Dual Roles of CD40 on Microbial Containment and the Development of Immunopathology in Response to Persistent Fungal Infection in the Lung

Abstract

Persistent pulmonary infection with Cryptococcus neoformans in C57BL/6 mice results in chronic inflammation that is characterized by an injurious Th2 immune response. In this study, we performed a comparative analysis of cryptococcal infection in wild-type versus CD40-deficient mice (in a C57BL/6 genetic background) to define two important roles of CD40 in the modulation of fungal clearance as well as Th2-mediated immunopathology. First, CD40 promoted microanatomic containment of the organism within the lung tissue. This protective effect was associated with: i) a late reduction in fungal burden within the lung; ii) a late accumulation of lung leukocytes, including macrophages, CD4 ؉ T cells, and CD8؉ T cells; iii) both early and late production of tumor necrosis factor-␣ and interferon-␥ by lung leukocytes; and iv) early IFN-␥ production at the site of T cell priming in the regional lymph nodes. In the absence of CD40, systemic cryptococcal dissemination was increased, and mice died of central nervous system infection. Second, CD40 promoted pathological changes in the airways, including intraluminal mucus production and subepithelial collagen deposition, but did not alter eosinophil recruitment or the alternative activation of lung macrophages. Collectively, these results demonstrate that CD40 helps limit progressive cryptococcal growth in the lung and protects against lethal central nervous system dissemination. CD40 also promotes some, but not all , elements of Th2-mediated immunopathology in response to persistent fungal infection in the lung.

Early or Late IL-10 Blockade Enhances Th1 and Th17 Effector Responses and Promotes Fungal Clearance in Mice with Cryptococcal Lung Infection

“…Our results demonstrated that infection of C57BL/6 mice with a moderately virulent encapsulated strain of C. neoformans , strain 52D (American Type Culture Collection 24067), resulted in a rapid and sustained increase in lung CFU by 7 days post-infection (dpi) which remained elevated at least to 35 dpi (Figure 1A) consistent with prior studies using this model system (16, 22, 23). Histologic evaluation of lung sections demonstrated that at 7 and 14 dpi, many C. neoformans were located extracellularly within alveolar spaces (data not shown and Figure 1B middle panel, respectively).…”

Interleukin-17A Enhances Host Defense against Cryptococcal Lung Infection through Effects Mediated by Leukocyte Recruitment, Activation, and Gamma Interferon Production

“…This observation was very reminiscent of the numerous extracellular cryptococci that we identified in the lungs of mice deficient in either granulocyte-macrophage colony-stimulating factor (GM-CSF), a dendritic cell (DC) and exudate macrophage growth and differentiation factor, or in CD40, an important costimulatory molecule (51,52). In those studies, the presence of numerous extracellular cryptococci was highly associated with reductions in IFN-␥ and impairments in myeloid cell activation.…”

“…6A) and total numbers (Fig. 6B) of CD4 and CD8 T cells expressing IFN-␥ (relative to uninfected WT mice); this Th1 component of the T-cell-mediated response is critical for containment of the infection in C57BL/6 mice and helps prevent progressive infection and lethal cryptococcal meningitis (11,13,22,52,62). In the infected IL-17A Ϫ/Ϫ mice, the percentage and total numbers of IFN-␥ ϩ CD4 and CD8 T cells also increased relative to uninfected IL-17A Ϫ/Ϫ mice ( Fig.…”

“…In this model, both Th1 and Th2 responses develop and evolve over time. In particular, signaling by activated antigenpresenting cells and the generation of IFN-␥ are critically important for preventing progressive lung infection and lethal dissemination to the CNS (11,13,22,51,52). Whether IL-17A exerts a protective or detrimental effect in this model is unclear.…”

Perfil de expressão de microRNAS no miocárdio na infecção aguda pelo Trypanosoma cruzi em camundongos

“…As previously described by Chaussabel et al CD40 ligation in T. cruziinfected mice has a protective effect because it is related to upregulation of IL-12 as well as NO by a direct stimulation of INF-activated macrophages [36]. Previous studies also showed that the CD40-CD40L signaling pathway mediated protective effect with other pathogens such as Leishmania [37], Schistosoma mansoni [38], Cryptococcus neoformans [39], Cryptosporidium parvum [40], and Pneumocystis carinii [41]. The enhanced production of IFN-, TNF-, and nitric oxide associated with CD40/CD40L signaling is thought to be responsible for this protective effect.…”