scholarly journals CNLAC1 Is Required for Extrapulmonary Dissemination of Cryptococcus neoformans but Not Pulmonary Persistence

2004 ◽  
Vol 72 (3) ◽  
pp. 1693-1699 ◽  
Author(s):  
Mairi C. Noverr ◽  
Peter R. Williamson ◽  
Ryan S. Fajardo ◽  
Gary B. Huffnagle
Keyword(s):  
Respiratory Tract ◽  
Cryptococcus Neoformans ◽  
Random Mutagenesis ◽  
Pathogenic Yeast ◽  
Infectious Dose ◽  
Cellular Immune Responses ◽  
Laccase Enzyme ◽  
Cellular Immune ◽  
The Brain

ABSTRACT The pathogenic yeast Cryptococcus neoformans produces a laccase enzyme (CNLAC1), which catalyzes the synthesis of melanin in the presence of phenolic compounds. A number of genes have been implicated in the regulation of laccase and melanization, including IPC1, GPA1, MET3, and STE12. Albino mutants derived from random mutagenesis techniques may contain mutations in genes that regulate multiple virulence factors, including CNLAC1. The goal of our study is to investigate the role of CNLAC1 in virulence and evasion of pulmonary host defenses after infection via the respiratory tract. Using a set of congenic laccase-positive (2E-TUC-4) and laccase-deficient (2E-TU-4) strains, we found that both strains are avirulent at a lower dose (104 CFU/mouse) in mice. After the infectious dose was increased to 106 CFU/mouse, 70% mortality was observed in mice infected with 2E-TUC-4 compared to no mortality in mice infected with 2E-TU-4 at day 30 postinfection. This observation confirms the requirement for CNLAC1 in virulence. Interestingly, we observed no differences between the two strains in pulmonary growth or in elicitation of cellular immune responses in the lung. The only measurable defect of 2E-TU-4 was in dissemination to extrapulmonary sites. To examine the role of CNLAC1 in dissemination, mice were infected intravenously. By week 3 postinfection, equal numbers of strains 2E-TUC-4 and 2E-TU-4 were recovered from the brain and spleen. This observation indicates that CNLAC1 facilitates escape from the lung, but not growth in the lungs or brain, and suggests a novel role for CNLAC1 in virulence during an infection aquired via the respiratory tract.

scholarly journals The transcription factor Pdr802 regulates Titan cell formation, quorum sensing, and pathogenicity of Cryptococcus neoformans

2020 ◽  
Author(s):  
Julia C. V. Reuwsaat ◽  
Daniel P. Agustinho ◽  
Heryk Motta ◽  
Holly Brown ◽  
Andrew L. Chang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Quorum Sensing ◽  
Cryptococcus Neoformans ◽  
Cell Formation ◽  
Negative Regulator ◽  
Pathogenic Yeast ◽  
Opportunistic Fungal Pathogen ◽  
The Brain

