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1.
iScience ; 26(5): 106717, 2023 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-37216116

RESUMO

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.

2.
Microorganisms ; 10(12)2022 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-36557672

RESUMO

Cryptococcus neoformans is an encapsulated pathogenic fungus that initially infects the lung but can migrate to the central nervous system (CNS), resulting in meningoencephalitis. The organism causes the CNS infection primarily in immunocompromised individuals including HIV/AIDS patients, but also, rarely, in immunocompetent individuals. In HIV/AIDS patients, limited inflammation in the CNS, due to impaired cellular immunity, cannot efficiently clear a C. neoformans infection. Antiretroviral therapy (ART) can rapidly restore cellular immunity in HIV/AIDS patients. Paradoxically, ART induces an exaggerated inflammatory response, termed immune reconstitution inflammatory syndrome (IRIS), in some HIV/AIDS patients co-infected with C. neoformans. A similar excessive inflammation, referred to as post-infectious inflammatory response syndrome (PIIRS), is also frequently seen in previously healthy individuals suffering from cryptococcal meningoencephalitis. Cryptococcal IRIS and PIIRS are life-threatening complications that kill up to one-third of affected people. In this review, we summarize the inflammatory responses in the CNS during HIV-associated cryptococcal meningoencephalitis. We overview the current understanding of cryptococcal IRIS developed in HIV/AIDS patients and cryptococcal PIIRS occurring in HIV-uninfected individuals. We also describe currently available animal models that closely mimic aspects of cryptococcal IRIS observed in HIV/AIDS patients.

3.
J Fungi (Basel) ; 8(10)2022 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-36294634

RESUMO

Cryptococcus neoformans (C. neoformans) is a pathogenic fungus with a global distribution. Humans become infected by inhaling the fungus from the environment, and the fungus initially colonizes the lungs. If the immune system fails to contain C. neoformans in the lungs, the fungus can disseminate to the blood and invade the central nervous system, resulting in fatal meningoencephalitis particularly in immunocompromised individuals including HIV/AIDS patients. Following brain invasion, C. neoformans will encounter host defenses involving resident as well as recruited immune cells in the brain. To overcome host defenses, C. neoformans possesses multiple virulence factors capable of modulating immune responses. The outcome of the interactions between the host and C. neoformans will determine the disease progression. In this review, we describe the current understanding of how C. neoformans migrates to the brain across the blood-brain barrier, and how the host immune system responds to the invading organism in the brain. We will also discuss the virulence factors that C. neoformans uses to modulate host immune responses.

4.
Immunohorizons ; 6(1): 78-89, 2022 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-35064029

RESUMO

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.


Assuntos
Aspergilose/imunologia , Interleucinas/metabolismo , Pulmão/patologia , Células Th1/imunologia , Animais , Aspergilose/microbiologia , Aspergilose/patologia , Aspergillus fumigatus/imunologia , Modelos Animais de Doenças , Interleucinas/genética , Pulmão/imunologia , Pulmão/microbiologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais
5.
PLoS Pathog ; 17(10): e1009968, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34614031

RESUMO

Liver macrophages internalize circulating bloodborne parasites. It remains poorly understood how this process affects the fate of the macrophages and T cell responses in the liver. Here, we report that infection by Trypanosoma brucei induced depletion of macrophages in the liver, leading to the repopulation of CXCL16-secreting intrahepatic macrophages, associated with substantial accumulation of CXCR6+CD4+ T cells in the liver. Interestingly, disruption of CXCR6 signaling did not affect control of the parasitemia, but significantly enhanced the survival of infected mice, associated with reduced inflammation and liver injury. Infected CXCR6 deficient mice displayed a reduced accumulation of CD4+ T cells in the liver; adoptive transfer experiments suggested that the reduction of CD4+ T cells in the liver was attributed to a cell intrinsic property of CXCR6 deficient CD4+ T cells. Importantly, infected CXCR6 deficient mice receiving wild-type CD4+ T cells survived significantly shorter than those receiving CXCR6 deficient CD4+ T cells, demonstrating that CXCR6+CD4+ T cells promote the mortality. We conclude that infection of T. brucei leads to depletion and repopulation of liver macrophages, associated with a substantial influx of CXCR6+CD4+ T cells that mediates mortality.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Fígado/imunologia , Macrófagos/imunologia , Tripanossomíase Africana/imunologia , Animais , Camundongos , Receptores CXCR6/imunologia , Trypanosoma brucei brucei/imunologia
6.
Cell Microbiol ; 23(6): e13330, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33745221

