Mouse Genetic Background Is a Major Determinant of Isotype-Related Differences for Antibody-Mediated Protective Efficacy against<i>Cryptococcus neoformans</i>

Rivera, Johanna; Casadevall, Arturo

doi:10.4049/jimmunol.174.12.8017

Cited by 48 publications

(36 citation statements)

References 66 publications

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“…Eosinophils have been mentioned before in murine models of cryptococcosis, 10,23,[41][42][43] observed in human cryptococcosis, 44 -46 and described with an emphasis on tissue damage. 41 Although in vitro eosinophils have phagocytosed C. neoformans 23 and presented cryptococcal antigens, 47 in vivo, no evidence for uptake of C. neoformans by eosinophils has been found by others 4 and in this study (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Eosinophils Contribute to IL-4 Production and Shape the T-Helper Cytokine Profile and Inflammatory Response in Pulmonary Cryptococcosis

Piehler

Stenzel

Grahnert

et al. 2011

The American Journal of Pathology

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Susceptibility to infection with Cryptococcus neoformans is tightly determined by production of IL-4. In this study, we investigated the time course of IL-4 production and its innate cellular source in mice infected intranasally with C. neoformans. We show that pulmonary IL-4 production starts surprisingly late after 6 weeks of infection. Interestingly, in the lungs of infected mice, pulmonary T helper (Th) cells and eosinophils produce significant amounts of IL-4. In eosinophil-deficient ⌬dblGATA mice, IL-33 receptor-expressing Th2s are significantly reduced, albeit not absent, whereas protective Th1 and Th17 responses are enhanced. In addition, recruitment of pulmonary inflammatory cells during infection with C. neoformans is reduced in the absence of eosinophils. These data expand previous findings emphasizing an exclusively destructive effector function by eosinophilic granulocytes. Moreover, in ⌬dblGATA mice, fungal control is slightly enhanced in the lung; however, dissemination of Cryptococcus is not prevented. Therefore, eosinophils play an immunoregulatory role that contributes to Th2-dependent susceptibility in allergic inflammation during bronchopulmonary mycosis. Cryptococcus neoformans is a facultative intracellular pathogen that is acquired by inhalation of spores and/or desiccated yeasts and leads to latent pulmonary infection in immunocompetent humans. 1 The development of cryptococcal meningitis occurs mainly in immunocompromised HIV-1-infected patients, most likely by reactivation of latent pulmonary C. neoformans infection. 2 It is estimated that 504,000 HIV-1-infected patients die every year from cryptococcal meningitis in sub-Saharan Africa, 3 which surprisingly exceeds the annual death rate of tuberculosis-associated HIV cases. Resistance against C. neoformans primarily involves monocytic effector mechanisms. 4 -6 In this context, T helper (Th) cells are central regulatory players with profound effects. Whereas IL-12-dependent Th1 responses are protective, with an additional contribution by IL-23-dependent Th17 responses, 7-9 Th2 cells producing IL-4, IL-13, and IL-5 are detrimental. 10,11 Studies 12-14 that used i.v. inoculation examined the traversal of the blood-brain barrier by C. neoformans and led to the conclusion that transmigration can occur with intracellular and extracellular fungi. In case of bronchopulmonary infection, dissemination seems to rely more on Th2 cytokines. This allergic Th2-driven inflammation represents the immunopathological pathway promoting disease by allowing cryptococci to grow inside the lung and finally enabling dissemination to the brain, ultimately causing fatal meningoencephalitis. 15 This sequela is accompanied by development of IL-4/IL-13-dependent alternatively activated macrophages, suggesting that those cells may be involved in dissemination. Alternatively activated macrophages are found only in susceptible mice 15 and show significantly reduced control of intracellular growth. 5 In addition, IL-13-dependent mucus production by goblet cells, IL-4 -...