ABSTRACTCryptococcus neoformans is a ubiquitous, opportunistic fungal pathogen that kills almost 200,000 people worldwide each year. It is acquired when mammalian hosts inhale the infectious propagules; these are deposited in the lung and, in the context of immunocompromise, may disseminate to the brain and cause lethal meningoencephalitis. Once inside the host, C. neoformans undergoes a variety of adaptive processes, including secretion of virulence factors, expansion of a polysaccharide capsule that impedes phagocytosis, and the production of giant (Titan) cells. The transcription factor Pdr802 is one regulator of these responses to the host environment. Expression of the corresponding gene is highly induced under host-like conditions in vitro and is critical for C. neoformans dissemination and virulence in a mouse model of infection. Direct targets of Pdr802 include the quorum sensing proteins Pqp1, Opt1 and Liv3; the transcription factors Stb4, Zfc3 and Bzp4, which regulate cryptococcal brain infectivity and capsule thickness; the calcineurin targets Had1 and Crz1, important for cell wall remodeling and C. neoformans virulence; and additional genes related to resistance to host temperature and oxidative stress, and to urease activity. Notably, cryptococci engineered to lack Pdr802 showed a dramatic increase in Titan cells, which are not phagocytosed and have diminished ability to directly cross biological barriers. This explains the limited dissemination of pdr802 mutant cells to the central nervous system and the consequently reduced virulence of this strain. The role of Pdr802 as a negative regulator of Titan cell formation is thus critical for cryptococcal pathogenicity.IMPORTANCEThe pathogenic yeast Cryptococcus neoformans presents a worldwide threat to human health, especially in the context of immunocompromise, and current antifungal therapy is hindered by cost, limited availability, and inadequate efficacy. After the infectious particle is inhaled, C. neoformans initiates a complex transcriptional program that integrates cellular responses and enables adaptation to the host lung environment. Here we describe the role of the transcription factor Pdr802 in the response to host conditions and its impact on C. neoformans virulence. We identified direct targets of Pdr802 and also discovered that it regulates cellular features that influence movement of this pathogen from the lung to the brain, where it causes fatal disease. These findings advance our understanding of a serious disease.

scholarly journals The Transcription Factor Pdr802 Regulates Titan Cell Formation and Pathogenicity of Cryptococcus neoformans

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Julia C. V. Reuwsaat ◽  
Daniel P. Agustinho ◽  
Heryk Motta ◽  
Andrew L. Chang ◽  
Holly Brown ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cryptococcus Neoformans ◽  
Cell Formation ◽  
Negative Regulator ◽  
Pathogenic Yeast ◽  
Content Type ◽  
Opportunistic Fungal Pathogen ◽  
The Brain

ABSTRACT Cryptococcus neoformans is a ubiquitous, opportunistic fungal pathogen that kills almost 200,000 people worldwide each year. It is acquired when mammalian hosts inhale the infectious propagules; these are deposited in the lung and, in the context of immunocompromise, may disseminate to the brain and cause lethal meningoencephalitis. Once inside the host, C. neoformans undergoes a variety of adaptive processes, including secretion of virulence factors, expansion of a polysaccharide capsule that impedes phagocytosis, and the production of giant (Titan) cells. The transcription factor Pdr802 is one regulator of these responses to the host environment. Expression of the corresponding gene is highly induced under host-like conditions in vitro and is critical for C. neoformans dissemination and virulence in a mouse model of infection. Direct targets of Pdr802 include the quorum sensing proteins Pqp1, Opt1, and Liv3; the transcription factors Stb4, Zfc3, and Bzp4, which regulate cryptococcal brain infectivity and capsule thickness; the calcineurin targets Had1 and Crz1, important for cell wall remodeling and C. neoformans virulence; and additional genes related to resistance to host temperature and oxidative stress, and to urease activity. Notably, cryptococci engineered to lack Pdr802 showed a dramatic increase in Titan cells, which are not phagocytosed and have diminished ability to directly cross biological barriers. This explains the limited dissemination of pdr802 mutant cells to the central nervous system and the consequently reduced virulence of this strain. The role of Pdr802 as a negative regulator of Titan cell formation is thus critical for cryptococcal pathogenicity. IMPORTANCE The pathogenic yeast Cryptococcus neoformans presents a worldwide threat to human health, especially in the context of immunocompromise, and current antifungal therapy is hindered by cost, limited availability, and inadequate efficacy. After the infectious particle is inhaled, C. neoformans initiates a complex transcriptional program that integrates cellular responses and enables adaptation to the host lung environment. Here, we describe the role of the transcription factor Pdr802 in the response to host conditions and its impact on C. neoformans virulence. We identified direct targets of Pdr802 and also discovered that it regulates cellular features that influence movement of this pathogen from the lung to the brain, where it causes fatal disease. These findings significantly advance our understanding of a serious disease.

scholarly journals Proteome-Wide Mapping and Reverse Vaccinology Approaches to Design a Multi-Epitope Vaccine against Clostridium perfringens