RESUMO

Migration of Cryptococcus neoformans from the blood to the brain parenchyma is crucial to cause fatal meningoencephalitis. Although mechanisms involved in brain migration of C. neoformans have been widely studied in vitro, less is known about how the fungus crosses the blood-brain barrier (BBB) in vivo. This is in part because of the lack of an approach to quantitatively analyse the dynamics of fungal transmigration into the brain across the BBB in vivo. In this study, we report a novel approach to quantitatively analyse the interactions between C. neoformans and brain endothelial cells in a mouse model using flow cytometry. Using this system, we show that C. neoformans was internalised by brain endothelial cells in vivo and that mice infected with acapsular or heat-killed C. neoformans yeast cells displayed a lower frequency of brain endothelial cells containing the yeast cell compared to mice infected with wild-type or viable yeast cells, respectively. We further demonstrate that brain endothelial cells were invaded by serotype A strain (H99 strain) at a higher rate compared to serotype D strain (52D strain). Our experiments established that internalisation of C. neoformans by brain endothelial cells occurred in vivo and offered a powerful approach to quantitatively analyse fungal migration into the brain.


Assuntos
Barreira Hematoencefálica/microbiologia , Encéfalo/microbiologia , Cryptococcus neoformans/patogenicidade , Células Endoteliais/microbiologia , Citometria de Fluxo/métodos , Animais , Transporte Biológico , Encéfalo/citologia , Criptococose/microbiologia , Modelos Animais de Doenças , Proteínas de Fluorescência Verde , Meningoencefalite/microbiologia , Camundongos , Camundongos Endogâmicos C57BL
7.
mBio ; 12(1)2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33593983

RESUMO

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 (Ly6C+) monocytes and their differentiation into Tip-DCs. Blocking Tip-DC development significantly ameliorates liver injury and increases the survival of infected IL-27R-/- mice. Mechanistically, Ly6C+ monocyte differentiation into pathogenic Tip-DCs in infected IL-27R-/- mice is driven by a CD4+ T cell-interferon gamma (IFN-γ) axis via cell-intrinsic IFN-γ signaling. In parallel, hyperactive IFN-γ signaling induces cell death of Ly6C-negative (Ly6C-) 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 Ly6C- monocytes on Ly6C+ monocyte differentiation into Tip-DCs. Thus, IL-27 inhibits the dual-track exacerbation of Tip-DC development induced by a CD4+ T cell-IFN-γ axis. We conclude that IL-27 negatively regulates Tip-DC development by preventing the cell-intrinsic effects of IFN-γ and that the regulation involves CD4+ T cells and Ly6C- monocytes. Targeting IL-27 signaling may manipulate Tip-DC development for therapeutic intervention.IMPORTANCE TNF/iNOS-producing dendritic cells (Tip-DCs) are at the front line as immune effector cells to fight off a broad range of invading microbes. Excessive development of Tip-DCs contributes to tissue destruction. Thus, identifying master regulators of Tip-DC development is fundamental for developing new therapeutic strategies. Here, we identify Tip-DCs as a terminal target of IL-27, which prevents Tip-DC-mediated early mortality during parasitic infections. We demonstrate that IL-27 inhibits Tip-DC development via a dual-track mechanism involving the complex interactions of effector CD4+ T cells, Ly6C- monocytes, and Ly6C+ monocytes. These findings delineate an in-depth view of mechanisms of Tip-DC differentiation that may have significant implications for the ongoing development of IL-27-based immunotherapy.


