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

Murdock, Benjamin J.; Huffnagle, Gary B.; Olszewski, Michal A.; Osterholzer, John J.

doi:10.1128/iai.01477-13

Cited by 81 publications

(92 citation statements)

References 68 publications

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“…engulf fungal cells in granulomas is associated with protection from cryptococcosis due to C. neoforomans, which is also associated with an increase in cytokine-producing T cells, such as Th1 and Th17 cells (30)(31)(32)(33). Because DC-based vaccines reportedly augmented cytokine-producing effector T cells (17,34), we assessed cytokine-producing T cells in the spleen and lungs after vaccination.…”

Section: Resultsmentioning

confidence: 99%

“…It has also been shown that IL-17A was required for leukocyte accumulation, including numerous granulocytes, at the early phase of infection and for the development of MGCs that engulfed fungal cells at the late phase of C. neoformans infection. Thus, fungal clearance was impaired in IL-17A KO mice (33).…”

Section: Discussionmentioning

confidence: 99%

“…Several reports showed that IL-17A-producing CD4 T cells were increased in the lungs after pulmonary infection with C. neoformans (33,42). Two reports indicated that IL-17A was dispensable for protection against pulmonary infection with C. neoformans (42,43), while another report showed that IL-17A enhanced host defenses against pulmonary C. neoformans infection (33). It has also been shown that IL-17A was required for leukocyte accumulation, including numerous granulocytes, at the early phase of infection and for the development of MGCs that engulfed fungal cells at the late phase of C. neoformans infection.…”

Section: Discussionmentioning

confidence: 99%

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Dendritic Cell-Based Immunization Ameliorates Pulmonary Infection with Highly Virulent Cryptococcus gattii

et al. 2015

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h Cryptococcosis due to a highly virulent fungus, Cryptococcus gattii, emerged as an infectious disease on Vancouver Island in Canada and surrounding areas in 1999, causing deaths among immunocompetent individuals. Previous studies indicated that C. gattii strain R265 isolated from the Canadian outbreak had immune avoidance or immune suppression capabilities. However, protective immunity against C. gattii has not been identified. In this study, we used a gain-of-function approach to investigate the protective immunity against C. gattii infection using a dendritic cell (DC)-based vaccine. Bone marrow-derived dendritic cells (BMDCs) efficiently engulfed acapsular C. gattii (⌬cap60 strain), which resulted in their expression of costimulatory molecules and inflammatory cytokines. This was not observed for BMDCs that were cultured with encapsulated strains. When ⌬cap60 strain-pulsed BMDCs were transferred to mice prior to intratracheal R265 infection, significant amelioration of pathology, fungal burden, and the survival rate resulted compared with those in controls. Inhalation of the airborne fungal pathogens Cryptococcus neoformans and Cryptococcus gattii causes life-threatening infectious diseases despite treatment with antifungal drugs. These two species are genetically close, although they have some distinct features. C. neoformans typically causes fatal infections, such as meningitis, in immunocompromised hosts, whereas C. gattii causes similar infections in immunocompetent hosts. Although cryptococcosis caused by C. gattii is endemic in tropical areas, such as Australia and Papua New Guinea, outbreaks of C. gattii, including fatalities among healthy individuals, were reported on Vancouver Island and surrounding areas beginning in 1999 (1, 2). In response to this, the Centers for Disease Control and Prevention (CDC) of the United States and British Columbia organized a public health working group to promote awareness of this outbreak (3-5).Using mouse pulmonary infection models, two groups independently showed that C. gattii strain R265, which was clinically isolated during the Canadian outbreak, was more virulent than C. neoformans strain H99, which is frequently studied (6, 7). Although the mechanisms for its hypervirulence remain unknown, there is evidence that C. gattii induces a less severe inflammatory response than that induced by C. neoformans infection. Histological and flow cytometry analyses showed reduced migration of inflammatory cells into the lungs of mice infected with R265 compared with those infected with H99 (7-9). Additionally, a smaller amount of inflammatory cytokines was found in the lungs of mice infected with C. gattii (9) and in the cerebrospinal fluid of humans infected with C. gattii (10,11). These findings suggest that C. gattii has a superior ability to suppress or evade the inflammatory response.Previous studies indicated that one of the capsular components of C. gattii may have been involved in immune avoidance or immune suppression and was required for the complete virulence of...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Dendritic Cell-Based Immunization Ameliorates Pulmonary Infection with Highly Virulent Cryptococcus gattii

et al. 2015

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“…The cytokines TNF-␣ and IL-1␣ have been shown to be important for leukocyte recruitment and control of infection of the pathogen Aspergillus fumigatus in mice (12,13). Examination of Cryptococcus neoformans in a C57BL/6 mouse model of infection showed that IL-17␣ increase is mediated by leukocyte recruitment and activation and IFN-␥ production after intratracheal challenge (14).…”

