Department of Veterinary Medicine

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Author: search.filters.author.Sun, Donglei

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    Alternatively activated lung alveolar and interstitial macrophages promote fungal growth
    (Elsevier, 2023-05-19) Strickland, Ashley B.; Chen, Yanli; Sun, Donglei; Shi, Meiqing
    How lung macrophages, especially interstitial macrophages (IMs), respond to invading pathogens remains elusive. Here, we show that mice exhibited a rapid and substantial expansion of macrophages, especially CX3CR1+ IMs, in the lung following infection with Cryptococcus neoformans, a pathogenic fungus leading to high mortality among patients with HIV/AIDS. The IM expansion correlated with enhanced CSF1 and IL-4 production and was affected by the deficiency of CCR2 or Nr4a1. Both alveolar macrophages (AMs) and IMs were observed to harbor C. neoformans and became alternatively activated following infection, with IMs being more polarized. The absence of AMs by genetically disrupting CSF2 signaling reduced fungal loads in the lung and prolonged the survival of infected mice. Likewise, infected mice depleted of IMs by the CSF1 receptor inhibitor PLX5622 displayed significantly lower pulmonary fungal burdens. Thus, C. neoformans infection induces alternative activation of both AMs and IMs, which facilitates fungal growth in the lung.
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    IL-27 Signaling Promotes Th1 Responses and Is Required to Inhibit Fungal Growth in the Lung during Repeated Exposure to Aspergillus fumigatus
    (American Association of Immunologists, 2022-01-01) Strickland, Ashley B.; Sun, Donglei; Sun, Peng; Chen, Yanli; Liu, Gongguan; Shi, Meiqing
    Aspergillus fumigatus is an opportunistic fungal pathogen that causes a wide spectrum of diseases in humans, including life-threatening invasive infections as well as several hypersensitivity respiratory disorders. Disease prevention is predicated on the host’s ability to clear A. fumigatus from the lung while also limiting inflammation and preventing allergic responses. IL-27 is an important immunoregulatory cytokine, but its role during A. fumigatus infection remains poorly understood. In contrast to most infection settings demonstrating that IL-27 is anti-inflammatory, in this study we report that this cytokine plays a proinflammatory role in mice repeatedly infected with A. fumigatus. We found that mice exposed to A. fumigatus had significantly enhanced secretion of IL-27 in their lungs. Genetic ablation of IL-27Rα in mice resulted in significantly higher fungal burdens in the lung during infection. The increased fungal growth in IL-27Rα−/− mice was associated with reduced secretion of IL-12, TNF-α, and IFN-γ, diminished T-bet expression, as well as a reduction in CD4+ T cells and their activation in the lung, demonstrating that IL-27 signaling promotes Th1 immune responses during repeated exposure to A. fumigatus. In addition, infected IL-27Rα−/− mice displayed reduced accumulation of dendritic cells and exudate macrophages in their lungs, and these cells had a lower expression of MHC class II. Collectively, this study suggests that IL-27 drives type 1 immunity and is indispensable for inhibiting fungal growth in the lungs of mice repeatedly exposed to A. fumigatus, highlighting a protective role for this cytokine during fungal infection.
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    IL-27 Negatively Regulates Tip-DC Development during Infection
    (American Society for Microbiology, 2021-02-16) Liu, Gongguan; Abas, Osama; Fu, Yong; Chen, Yanli; Strickland, Ashley B.; Sun, Donglei; Shi, Meiqing
    Tumor necrosis factor (TNF)/inducible nitric oxide synthase (iNOS)-producing dendritic cells (Tip-DCs) have profound impacts on host immune responses during infections. The mechanisms regulating Tip-DC development remain largely unknown. Here, using a mouse model of infection with African trypanosomes, we show that a deficiency in interleukin-27 receptor (IL-27R) signaling results in escalated intrahepatic accumulation of Ly6C-positive (Ly6C1) monocytes and their differentiation into Tip-DCs. Blocking Tip-DC development significantly ameliorates liver injury and increases the survival of infected IL-27R2/2 mice. Mechanistically, Ly6C1 monocyte differentiation into pathogenic Tip-DCs in infected IL-27R2/2 mice is driven by a CD41 T cell-interferon gamma (IFN-g) axis via cell-intrinsic IFN-g signaling. In parallel, hyperactive IFN-g signaling induces cell death of Ly6C-negative (Ly6C2) monocytes in a cell-intrinsic manner, which in turn aggravates the development of pathogenic Tip-DCs due to the loss of the negative regulation of Ly6C2 monocytes on Ly6C1 monocyte differentiation into Tip-DCs. Thus, IL-27 inhibits the dual-track exacerbation of Tip-DC development induced by a CD41 T cell–IFN-g axis. We conclude that IL-27 negatively regulates Tip-DC development by preventing the cell-intrinsic effects of IFN-g and that the regulation involves CD41 T cells and Ly6C2 monocytes. Targeting IL-27 signaling may manipulate Tip-DC development for therapeutic intervention.
