Antibodies Produced in Response to<i>Cryptococcus neoformans</i>Pulmonary Infection in Mice Have Characteristics of Nonprotective Antibodies

Zaragoza, Óscar; Casadevall, Arturo

doi:10.1128/iai.72.7.4271-4274.2004

Cited by 21 publications

(14 citation statements)

References 38 publications

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“…Antibody responses can also promote the development of protective T cell responses against C. neoformans (76,77). Recently, it was demonstrated that passively administered Ab in C. neoformans-infected C57BL/6 mice could down-modulate the inflammatory responses to the infection (78).…”

Section: Discussionmentioning

confidence: 99%

Role of IFN-γ in Regulating T2 Immunity and the Development of Alternatively Activated Macrophages during Allergic Bronchopulmonary Mycosis

Arora

Hernández

Erb-Downward

et al. 2005

The Journal of Immunology

138

193

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Pulmonary Cryptococcus neoformans infection of C57BL/6 mice is an established model of a chronic pulmonary fungal infection accompanied by an “allergic” response (T2) to the infection, i.e., a model of an allergic bronchopulmonary mycosis. Our objective was to determine whether IFN-γ plays a role in regulating the pulmonary T2 immune response in C. neoformans-infected C57BL/6 mice. Long-term pulmonary fungistasis was lost in IFN-γ knockout (KO) mice, resulting in an increased pulmonary burden of fungi at wk 3. IFN-γ was required for the early influx of leukocytes into the lungs but was not required later in the infection. By wk 3, eosinophil and macrophage numbers were elevated in the absence of IFN-γ. The inducible NO synthase to arginase ratio was lower in the lungs of IFN-γ KO mice and the macrophages had increased numbers of intracellular cryptococci and YM1 crystals, indicative of alternatively activated macrophages in these mice. There was evidence of pulmonary fibrosis in both wild-type and IFN-γ KO mice by 5 wk postinfection. IFN-γ production was not required for the development of T2 cytokine (IL-4, IL-5, IL-13) producing cells in the lungs and lung-associated lymph nodes or induction of an IgE response. At a number of time points, T2 cytokine production was enhanced in IFN-γ KO mice. Thus, in the absence of IFN-γ, C57BL/6 mice develop an augmented allergic response to C. neoformans, including enhanced generation of alternatively activated macrophages, which is accompanied by a switch from a chronic to a progressive pulmonary cryptococcal infection.

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Section: Discussionmentioning

confidence: 99%

Role of IFN-γ in Regulating T2 Immunity and the Development of Alternatively Activated Macrophages during Allergic Bronchopulmonary Mycosis

Arora

Hernández

Erb-Downward

et al. 2005

The Journal of Immunology

138

193

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“…This could in turn influence B-cells isotype switching to yield Abs with different specificity (43, 69). We previously observed in another susceptible mouse strain (C57BL/6J) that the in vivo binding pattern was punctuate (76), a finding that has been associated with lack of protection (11,57). Although an efficient response seems to be mainly Th1 polarized and T-cell mediated, the role of Abs in natural infection remains uncertain.…”

Section: Discussionmentioning

confidence: 99%

“…Mice were infected with C. neoformans strain 24067 as described above and sacrificed after 7 days, and cells were obtained as described previously (76). Abs bound to the capsule were then detected by immunofluorescence using secondary Abs to mouse IgG or IgM conjugated to tetramethyl rhodamine isothiocyanate (Southern Biotechnologies Associates, Birmingham, AL).…”

Section: Yeast Strain and Preparation Of Inocula For Infectionmentioning

confidence: 99%

“…model, such that for BALB/c mice, Ab titers were barely above the detection limit of the method used, and no Abs to GXM could be detected in the sera of infected CBA/J mice (results not shown). Endogenously produced mouse Abs to C. neoformans have been reported to have immunofluorescence characteristics of nonprotective Abs with a punctate pattern (76). Hence, we studied the pattern of binding of serum Abs in these mouse strains.…”

Section: Vol 75 2007 Mouse Strain Susceptibility To Cryptococcus Nementioning

confidence: 99%

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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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“…This discovery has led to a new paradigm, one which accepts that some Abs can protect against fungi but which leaves the role of natural humoral immunity uncertain, since whether Ab responses during infection are protective is unknown. Some serological studies of human and mouse Abs provide strong circumstantial evidence that natural Ab responses contribute to protection (18,25), while other studies suggest that Ab responses to infection are dominated by nonprotective Abs (62). The strategy of evaluating the potential of humoral immunity by testing individual MAbs has now been applied to other pathogens, but the role of natural Ab responses to these pathogens is also uncertain.…”

mentioning

confidence: 99%

Antibody-Mediated Protection againstCryptococcus neoformansPulmonary Infection Is Dependent on B Cells

Rivera¹,

Zaragoza²,

Casadevall

2005

Infect Immun

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. These observations suggest that IgG1-mediated protection in this system is a consequence of alterations in the inflammatory response that translate into less damage to the host without directly reducing the fungal burden. For hosts with impaired immunities, the ineffectiveness of passive antibody (Ab) may reflect an inability to down-regulate inflammation and avoid self-damage. The results indicate an important role for B cells in host defense against C. neoformans infection and demonstrate a surprising dependence of Ab-mediated protection on B cells in this system.

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Antibodies Produced in Response toCryptococcus neoformansPulmonary Infection in Mice Have Characteristics of Nonprotective Antibodies

Cited by 21 publications

References 38 publications

Role of IFN-γ in Regulating T2 Immunity and the Development of Alternatively Activated Macrophages during Allergic Bronchopulmonary Mycosis

Role of IFN-γ in Regulating T2 Immunity and the Development of Alternatively Activated Macrophages during Allergic Bronchopulmonary Mycosis

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

Antibody-Mediated Protection againstCryptococcus neoformansPulmonary Infection Is Dependent on B Cells

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