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Section: Discussionmentioning

confidence: 99%

Eosinophils Contribute to IL-4 Production and Shape the T-Helper Cytokine Profile and Inflammatory Response in Pulmonary Cryptococcosis

Piehler

Stenzel

Grahnert

et al. 2011

The American Journal of Pathology

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“…C. neoformans infection is associated with increased IgE levels (3,59,60). Given that IgE levels reflect the balance between Th1 and Th2 responses, we measured serum IgE before and after infection in both mouse strains.…”

Section: Vol 75 2007 Mouse Strain Susceptibility To Cryptococcus Nementioning

confidence: 99%

“…Despite considerable evidence that Th2-polarized responses are less protective than Th1-polarized responses, there is conclusive evidence from multiple laboratories that certain antibodies (Abs) affect the course of disease during C. neoformans infection (19,39,49,51,62). The Ab response includes both protective and nonprotective Abs, with the functional quality depending on specificity and isotype as well as on the mouse strain (59,74,75). Further complicating the assessment of humoral immunity are large dose-dependent effects such as the prozone-like effects that can occur in passive Ab experiments, whereby the protective efficacy of the Ab is abrogated in conditions where large doses are administered (67,68).…”

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confidence: 99%

The Relative Susceptibility of Mouse Strains to PulmonaryCryptococcus neoformansInfection Is Associated with Pleiotropic Differences in the Immune Response

Zaragoza¹,

Alvarez²,

Telzak³

et al. 2007

Infect Immun

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CBA/J mice were highly susceptible to intratracheal (i.t.) Cryptococcus neoformans infection relative to BALB/c mice, while both strains were equally susceptible to intravenous (i.v.) infection. Increased susceptibility in i.t. infection was associated with higher brain CFU, lower serum immunoglobulin M (IgM) and IgG responses to glucuronoxylomannan (GXM), lack of IgE regulation during infection, and alveolar macrophage permissiveness to intracellular replication in vitro. In contrast, for BALB/c mice, relative resistance was associated with increased interleukin-12 (IL-12) and decreased IL-10 pulmonary levels. In CBA/J mice, relative susceptibility was associated with a decreased proportion of CD4 ؉ and CD8 ؉ T cells and an increase in macrophage percentage in pulmonary infiltrates. In contrast, no significant differences in these cytokines or cell recruitment were observed in the i.v. model, consistent with no differences in the survival rate. Passive antibody (Ab) protection experiments revealed a prozone effect in the BALB/c mice with i.v. infection, such that Ab efficacy decreased at higher doses. In the i.t. model using CBA/J mice, low Ab doses were disease enhancing and protection was observed only at high doses. Our results show (i) that differences in mouse strain susceptibility are a function of the infection model, (ii) that susceptibility to pulmonary infection was associated with macrophage permissiveness for intracellular replication, and (iii) that the efficacy of passive Ab in pulmonary infection is a function of dose and mouse strain. The results highlight significant differences in the pathogenesis of cryptococcal infection among inbred mice and associate their relative susceptibility with differences in numerous components of the innate and adaptive immune responses.Cryptococcus neoformans is a fungal pathogen for individuals with late-stage human immunodeficiency virus infection. The initial infection is usually controlled and either cleared or contained by immunocompetent hosts into a latent asymptomatic state, and there is evidence that persistent infection might be associated with reactive airway disease (24). However, in immunocompromised individuals dissemination and/or reactivation of latent infection can lead to a life-threatening meningoencephalitis (for a review, see reference 9).C. neoformans has several well-characterized virulence factors, including a polysaccharide capsule, melanin production, phospholipase, urease, and the alpha mating factor, among others (for reviews, see references 9, 42, and 55). A recent study analyzing the relative contribution of each virulence factor showed that the capsular polysaccharide makes the largest contribution to C. neoformans virulence (41). The polysaccharide capsule is composed primarily of glucuronoxylomannan (GXM). The capsule participates in virulence through pleitropic effects on the immune system (9, 71, 72). Furthermore, C. neoformans strains that differ in virulence elicit different immune responses in the host (5, 14).