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    VCAM1/VLA4 interaction mediates Ly6Clow monocyte recruitment to the brain in a TNFR signaling dependent manner during fungal infection
    (PLoS, 2020-02-26) Sun, Donglei; Zhang, Mingshun; Sun, Peng; Liu, Gongguan; Strickland, Ashley B.; Chen, Yanli; Fu, Yong; Yosri, Mohammed; Shi, Meiqing
    Monocytes exist in two major populations, termed Ly6C^hi and Ly6C^low monocytes. Compared to Ly6C^hi monocytes, less is known about Ly6C^low monocyte recruitment and mechanisms involved in the recruitment of this subset. Furthermore, the role of Ly6C^low monocytes during infections is largely unknown. Here, using intravital microscopy, we demonstrate that Ly6C^low monocytes are predominantly recruited to the brain vasculature following intravenous infection with Cryptococcus neoformans, a fungal pathogen causing meningoencephalitis. The recruitment depends primarily on the interaction of VCAM1 expressed on the brain endothelium with VLA4 expressed on Ly6C^low monocytes. Furthermore, TNFR signaling is essential for the recruitment through enhancing VLA4 expression on Ly6C^low monocytes. Interestingly, the recruited Ly6C^low monocytes internalized C. neoformans and carried the organism while crawling on and adhering to the luminal wall of brain vasculature and migrating to the brain parenchyma. Our study reveals a substantial recruitment of Ly6C^low monocytes to the brain and highlights important properties of this subset during infection.
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    Fungal dissemination is limited by liver macrophage filtration of the blood
    (Springer Nature, 2019-10-08) Sun, Donglei; Sun, Peng; Li, Hongmei; Zhang, Mingshun; Liu, Gongguan; Strickland, Ashley B.; Chen, Yanli; Fu, Yong; Xu, Juan; Yosri, Mohammed; Nan, Yuchen; Zhou, Hong; Zhang, Xiquan; Shi, Meiqing
    Fungal dissemination into the bloodstream is a critical step leading to invasive fungal infections. Here, using intravital imaging, we show that Kupffer cells (KCs) in the liver have a prominent function in the capture of circulating Cryptococcus neoformans and Candida albicans, thereby reducing fungal dissemination to target organs. Complement C3 but not C5, and complement receptor CRIg but not CR3, are involved in capture of C. neoformans. Internalization of C. neoformans by KCs is subsequently mediated by multiple receptors, including CR3, CRIg, and scavenger receptors, which work synergistically along with C5aR signaling. Following phagocytosis, the growth of C. neoformans is inhibited by KCs in an IFN-γ independent manner. Thus, the liver filters disseminating fungi from circulation via KCs, providing a mechanistic explanation for the enhanced risk of cryptococcosis among individuals with liver diseases, and suggesting a therapeutic strategy to prevent fungal dissemination through enhancing KC functions.
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    INTRAVASCULAR CLEARANCE OF DISSEMINATING CRYPTOCOCCUS NEOFORMANS
    (2018) Sun, Donglei; Shi, Meiqing; Veterinary Medical Science; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Cryptococcus neoformans (C. neoformans) is an opportunistic fungal pathogen causing fatal cryptococcal meningoencephalitis in humans. The initial infection organ of C. neoformans is the lung; however, lung infection is commonly seen in healthy individuals and does not always have symptoms. Under certain conditions, the fungi may disseminate out of the lung and enter blood circulation. The fungi, once trapped in the brain vasculature, will breach the blood-brain barrier and proliferate rapidly leading to fatal outcomes. Considering the weak immune responses in the brain, it is important to limit the possibility for fungi to arrive at the brain. The current dissertation focused on the interactions of C. neoformans with host immune cells after pulmonary dissemination, seeking mechanisms that can clear the fungi from circulation. It is identified that neutrophils have the ability to remove fungi from the brain vasculature. This effective fungicidal cell kills C. neoformans via C5a-C5aR and CD11b axis. The C5aR signaling provides navigation and alerts neutrophils by up-regulating CD11b surface expression, CD11b as complement receptor is essential for subsequent uptake and killing of fungi by neutrophils. In vivo, neutrophil clearance of C. neoformans occurs in the brain vasculature but the effect is more efficient in the lung vasculature because lung is able to recruit massive amount of neutrophils into the vasculature through complement activation and C5aR signaling, which induce neutrophil actin polymerization and increase their retention. Neutrophils once activated by C. neoformans can further augment self-recruitment through the release of leukotriene B4. Directing neutrophils to the brain can help with fungal clearance in the brain. Moreover, using intravital microscopy, we reported that liver Kupffer cells can filter disseminating C. neoformans. This filtering requires C3b deposition on the fungal surface to provide the holding force and CRIg on the Kupffer cells. Without the holding force, fungi in the liver have higher tendency to be flushed back into circulation. The Kupffer cells rapidly phagocytize the captured fungi and suppress their proliferation in an IFN-γ independent way. Collectively, the results suggest that neutrophils and liver Kupffer cells are critically involved during intravascular clearance of C. neoformans.