Evidence for the requirement of T cell costimulation in the pathogenesis of natural Pneumocystis carinii pulmonary infection

Roxanne E. Baumgartner, Pamela J. Durant, Yvonne Van Gessel, Suchismita Chattopadhyay, Richard L. Beswick, Douglas K. Tadaki, Mark E. Lasbury, Chao Hung Lee, Peter J. Perrin, Kelvin P. Lee

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Pneumocystis carinii pneumonia (PCP) is a frequent and serious opportunistic infection in immunocompromized patients. Although the pathogenesis of PCP-mediated lung injury is poorly understood, a central involvement of host inflammatory responses has been implicated. We have found that while the loss of specific T cell costimulatory signals increases susceptibility to the spontaneous pneumocystis infection, PCP-induced pulmonary injury (and subsequent morbidity and mortality) involves other intact costimulatory pathways. Mice that are genetically deficient for the costimulatory receptor CD154 (CD154 knockout (ko) mice) spontaneously developed PCP, consistent with the increased susceptibility of X-linked hyper IgM syndrome patients (caused by CD154 gene mutations) to P. carinii infection. In these mice PCP was manifested by progressive weight loss, dyspnea and death. In contrast, CD154 ko mice also genetically lacking ICAM1 (CD154 ko x ICAM1 ko) or CD28 (CD154 ko x CD28 ko) costimulatory receptors had later onset of weight loss and significantly prolonged survival. Although onset of infection and age-matched P. carinii organism burden were equivalent, the CD154 single knockout mice had evidence of greater pulmonary inflammation vs. the double ko's. These findings suggest that costimulation-dependent T cell-mediated inflammation plays an important role in both susceptibility to and pathogenesis of PCP, and may identify potential molecular targets for novel immunomodulatory treatment approaches.

Original languageEnglish (US)
Pages (from-to)193-201
Number of pages9
JournalMicrobial Pathogenesis
Volume33
Issue number5
DOIs
StatePublished - Jan 1 2002

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Keywords

  • Costimulation
  • Inflammation
  • Murine
  • Pneumocystis
  • T cell

ASJC Scopus subject areas

  • Microbiology
  • Infectious Diseases

Cite this

Baumgartner, R. E., Durant, P. J., Van Gessel, Y., Chattopadhyay, S., Beswick, R. L., Tadaki, D. K., Lasbury, M. E., Lee, C. H., Perrin, P. J., & Lee, K. P. (2002). Evidence for the requirement of T cell costimulation in the pathogenesis of natural Pneumocystis carinii pulmonary infection. Microbial Pathogenesis, 33(5), 193-201. https://doi.org/10.1006/mpat.2002.0528