Inheritance of Immune Polarization Patterns Is Linked to Resistance versus Susceptibility to<i>Cryptococcus neoformans</i>in a Mouse Model

Chen, Gwo Hsiao; McNamara, David A.; Hernández, Yanitza Meriño; Huffnagle, Gary B.; Toews, Galen B.; Olszewski, Michal A.

doi:10.1128/iai.01143-07

Cited by 80 publications

(133 citation statements)

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“…The early changes in cytokine expression direct subsequent immune polarization in C. neoformans-infected mice. 7,11,21,26 We found that mRNA induction levels for pro-Th1 IL-12p35 and pro-Th17 IL-23p19 were significantly higher in IL-4/ 13 Ϫ/Ϫ compared with wild-type mice at week 1 (1.64 Ϯ 0.53 versus 0.37 Ϯ 0.04 and 1.36 Ϯ 0.22 versus 0.46 Ϯ 0.01, respectively). In contrast, p40 shared by IL-12 and IL-23, but also forming inhibitory p40(2) homodimer, was Ϫ/Ϫ and wild-type) were infected with 10 4 CFU via the intratracheal route with C. neoformans H99 and analyzed at weeks 2 and 3 postinfection.…”

Section: Combined Deletion Of Il-4 and Il-13 Prevented Th2 And Promotmentioning

confidence: 83%

“…After inoculation, the skin was closed with cyanoacrylate adhesive. 8,26 Organ CFU assay For determination of microbial burden in the lungs, small aliquots of dispersed lungs were collected following the digest procedure. For determination of brain and spleen CFU, the brains and spleens were dissected using sterile instruments, placed in 2 ml of sterile water, and homogenized.…”

Section: Il-4/13mentioning

confidence: 99%

“…All plates were read on a Versamax plate reader (Molecular Devices, Sunnyvale, CA). 8,26 Real-Time PCR Total RNA was prepared using RNeasy Plus Mini Kit (Qiagen) and first-strand cDNA was synthesized using SuperScriptIII (Invitrogen, Carlsbad, CA) according to the manufacturer's instructions. Cytokine mRNA was quantified with SYBR Green-based detection using an MX 3000P system (Stratagene, La Jolla, CA) according to the manufacturer's protocols.…”

Section: Cytokine Productionmentioning

confidence: 99%

“…8,17,19 Therefore promotion of AAM has been postulated to be the mechanism by which Th2 bias promotes uncontrolled growth and persistence of C. neoformans in the lungs. 8,16,17,23,[25][26][27][28][29][30] C. neoformans H99 is a human isolate that expresses one of the highest virulence levels among C. neoformans strains used for experimental infections. This strain grows in the lungs in an uncontrolled fashion, readily disseminates into CNS, and causes 100% mortality in a variety of immunocompetent mouse strains such as C57BL/6, BALB/c, CB6129F2, and CBA/J mice.…”

mentioning

confidence: 99%

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Robust Th1 and Th17 Immunity Supports Pulmonary Clearance but Cannot Prevent Systemic Dissemination of Highly Virulent Cryptococcus neoformans H99

Zhang

Wang

Tompkins

et al. 2009

The American Journal of Pathology

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153

184

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The present study dissected the role of a Th2 bias in pathogenesis of Cryptococcus neoformans H99 infection by comparing inhalational H99 infections in wild-type BALB/c and IL-4/IL-13 double knockout mice. H99-infected wild-type mice showed all major hallmarks of Th2 but not Th1/Th17 immunity in the lungs and lung-associated lymph nodes. In contrast, the IL-4/13 ؊/؊ mice developed robust hallmarks of Th1 and Th17 but not Th2 polarization. The IL-4/IL-13 deletion prevented pulmonary eosinophilia, goblet cell metaplasia in the airways and resulted in elevated serum IgE, and a switch from alternative to classical activation of macrophages. The development of a robust Th1/Th17 response and classical activation of macrophages resulted in significant containment of H99 in the lungs of IL-4/13 ؊/؊ mice compared with unopposed growth of H99 in the lungs of wild-type mice. However, IL-4/13 ؊/؊ mice showed only 1-week longer survival compared with wild-type mice. The comparison of brain and spleen cryptococcal loads at weeks 2, 3, and 4 postinfection revealed that the systemic dissemination in IL-4/13 ؊/؊ mice occurred with an approximate 1-week delay but subsequently progressed with similar rate as in the wild-type mice. Furthermore, wild-type and IL-4/13 ؊/؊ mice developed equivalently severe meningitis/encephalitis at the time of death. These data indicate that the Th2 immune bias is a crucial mechanism for pulmonary virulence of H99, whereas other mechanisms are largely responsible for its central nervous system tropism and systemic dissemination.

