Dataset Information

Monocyte and Macrophage-Mediated Pathology and Protective Immunity During Schistosomiasis.

ABSTRACT: Infection by Schistosoma parasites culminates in a chronic granulomatous disease characterized by intense tissue fibrosis. Along the course of schistosomiasis, diverse leukocytes are recruited for inflammatory foci. Innate immune cell accumulation in Th2-driven granulomas around Schistosoma eggs is associated with increased collagen deposition, while monocytes and macrophages exert critical roles during this process. Monocytes are recruited to damaged tissues from blood, produce TGF-? and differentiate into monocyte-derived macrophages (MDMs), which become alternatively activated by IL-4/IL-13 signaling via IL-4R? (AAMs). AAMs are key players of tissue repair and wound healing in response to Schistosoma infection. Alternative activation of macrophages is characterized by the activation of STAT6 that coordinates the transcription of Arg1, Chi3l3, Relma, and Mrc1. In addition to these markers, monocyte-derived AAMs also express Raldh2 and Pdl2. AAMs produce high levels of IL-10 and TGF-? that minimizes tissue damage caused by Schistosoma egg accumulation in tissues. In this review, we provide support to previous findings about the host response to Schistosoma infection reusing public transcriptome data. Importantly, we discuss the role of monocytes and macrophages with emphasis on the mechanisms of alternative macrophage activation during schistosomiasis.

SUBMITTER: Souza COS

PROVIDER: S-EPMC7456899 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Monocyte and Macrophage-Mediated Pathology and Protective Immunity During Schistosomiasis.

Souza Camila Oliveira Silva COS Gardinassi Luiz Gustavo LG Rodrigues Vanderlei V Faccioli Lúcia Helena LH

Frontiers in microbiology 20200812

Infection by <i>Schistosoma</i> parasites culminates in a chronic granulomatous disease characterized by intense tissue fibrosis. Along the course of schistosomiasis, diverse leukocytes are recruited for inflammatory foci. Innate immune cell accumulation in Th2-driven granulomas around <i>Schistosoma</i> eggs is associated with increased collagen deposition, while monocytes and macrophages exert critical roles during this process. Monocytes are recruited to damaged tissues from blood, produce TG ...[more]

PMID: 32922381

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Project description:Schistosomiasis is a neglected tropical disease caused by worms of the genus Schistosoma spp. The progression of disease results in intense tissue fibrosis and high mortality rate. After egg deposition by adult worms, the inflammatory response is characterized by the robust activation of type 2 immunity. Monocytes and macrophages play critical roles during schistosomiasis. Inflammatory Ly6Chigh monocytes are recruited from the blood to the inflammatory foci and differentiate into alternatively activated macrophages (AAMs), which promote tissue repair. The common chain of β2-integrins (CD18) regulates monocytopoiesis and mediates resistance to experimental schistosomiasis. There is still limited knowledge about mechanisms controlled by CD18 that impact monocyte development and effector cells such as macrophages during schistosomiasis. Here, we show that CD18low mice chronically infected with S. mansoni display monocyte progenitors with reduced proliferative capacity, resulting in the accumulation of the progenitor cell denominated proliferating-monocyte (pMo). Consequently, inflammatory Ly6Chigh and patrolling Ly6Clow monocytes are reduced in the bone marrow and blood. Mechanistically, low CD18 expression decreases Irf8 gene expression in pMo progenitor cells, whose encoded transcription factor regulates CSFR1 (CD115) expression on the cell surface. Furthermore, low CD18 expression affects the accumulation of inflammatory Ly6Chigh CD11b+ monocytes in the liver while the adoptive transference of these cells to infected-CD18low mice reduced the inflammatory infiltrate and fibrosis in the liver. Importantly, expression of Il4, Chil3l3 and Arg1 was downregulated, CD206+PD-L2+ AAMs were reduced and there were lower levels of IL-10 in the liver of CD18low mice chronically infected with S. mansoni. Overall, these findings suggest that CD18 controls the IRF8-CD115 axis on pMo progenitor cells, affecting their proliferation and maturation of monocytes. At the same time, CD18 is crucial for the appropriate polarization and function of AAMs and tissue repair during chronic schistosomiasis.