Assuntos
Diferenciação Celular/imunologia , Células Dendríticas/fisiologia , Regulação da Expressão Gênica , Interleucinas/genética , Óxido Nítrico Sintase Tipo II/imunologia , Receptores de Interleucina/genética , Trypanosoma congolense/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Interferon gama/genética , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucinas/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Monócitos/fisiologia , Óxido Nítrico Sintase Tipo II/biossíntese , Receptores de Interleucina/imunologia , Transdução de Sinais/imunologia , Trypanosoma brucei brucei/imunologia , Fator de Necrose Tumoral alfa/biossíntese
8.
Cell Mol Life Sci ; 78(7): 3219-3238, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33449153

RESUMO

Fungal infections are an increasing threat to global public health. There are more than six million fungal species worldwide, but less than 1% are known to infect humans. Most of these fungal infections are superficial, affecting the hair, skin and nails, but some species are capable of causing life-threatening diseases. The most common of these include Cryptococcus neoformans, Aspergillus fumigatus and Candida albicans. These fungi are typically innocuous and even constitute a part of the human microbiome, but if these pathogens disseminate throughout the body, they can cause fatal infections which account for more than one million deaths worldwide each year. Thus, systemic dissemination of fungi is a critical step in the development of these deadly infections. In this review, we discuss our current understanding of how fungi disseminate from the initial infection sites to the bloodstream, how immune cells eliminate fungi from circulation and how fungi leave the blood and enter distant organs, highlighting some recent advances and offering some perspectives on future directions.


Assuntos
Antifúngicos/uso terapêutico , Fungos/patogenicidade , Interações Hospedeiro-Patógeno/imunologia , Micoses/tratamento farmacológico , Animais , Fungos/classificação , Fungos/isolamento & purificação , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Micoses/microbiologia , Virulência
9.
PLoS Pathog ; 16(2): e1008361, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32101593

RESUMO

Monocytes exist in two major populations, termed Ly6Chi and Ly6Clow monocytes. Compared to Ly6Chi monocytes, less is known about Ly6Clow monocyte recruitment and mechanisms involved in the recruitment of this subset. Furthermore, the role of Ly6Clow monocytes during infections is largely unknown. Here, using intravital microscopy, we demonstrate that Ly6Clow 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 Ly6Clow monocytes. Furthermore, TNFR signaling is essential for the recruitment through enhancing VLA4 expression on Ly6Clow monocytes. Interestingly, the recruited Ly6Clow 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 Ly6Clow monocytes to the brain and highlights important properties of this subset during infection.


Assuntos
Criptococose/imunologia , Monócitos/imunologia , Molécula 1 de Adesão de Célula Vascular/metabolismo , Animais , Encéfalo/imunologia , Criptococose/metabolismo , Cryptococcus neoformans/metabolismo , Cryptococcus neoformans/patogenicidade , Modelos Animais de Doenças , Feminino , Integrina alfa4beta1/metabolismo , Masculino , Meningoencefalite/metabolismo , Meningoencefalite/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Micoses/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais
10.
Proc Natl Acad Sci U S A ; 116(48): 24214-24220, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31723045

RESUMO

Although CRIg was originally identified as a macrophage receptor for binding complement C3b/iC3b in vitro, recent studies reveal that CRIg functions as a pattern recognition receptor in vivo for Kupffer cells (KCs) to directly bind bacterial pathogens in a complement-independent manner. This raises the critical question of whether CRIg captures circulating pathogens through interactions with complement in vivo under flow conditions. Furthermore, the role of CRIg during parasitic infection is unknown. Taking advantage of intravital microscopy and using African trypanosomes as a model, we studied the role of CRIg in intravascular clearance of bloodborne parasites. Complement C3 is required for intravascular clearance of African trypanosomes by KCs, preventing the early mortality of infected mice. Moreover, antibodies are essential for complement-mediated capture of circulating parasites by KCs. Interestingly, reduced antibody production was observed in the absence of complement C3 during infection. We further demonstrate that CRIg but not CR3 is critically involved in KC-mediated capture of circulating parasites, accounting for parasitemia control and host survival. Of note, CRIg cannot directly catch circulating parasites and antibody-induced complement activation is indispensable for CRIg-mediated parasite capture. Thus, we provide evidence that CRIg, by interacting with complement in vivo, plays an essential role in intravascular clearance of bloodborne parasites. Targeting CRIg may be considered as a therapeutic strategy.