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confidence: 99%

Differences in Host Innate Responses among Coccidioides Isolates in a Murine Model of Pulmonary Coccidioidomycosis

et al. 2015

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e Coccidioides immitis and Coccidioides posadasii are soil-dwelling fungi and the causative agents of coccidioidomycosis, a mycosis endemic to certain semiarid regions in the Americas. The most common route of infection is by inhalation of airborne Coccidioides arthroconidia. Once a susceptible host inhales the conidia, a transition to mature endosporulated spherules can occur within the first 5 days of infection. For this study, we examined the host response in a murine model of coccidioidomycosis during a time period of infection that has not been well characterized. We collected lung tissue and bronchoalveolar lavage fluid (BALF) from BALB/c mice that were infected with a C. immitis pure strain, a C. immitis hybrid strain, or a C. posadasii strain as well as uninfected mice. We compared the host responses to the Coccidioides strains used in this study by assessing the level of transcription of selected cytokine genes in lung tissues and characterized host and fungal proteins present in BALF. Host response varied depending on the Coccidioides strain that was used and did not appear to be overly robust. This study provides a foundation to begin to dissect the host immune response early in infection, to detect abundant Coccidioides proteins, and to develop diagnostics that target these early time points of infection.

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“…Upon contact with Cryptococcus, DC and AM also produce proinflammatory cytokines such as tumor necrosis factor alpha (TNF-␣), interleukin-1␤ (IL-1␤), and IL-6 that are required for the generation of protective immunity (25)(26)(27). Resistance to cryptococcal infection is dependent on recruitment of antigen-specific CD4 ϩ T lymphocytes to the site of infection and T-helper 1 (Th1)/T-helper 17 (Th17) polarization of the adaptive immune response characterized by the cytokines gamma interferon (IFN-␥), IL-12, IL-17(A), and IL-22 (28)(29)(30)(31)(32)(33). Effector cells such as NK cells and CD8 ϩ T cells also produce perforin/granulysin, which kills extracellular C. neoformans as well as host cells bearing intracellular cryptococci (34,35).…”

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confidence: 99%

TheCnes2Locus on Mouse Chromosome 17 Regulates Host Defense against Cryptococcal Infection through Pleiotropic Effects on Host Immunity

et al. 2015

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The genetic basis of natural susceptibility to progressive Cryptococcus neoformans infection is not well understood. Using C57BL/6 and CBA/J inbred mice, we previously identified three chromosomal regions associated with C. neoformans susceptibility (Cnes1, Cnes2, and Cnes3). To validate and characterize the role of Cnes2 during the host response, we constructed a congenic strain on the C57BL/6 background (B6.CBA-Cnes2). Phenotypic analysis of B6.CBA-Cnes2 mice 35 days after C. neoformans infection showed a significant reduction of fungal burden in the lungs and spleen with higher pulmonary expression of gamma interferon (IFN-␥) and interleukin-12 (IL-12), lower expression of IL-4, IL-5, and IL-13, and an absence of airway epithelial mucus production compared to that in C57BL/6 mice. Multiparameter flow cytometry of infected lungs also showed a significantly higher number of neutrophils, exudate macrophages, CD11b؉ dendritic cells, and CD4 ؉ cells in B6.CBA-Cnes2 than in C57BL/6 mice. The activation state of recruited macrophages and dendritic cells was also significantly increased in B6.CBA-Cnes2 mice. Taken together, these findings demonstrate that the Cnes2 interval is a potent regulator of host defense, immune responsiveness, and differential Th1/Th2 polarization following C. neoformans infection.

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

Cited by 81 publications

References 68 publications

Dendritic Cell-Based Immunization Ameliorates Pulmonary Infection with Highly Virulent Cryptococcus gattii

Dendritic Cell-Based Immunization Ameliorates Pulmonary Infection with Highly Virulent Cryptococcus gattii

Differences in Host Innate Responses among Coccidioides Isolates in a Murine Model of Pulmonary Coccidioidomycosis

TheCnes2Locus on Mouse Chromosome 17 Regulates Host Defense against Cryptococcal Infection through Pleiotropic Effects on Host Immunity

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