MyD88 Signaling Regulates Both Host Defense and Immunopathogenesis during Pneumocystis Infection

Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
The Journal of Immunology (Impact Factor: 4.92). 11/2013; 192(1). DOI: 10.4049/jimmunol.1301431
Source: PubMed


The immune response protects against Pneumocystis infection but is also a key component of Pneumocystis pneumonia (PcP)-related immunopathogenesis. Signaling through myeloid differentiation factor 88 (MyD88) is critical for activation of immune pathways downstream of TLRs and IL-1R. To determine whether MyD88 regulates normal host defense against Pneumocystis, nonimmunosuppressed wild-type (WT) and MyD88-deficient mice were infected. MyD88(-/-) mice had higher early Pneumocystis burdens than did WT mice but mounted an effective adaptive immune response and cleared Pneumocystis similarly to WT. However, MyD88(-/-) mice displayed a more intense and prolonged pulmonary immune response than did WT mice. To determine the role of MyD88 in the development of PcP-related immunopathogenesis, WT and MyD88(-/-) mice were rendered susceptible to PcP by depletion of CD4(+) T cells. At 4 wk postinfection, CD4-depleted WT and MyD88(-/-) mice harbored similar organism burdens, but MyD88(-/-) mice were protected from the PcP-related respiratory impairment observed in WT mice. Improved pulmonary physiology in MyD88(-/-) mice correlated with lower lung CCL2 levels and reduced cell recruitment. However, by 5 wk postinfection, the overall health of MyD88(-/-) mice began to deteriorate rapidly relative to WT, with accelerated weight loss, impaired lung function, and exacerbated alveolar inflammation. This physiological decline of MyD88(-/-) mice was associated with increased TNF-α and IFN-γ in the lung, and by the inability to control Pneumocystis burden. Thus, MyD88 is not required for resistance to Pneumocystis infection, but limits the adaptive immune response in immunocompetent mice. In the setting of active PcP, MyD88 signaling contributes to both immunopathogenesis and control of fungal burden.

8 Reads
  • Source
    • "Most studies with Pneumocystis have utilized cells from MyD88-deficient mice and explored short-term immune responses [8] [15] [16]. The lack of susceptibility of MyD88-deficient mice to Pneumocystis infection, using a bolus intratracheal inoculation model, has very recently been reported [17]. The current study was undertaken to address the role of MyD88 in a natural infection model, which more closely mimics human disease, by exposing MyD88-deficient but otherwise immunocompetent mice to Pneumocystis-infected seeder mice and comparing the kinetics of infection to wild-type mice as well as CD40-deficient mice. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To determine if myeloid differentiation factor 88 (MyD88), which is necessary for signaling by most TLRs and IL-1Rs, is necessary for control of Pneumocystis infection, MyD88-deficient and wild-type mice were infected with Pneumocystis by exposure to infected seeder mice and were followed for up to 106 days. MyD88-deficient mice showed clearance of Pneumocystis and development of anti-Pneumocystis antibody responses with kinetics similar to wild-type mice. Based on expression levels of select genes, MyD88-deficient mice developed immune responses similar to wild-type mice. Thus, MyD88 and the upstream pathways that rely on MyD88 signaling are not required for control of Pneumocystis infection.
    Microbes and Infection 06/2014; 16(6). DOI:10.1016/j.micinf.2014.03.005 · 2.86 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Since its initial misidentification as a trypanosome some 100 years ago, Pneumocystis has remained recalcitrant to study. Although we have learned much, we still do not have definitive answers to such basic questions as, where is the reservoir of infection, how does Pneumocystis reproduce, what is the mechanism of infection, and are there true species of Pneumocystis? The goal of this review is to provide the reader the most up to date information available about the biology of Pneumocystis and the disease it produces.
    Cold Spring Harbor Perspectives in Medicine 11/2014; 4(12). DOI:10.1101/cshperspect.a019828 · 9.47 Impact Factor