Assuntos
Complemento C3b/metabolismo , Interações Hospedeiro-Parasita/fisiologia , Parasitemia/parasitologia , Receptores de Complemento/fisiologia , Tripanossomíase Africana/sangue , Animais , Complemento C3b/imunologia , Microscopia Intravital , Células de Kupffer/imunologia , Células de Kupffer/parasitologia , Antígeno de Macrófago 1/metabolismo , Macrófagos/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Trypanosoma brucei brucei/genética , Trypanosoma brucei brucei/patogenicidade , Trypanosoma congolense/patogenicidade , Tripanossomíase Africana/mortalidade , Tripanossomíase Africana/parasitologia
11.
Nat Commun ; 10(1): 4566, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594939

RESUMO

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.


Assuntos
Infecções Fúngicas Invasivas/imunologia , Células de Kupffer/imunologia , Fígado/imunologia , Fagocitose , Animais , Candida albicans/imunologia , Candida albicans/isolamento & purificação , Candida albicans/patogenicidade , Complemento C3/genética , Complemento C3/imunologia , Complemento C3/metabolismo , Cryptococcus neoformans/imunologia , Cryptococcus neoformans/isolamento & purificação , Cryptococcus neoformans/patogenicidade , Modelos Animais de Doenças , Feminino , Humanos , Microscopia Intravital , Infecções Fúngicas Invasivas/sangue , Infecções Fúngicas Invasivas/microbiologia , Células de Kupffer/metabolismo , Células de Kupffer/microbiologia , Fígado/citologia , Fígado/diagnóstico por imagem , Masculino , Camundongos , Camundongos Knockout , Microscopia Confocal , Receptores de Complemento/genética , Receptores de Complemento/imunologia , Receptores de Complemento/metabolismo
12.
J Immunol ; 201(10): 2923-2933, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30305328

RESUMO

Allergic asthma is a disease initiated by a breach of the lung mucosal barrier and an inappropriate Th2 inflammatory immune response that results in M2 polarization of alveolar macrophages (AM). The number of M2 macrophages in the airway correlates with asthma severity in humans. Sex differences in asthma suggest that sex hormones modify lung inflammation and macrophage polarization. Asthmatic women have more M2 macrophages than asthmatic men and androgens have been used as an experimental asthma treatment. In this study, we demonstrate that although androgen (dihydrotestosterone) reconstitution of castrated mice reduced lung inflammation in a mouse model of allergic lung inflammation, it enhanced M2 polarization of AM. This indicates a cell-specific role for androgens. Dihydrotestosterone also enhanced IL-4-stimulated M2 macrophage polarization in vitro. Using mice lacking androgen receptor (AR) in monocytes/macrophages (ARfloxLysMCre), we found that male but not female mice exhibited less eosinophil recruitment and lung inflammation due to impaired M2 polarization. There was a reduction in eosinophil-recruiting chemokines and IL-5 in AR-deficient AM. These data reveal an unexpected and novel role for androgen/AR in promoting M2 macrophage polarization. Our findings are also important for understanding pathology in diseases promoted by M2 macrophages and androgens, such as asthma, eosinophilic esophagitis, and prostate cancer, and for designing new approaches to treatment.


Assuntos
Androgênios/imunologia , Ativação de Macrófagos/imunologia , Macrófagos Alveolares/imunologia , Eosinofilia Pulmonar/imunologia , Receptores Androgênicos/imunologia , Androgênios/farmacologia , Animais , Asma/imunologia , Castração , Quimiotaxia de Leucócito/efeitos dos fármacos , Quimiotaxia de Leucócito/imunologia , Di-Hidrotestosterona/imunologia , Di-Hidrotestosterona/farmacologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Feminino , Hipersensibilidade/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Alveolares/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/imunologia , Eosinofilia Pulmonar/metabolismo
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