A proteomic‐based approach for the identification of immunodominant <b><i>Cryptococcus neoformans</i></b> proteins

Young, Mattie L.; Macias, Sandra; Thomas, Derek P.; Wormley, Floyd L.

doi:10.1002/pmic.200800713

Cited by 39 publications

(78 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…23,29 To verify a reduction in fungal load and to assess macrophage recruitment during C. neoformans strain H99␥ infection, BALB/c mice were given an intranasal inoculation with 1 ϫ 10 4 CFU of either C. neoformans strain H99␥ or wild-type C. neoformans strain H99, and the pulmonary fungal burden was quantified on days 3, 7, and 14 postinoculation. Figure 1A demonstrates that pulmonary fungal burden was significantly decreased on day 14 postinoculation in mice given an experimental pulmonary infection with C. neoformans strain H99␥ compared with wild-type infected mice (P Ͻ 0.01).…”

Section: Effect Of Ifn-␥ Transgene Expression By C Neoformans Strainmentioning

confidence: 99%

Pulmonary Infection with an Interferon-γ-Producing Cryptococcus neoformans Strain Results in Classical Macrophage Activation and Protection

Hardison

Ravi

Wozniak

et al. 2010

The American Journal of Pathology

Self Cite

109

127

View full text Add to dashboard Cite

Alternative macrophage activation is associated with exacerbated disease in murine models of pulmonary cryptococcosis. The present study evaluated the efficacy of interferon-␥ transgene expression by Cryptococcus neoformans strain H99␥ in abrogating alternative macrophage activation in infected mice. Macrophage recruitment into the lungs of mice after infection with C. neoformans strain H99␥ was comparable with that observed in mice challenged with wild-type C. neoformans. However, pulmonary infection in mice with C. neoformans strain H99␥ was associated with reduced pulmonary fungal burden, increased pulmonary Th1-type and interleukin-17 cytokine production, and classical macrophage activation as evidenced by increased inducible nitric oxide synthase expression, histological evidence of enhanced macrophage fungicidal activity, and resolution of inflammation. In contrast, progressive pulmonary infection, enhanced Th2-type cytokine production, and the induction of alternatively activated macrophages expressing arginase-1, found in inflammatory zone 1, Ym1, and macrophage mannose receptor were observed in the lungs of mice infected with wild-type C. neoformans. These alternatively activated macrophages were also shown to harbor highly encapsulated , replicating cryptococci. Our results demonstrate that pulmonary infection with C. neoformans strain H99␥ results in the induction of classically activated macrophages and promotes fungal clearance. These studies indicate that phenotype , as opposed to quantity , of infiltrating macrophages correlates with protection against pulmonary C . neoformans infection.

show abstract

Section: Effect Of Ifn-␥ Transgene Expression By C Neoformans Strainmentioning

confidence: 99%

Pulmonary Infection with an Interferon-γ-Producing Cryptococcus neoformans Strain Results in Classical Macrophage Activation and Protection

Hardison

Ravi

Wozniak

et al. 2010

The American Journal of Pathology

Self Cite

109

127

View full text Add to dashboard Cite

show abstract

“…Previous studies demonstrated that experimental pulmonary infection with a C. neoformans strain engineered to express IFN-␥, strain H99␥, results in the generation of a polarized Th1-type cytokine response in mice (36). Mice given a pulmonary infection with C. neoformans strain H99␥ resolve the acute infection and are completely protected from a secondary infection with wild-type (WT) cryptococci (36,38,40). Recently, we demonstrated that clearance of infection with C. neoformans strain H99␥ is associated with the induction of inducible nitric oxide synthase (iNOS) expression, caMac, and pulmonary Th1-type cytokine production (15).…”

mentioning

confidence: 99%

Interleukin-17 Is Not Required for Classical Macrophage Activation in a Pulmonary Mouse Model ofCryptococcus neoformansInfection

et al. 2010

Self Cite

View full text Add to dashboard Cite

Cryptococcus neoformans is an opportunistic fungal pathogen that causes disease in individuals with suppressed cell-mediated immunity. Recent studies in our laboratory have shown that increases in pulmonary Th1-type and interleukin-17A (IL-17A) cytokine production, classical macrophage activation, and sterilizing immunity are elicited in response to infection with a gamma interferon (IFN-␥)-producing C. neoformans strain, H99␥. IL-17A-treated macrophages, compared to IL-4-treated macrophages, have been demonstrated to exhibit increased microbicidal activity in vitro, a characteristic consistent with classical macrophage activation. The purpose of these studies is to determine the role of IL-17A in the induction of classically activated macrophages following infection with C. neoformans. Immunohistochemistry and real-time PCR were used to characterize the macrophage activation phenotype in lung tissues of mice treated with isotype control or anti-IL-17A antibodies and given an experimental pulmonary infection with C. neoformans strain H99␥. The pulmonary fungal burden was resolved, albeit more slowly, in mice depleted of IL-17A compared to the fungal burden in isotype control-treated mice. Nonetheless, no difference in classical macrophage activation was observed in IL-17A-depleted mice. Similarly, classical macrophage activation was evident in mice deficient in IL-17A or the IL-17 receptor A, which mediates IL-17A signaling, following pulmonary infection with wild-type C. neoformans strain H99 or H99␥. These studies suggest that IL-17A may play a role in the early immune response to C. neoformans but is not required for classical macrophage activation in mice experimentally infected with C. neoformans.

