaired surfactant biophysical function, and decreased amounts of surfactant phospholipid and surfactant protein (SP)-B. Paradoxically, IRD mice also had substantial increases in the lung collectin SP-D, including significant amounts of an S-nitrosylated form. By native PAGE, formation of S-nitrosylated SP-D in vivo resulted in disruption of SP-D multimers. Bronchoalveolar lavage fluid from IRD mice selectively enhanced macrophage chemotaxis in vitro, an effect that was blocked by ascorbate treatment. We conclude that while PCP impairs pulmonary function and produces abnormalities in surfactant components and biophysics, these responses are exacerbated by IRD. This worsening of pulmonary inflammation, in response to persistent Pneumocystis Ags, is mediated by recruitment of effector cells modulated by S-nitrosylated SP-D.

Original languageEnglish
Pages (from-to)2277-2287
Number of pages11
JournalJournal of Immunology
Volume182
Issue number4
DOIs
Publication statusPublished - 15 Feb 2009
Externally publishedYes

Fingerprint

Immune Reconstitution Inflammatory Syndrome
Pneumocystis Infections
Surface-Active Agents
Pulmonary Surfactant-Associated Protein D
Pneumocystis Pneumonia
Bronchoalveolar Lavage Fluid
Lung
Pneumocystis
Pneumonia
Pulmonary Surfactant-Associated Proteins
Collectins
Murinae
Biophysics
Native Polyacrylamide Gel Electrophoresis
Opportunistic Infections
Chemotaxis
Inbred C57BL Mouse
Respiratory Insufficiency
HIV Infections
Cysts

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Immune reconstitution during Pneumocystis lung infection : Disruption of surfactant component expression and function by S-nitrosylation. / Atochina-Vasserman, Elena N.; Gow, Andrew J.; Abramova, Helen; Guo, Chang Jiang; Tomer, Yaniv; Preston, Angela M.; Beck, James M.; Beers, Michael F.

In: Journal of Immunology, Vol. 182, No. 4, 15.02.2009, p. 2277-2287.

Research output: Contribution to journalArticle

Atochina-Vasserman, Elena N. ; Gow, Andrew J. ; Abramova, Helen ; Guo, Chang Jiang ; Tomer, Yaniv ; Preston, Angela M. ; Beck, James M. ; Beers, Michael F. / Immune reconstitution during Pneumocystis lung infection : Disruption of surfactant component expression and function by S-nitrosylation. In: Journal of Immunology. 2009 ; Vol. 182, No. 4. pp. 2277-2287.
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abstract = "Pneumocystis pneumonia (PCP), the most common opportunistic pulmonary infection associated with HIV infection, is marked by impaired gas exchange and significant hypoxemia. Immune reconstitution disease (IRD) represents a syndrome of paradoxical respiratory failure in patients with active or recently treated PCP subjected to immune reconstitution. To model IRD, C57BL/6 mice were selectively depleted of CD4+ T cells using mAb GK1.5. Following inoculation with Pneumocystis murina cysts, infection was allowed to progress for 2 wk, GK1.5 was withdrawn, and mice were followed for another 2 or 4 wk. Flow cytometry of spleen cells demonstrated recovery of CD4+ cells to >65{\%} of nondepleted controls. Lung tissue and bronchoalveolar lavage fluid harvested from IRD mice were analyzed in tandem with samples from CD4-depleted mice that manifested progressive PCP for 6 wks. Despite significantly decreased pathogen burdens, IRD mice had persistent parenchymal lung inflammation, increased bronchoalveolar lavage fluid cellularity, markedly impaired surfactant biophysical function, and decreased amounts of surfactant phospholipid and surfactant protein (SP)-B. Paradoxically, IRD mice also had substantial increases in the lung collectin SP-D, including significant amounts of an S-nitrosylated form. By native PAGE, formation of S-nitrosylated SP-D in vivo resulted in disruption of SP-D multimers. Bronchoalveolar lavage fluid from IRD mice selectively enhanced macrophage chemotaxis in vitro, an effect that was blocked by ascorbate treatment. We conclude that while PCP impairs pulmonary function and produces abnormalities in surfactant components and biophysics, these responses are exacerbated by IRD. This worsening of pulmonary inflammation, in response to persistent Pneumocystis Ags, is mediated by recruitment of effector cells modulated by S-nitrosylated SP-D.",
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