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“…Macrophages and pulmonary dendritic cells rapidly internalize C. neoformans organisms in murine models of pneumonia (17,67); however, in vivo depletion of neutrophils unexpectedly enhanced the host defense (45). B-cell-mediated humoral immunity participates in host resistance against cryptococcal infection (2,57,65), although its protective efficacy depends on the genetic background of the host (56,69,70). A clear role for cytokines such as tumor necrosis factor alpha (TNF-␣), gamma interferon (IFN-␥), interleukin 12 (IL-12), and IL-18, as well as chemokines such as monocyte chemoattractant protein-1 (MCP-1/C-C motif ligand 2 [CCL2]) and macrophage inflammatory protein-1-alpha (MIP-1␣/CCL3) in leukocyte recruitment and effective host defense (33) has been demonstrated.…”

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confidence: 99%

Enhanced Innate Immune Responsiveness to PulmonaryCryptococcus neoformansInfection Is Associated with Resistance to Progressive Infection

et al. 2008

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Genetically regulated mechanisms of host defense against Cryptococcus neoformans infection are not well understood. In this study, pulmonary infection with the moderately virulent C. neoformans strain 24067 was used to compare the host resistance phenotype of C57BL/6J with that of inbred mouse strain SJL/J. At 7 days or later after infection, C57BL/6J mice exhibited a significantly greater fungal burden in the lungs than SJL/J mice. Characterization of the pulmonary innate immune response at 3 h after cryptococcal infection revealed that resistant SJL/J mice exhibited significantly higher neutrophilia, with elevated levels of inflammatory cytokine tumor necrosis factor alpha (TNF-␣) and keratinocyte-derived chemokine (KC)/CXCL1 in the airways, as well as increased whole-lung mRNA expression of chemokines KC/CXCL1, MIP-1␣/CCL3, MIP-1␤/CCL4, MIP-2/CXCL2, and MCP-1/CCL2 and cytokines interleukin 1␤ (IL-1␤) and IL-1Ra. At 7 and 14 days after infection, SJL/J mice maintained significantly higher levels of TNF-␣ and KC/CXCL1 in the airways and exhibited a Th1 response characterized by elevated levels of lung gamma interferon (IFN-␥) and IL-12/IL-23p40, while C57BL/6J mice exhibited Th2 immunity as defined by eosinophilia and IL-4 production. Alveolar and resident peritoneal macrophages from SJL/J mice also secreted significantly greater amounts of TNF-␣ and KC/CXCL1 following in vitro stimulation with C. neoformans. Intracellular signaling analysis demonstrated that TNF-␣ and KC/CXCL1 production was regulated by NF-B and phosphatidylinositol 3 kinase in both strains; however, SJL/J macrophages exhibited heightened and prolonged activation in response to C. neoformans infection compared to that of C57BL/6J. Taken together, these data demonstrate that an enhanced innate immune response against pulmonary C. neoformans infection in SJL/J mice is associated with natural resistance to progressive infection.

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Mouse Genetic Background Is a Major Determinant of Isotype-Related Differences for Antibody-Mediated Protective Efficacy againstCryptococcus neoformans

Cited by 48 publications

References 66 publications

Eosinophils Contribute to IL-4 Production and Shape the T-Helper Cytokine Profile and Inflammatory Response in Pulmonary Cryptococcosis

Eosinophils Contribute to IL-4 Production and Shape the T-Helper Cytokine Profile and Inflammatory Response in Pulmonary Cryptococcosis

The Relative Susceptibility of Mouse Strains to PulmonaryCryptococcus neoformansInfection Is Associated with Pleiotropic Differences in the Immune Response

Enhanced Innate Immune Responsiveness to PulmonaryCryptococcus neoformansInfection Is Associated with Resistance to Progressive Infection

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