show abstract

“…In addition to the results seen with enolase and GAPDH described above, the C. gattii VGIIb strain secreted glucose-6-phosphate isomerase, which has been linked to the development of rheumatoid arthritis following Aspergillus infection (56). Further, some non-classically secreted proteins identified in this study, including fungal serinetype endopeptidases (57) and transaldolase, an immunodominant protein in C. neoformans (58)(59)(60), have been found to bind IgE. The presence of immunogenic proteins in the VGIIb secretome might be expected to provoke rapid induction of the innate immune response, preventing the initiation of disease.…”

Section: Discussionmentioning

confidence: 88%

Cryptococcus Strains with Different Pathogenic Potentials Have Diverse Protein Secretomes

et al. 2015

View full text Add to dashboard Cite

bSecreted proteins are the frontline between the host and pathogen. In mammalian hosts, secreted proteins enable invasive infection and can modulate the host immune response. Cryptococcosis, caused by pathogenic Cryptococcus species, begins when inhaled infectious propagules establish to produce pulmonary infection, which, if not resolved, can disseminate to the central nervous system to cause meningoencephalitis. Strains of Cryptococcus species differ in their capacity to cause disease, and the mechanisms underlying this are not well understood. To investigate the role of secreted proteins in disease, we determined the secretome for three genome strains of Cryptococcus species, including a hypovirulent and a hypervirulent strain of C. gattii and a virulent strain of C. neoformans. Sixty-seven unique proteins were identified, with different numbers and types of proteins secreted by each strain. The secretomes of the virulent strains were largely limited to proteolytic and hydrolytic enzymes, while the hypovirulent strain had a diverse secretome, including non-conventionally secreted canonical cytosolic and immunogenic proteins that have been implicated in virulence. The hypovirulent strain cannot establish pulmonary infection in a mouse model, but strains of this genotype have caused human meningitis. To directly test brain infection, we used intracranial inoculation and found that the hypovirulent strain was substantially more invasive than its hypervirulent counterpart. We suggest that immunogenic proteins secreted by this strain invoke a host response that limits pulmonary infection but that there can be invasive growth and damage if infection reaches the brain. Given their known role in virulence, it is possible that non-conventionally secreted proteins mediate this process. P rotein secretion is an essential process for all cells. Secretion has roles in various aspects of cell physiology and lifestyle, including nutrient acquisition, cell wall remodeling, signaling, quorum sensing, and defense against other organisms (1). For pathogenic organisms, the secretion of specific proteins can be key to disease progression, allowing the pathogen both to invade and obtain nutrients and to directly modulate the host organism's immune response.The ability to secrete proteins is of particular importance to fungal organisms. Fungi use exodigestion and absorptive nutrition to acquire nutrients and have evolved a complex suite of secreted proteins to degrade the diverse biopolymers encountered in the host or abiotic environment. Comparisons of characterized fungal secretomes suggest that their basal secretome consists of a core set of degradation enzymes. These include polysaccharideactive enzymes, including glycoside hydrolases, carbohydrate esterases, and polysaccharide lyases, which can degrade the major components of plant cell walls such as cellulose and pectin (2). Other degradative enzymes include proteases, for example, secreted aspartyl proteases (SAPs), which have been associated with pathogenicity in the human ...

show abstract

A proteomic‐based approach for the identification of immunodominant Cryptococcus neoformans proteins

Cited by 39 publications

References 80 publications

Pulmonary Infection with an Interferon-γ-Producing Cryptococcus neoformans Strain Results in Classical Macrophage Activation and Protection

Pulmonary Infection with an Interferon-γ-Producing Cryptococcus neoformans Strain Results in Classical Macrophage Activation and Protection

Interleukin-17 Is Not Required for Classical Macrophage Activation in a Pulmonary Mouse Model ofCryptococcus neoformansInfection

Cryptococcus Strains with Different Pathogenic Potentials Have Diverse Protein Secretomes

Contact Info

Product

Resources

About