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Section: Combined Deletion Of Il-4 and Il-13 Prevented Th2 And Promotmentioning

confidence: 83%

Section: Il-4/13mentioning

confidence: 99%

Section: Cytokine Productionmentioning

confidence: 99%

mentioning

confidence: 99%

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Robust Th1 and Th17 Immunity Supports Pulmonary Clearance but Cannot Prevent Systemic Dissemination of Highly Virulent Cryptococcus neoformans H99

Zhang

Wang

Tompkins

et al. 2009

The American Journal of Pathology

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153

184

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“…31,32,37 We used six-to eight-parameter flow cytometric analysis to assess the relative prevalence and phenotype of AMs and ExMs during the pre-effector and effector phases of the host response to infection and determined whether AMs or ExMs proliferate in the lungs of infected mice. We then performed a comparative analysis using gene-targeted mice deficient in CCR2 (CCR2 Ϫ/Ϫ mice; BALB/c genetic background) to determine whether accumulation of ExMs requires the recruitment and differentiation of blood monocytes.…”

mentioning

confidence: 99%

Chemokine Receptor 2-Mediated Accumulation of Fungicidal Exudate Macrophages in Mice That Clear Cryptococcal Lung Infection

Osterholzer

Chen

Olszewski

et al. 2011

The American Journal of Pathology

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112

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Clearance of pulmonary infection with the fungal pathogen Cryptococcus neoformans is associated with the accumulation and activation of lung macrophages. However, the phenotype of these macrophages and the mechanisms contributing to their accumulation are not well-defined. In this study, we used an established murine model of cryptococcal lung infection and flow cytometric analysis to identify alveolar macrophages (AMs) and the recently described exudate macrophages (ExMs). Exudate macrophages are distinguished from AMs by their strong expression of CD11b and major histocompatibility complex class II and modest expression of costimulatory molecules. Exudate macrophages substantially outnumber AMs during the effector phase of the immune response; and accumulation of ExMs, but not AMs, was chemokine receptor 2 (CCR2) dependent and attributable to the recruitment and subsequent differentiation of Ly-6C high monocytes originating from the bone marrow and possibly the spleen. Peak ExM accumulation in wild-type (CCR2 ؉/؉ ) mice coincided with maximal lung expression of mRNA for inducible nitric oxide synthase and correlated with the known onset of cryptococcal clearance in this strain of mice. Exudate macrophages purified from infected lungs displayed a classically activated effector phenotype characterized by cryptococcal-enhanced production of inducible nitric oxide synthase and tumor necrosis factor ␣. Cryptococcal killing by bone marrow-derived ExMs was CCR2 independent and superior to that of AMs. We conclude that clearance of cryptococcal lung infection requires the CCR2-mediated massive accumulation of fungicidal ExMs derived from circulating Ly-6C high monocytes.

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Murine Models of Cryptococcus Infection

Hansakon,

Angkasekwinai

2024

Current Protocols

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Cryptococcus is recognized as one of the emerging fungal pathogens that have major impact on diverse populations worldwide. Because of the high mortality rate and limited antifungal therapy options, there is an urgent need to understand the impact of dynamic processes between fungal pathogens and hosts that influence cryptococcal pathogenesis and disease outcomes. With known common limitations in human studies, experimental murine cryptococcosis models that can recapitulate human disease provide a valuable tool for studying fungal virulence and the host interaction, leading to development of better treatment strategies. Infection with Cryptococcus in mice via intranasal inhalation is mostly used because it is noninvasive and considered to be the most common mode of infection, strongly correlating with cryptococcal disease in humans. The protocols described in this article provide the procedures of establishing a murine model of Cryptococcus infection by intranasal inhalation and assessing the host immune response and disease progression during Cryptococcus infection. © 2024 Wiley Periodicals LLC.Basic Protocol 1: Murine model of pulmonary cryptococcal infection via intranasal inhalationBasic Protocol 2: Assessment of the pulmonary immune response during Cryptococcus infectionSupport Protocol: Evaluation of pulmonary gene expression by real‐time PCRBasic Protocol 3: Enumeration of survival rate and organ fungal burden

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Inheritance of Immune Polarization Patterns Is Linked to Resistance versus Susceptibility toCryptococcus neoformansin a Mouse Model

Abstract: Genetic background variation between inbred strains accounts for different levels of susceptibility to

Cited by 80 publications

References 40 publications

Robust Th1 and Th17 Immunity Supports Pulmonary Clearance but Cannot Prevent Systemic Dissemination of Highly Virulent Cryptococcus neoformans H99

Robust Th1 and Th17 Immunity Supports Pulmonary Clearance but Cannot Prevent Systemic Dissemination of Highly Virulent Cryptococcus neoformans H99

Chemokine Receptor 2-Mediated Accumulation of Fungicidal Exudate Macrophages in Mice That Clear Cryptococcal Lung Infection

Murine Models of Cryptococcus Infection

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