Project description:Experimental pulmonary Cryptococcus neoformans infection in BALB/c mice is associated with polarized Th2-type cytokine production, alternative macrophage activation, and severe bronchopneumonia. In contrast, pulmonary infection with a C. neoformans strain that secretes IFN-γ, H99γ, elicits Th1-type cytokine production and classical macrophage activation. Additionally, mice infected with H99γ resolve the acute infection and are subsequently protected against challenge with wild-type C. neoformans. The present study characterizes macrophage activation during the protective response to wild-type C. neoformans in mice previously immunized with H99γ. We observed increased pulmonary Th1-type cytokine production in lung homogenates and classical macrophage activation as evidenced by enhanced expression of inducible NO synthase in the lungs of H99γ-immunized mice compared with mice given a nonprotective immunization with heat-killed C. neoformans (HKCn). Furthermore, macrophages isolated from H99γ-immunized mice on day 7 postchallenge and cultured in vitro were fungistatic against C. neoformans, whereas cryptococcal growth was uncontrolled within macrophages from HKCn-immunized mice. Th2-type cytokine production and induction of alternatively activated macrophages were also observed in lungs of HKCn-immunized mice during rechallenge. Gene expression arrays showed that classical macrophage activation during challenge infection in H99γ-immunized mice was associated with induction of the transcription factor STAT1 and its downstream targets IFN regulatory factor-1, suppressor of cytokine signaling-1, CXCL9, and CXCL10. These studies demonstrate that protective responses to C. neoformans challenge in immunized mice include classical macrophage activation and enhanced macrophage fungistasis of C. neoformans yeasts. Finally, the classical activation phenotype of protective anticryptococcal macrophages is likely mediated via STAT1 signal transduction pathways.

Project description:Malaria and babesiosis, the two primary intraerythrocytic protozoan diseases of humans, have been reported in multiple cases of co-infection in endemic regions. As the geographic range and incidence of arthropod-borne infectious diseases is being affected by climate change, co-infection cases with Plasmodium and Babesia are likely to increase. The two parasites have been used in experimental settings, where prior infection with Babesia microti has been shown to protect against fatal malarial infections in mice and primates. However, the immunological mechanisms behind such phenomena of cross-protection remain unknown. Here, we investigated the effect of a primary B. microti infection on the outcome of a lethal P. chabaudi challenge infection using a murine model. Simultaneous infection with both pathogens led to high mortality rates in immunocompetent BALB/c mice, similar to control mice infected with P. chabaudi alone. On the other hand, mice with various stages of B. microti primary infection were thoroughly immune to a subsequent P. chabaudi challenge. Protected mice exhibited decreased levels of serum antibodies and pro-inflammatory cytokines during early stages of challenge infection. Mice repeatedly immunized with dead B. microti quickly succumbed to P. chabaudi infection, despite induction of high antibody responses. Notably, cross-protection was observed in mice lacking functional B and T lymphocytes. When the role of other innate immune effector cells was examined, NK cell-depleted mice with chronic B. microti infection were also found to be protected against P. chabaudi. Conversely, in vivo macrophage depletion rendered the mice vulnerable to P. chabaudi. The above results show that the mechanism of cross-protection conferred by B. microti against P. chabaudi is innate immunity-based, and suggest that it relies predominantly upon the function of macrophages. Further research is needed for elucidating the malaria-suppressing effects of babesiosis, with a vision toward development of novel tools to control malaria.

Dataset Information

Monocyte and Macrophage-Mediated Pathology and Protective Immunity During Schistosomiasis.

Publications

Monocyte and Macrophage-Mediated Pathology and Protective Immunity During Schistosomiasis.

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