Vaccines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1079
Author(s):  
Fahad M. Aldakheel ◽  
Amna Abrar ◽  
Samman Munir ◽  
Sehar Aslam ◽  
Khaled S. Allemailem ◽  
...  
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Epitope Vaccine ◽  
Ifn Gamma ◽  
Cellular Immune Responses ◽  
Medical Control ◽  
Food Borne ◽  
Food Borne Illness ◽  
Cellular Immune ◽  
The Brain

C. perfringens is a highly versatile bacteria of livestock and humans, causing enteritis (a common food-borne illness in humans), enterotoxaemia (in which toxins are formed in the intestine which damage and destroy organs, i.e., the brain), and gangrene (wound infection). There is no particular cure for the toxins of C. perfringens. Supportive care (medical control of pain, intravenous fluids) is the standard treatment. Therefore, a multiple-epitope vaccine (MEV) should be designed to battle against C. perfringens infection. Furthermore, the main objective of this in silico investigation is to design an MEV that targets C. perfringens. For this purpose, we selected the top three proteins that were highly antigenic using immuno-informatics approaches, including molecular docking. B-cells, IFN-gamma, and T cells for target proteins were predicted and the most conserved epitopes were selected for further investigation. For the development of the final MEV, epitopes of LBL5, CTL17, and HTL13 were linked to GPGPG, AAY, and KK linkers. The vaccine N-end was joined to an adjuvant through an EAAK linker to improve immunogenicity. After the attachment of linkers and adjuvants, the final construct was 415 amino acids. B-cell and IFN-gamma epitopes demonstrate that the model structure is enhanced for humoral and cellular immune responses. To validate the immunogenicity and safety of the final construct, various physicochemical properties, and other properties such as antigenicity and non-allergens, were evaluated. Furthermore, molecular docking was carried out for verification of vaccine compatibility with the receptor, evaluated in silico. Also, in silico cloning was employed for the verification of the proper expression and credibility of the construct.

scholarly journals Depletion of Alveolar Macrophages Decreases the Dissemination of a Glucosylceramide-Deficient Mutant of Cryptococcus neoformans in Immunodeficient Mice

2007 ◽  
Vol 75 (10) ◽  
pp. 4792-4798 ◽  
Author(s):  
Talar B. Kechichian ◽  
John Shea ◽  
Maurizio Del Poeta
Keyword(s):  
Cryptococcus Neoformans ◽  
Alveolar Macrophages ◽  
Nk Cell ◽  
Granuloma Formation ◽  
Immunodeficient Mice ◽  
Virulence Phenotype ◽  
Alkaline Environments ◽  
The Central Nervous System ◽  
The Brain

ABSTRACT In previous studies we showed that a Cryptococcus neoformans mutant lacking glucosylceramide (Δgcs1) is avirulent and unable to reach the brain when it is administered intranasally into an immunocompetent mouse and is contained in a lung granuloma. To determine whether granuloma formation is key for containment of C. neoformans Δgcs1, we studied the role of C. neoformans glucosylceramide in a T- and NK-cell-immunodeficient mouse model (Tgε26) in which alveolar macrophages (AMs) are not activated and granuloma formation is not expected. The results show that Tgε26 mice infected with Δgcs1 do not produce a lung granuloma and that the Δgcs1 mutant proliferates in the lungs and does disseminate to the brain, although its virulence phenotype is dramatically reduced. Since Δgcs1 can grow only in acidic niches, such as the phagolysosome of AMs, and not in neutral or alkaline environments, such as the extracellular spaces, we hypothesize that in immunodeficient mice Δgcs1 proliferates inside AMs. Indeed, we found that depletion of AMs significantly improved Tgε26 mouse survival and decreased the dissemination of Δgcs1 cells to the central nervous system. Thus, these results suggest that the growth of Δgcs1 in immunodeficient mice is maintained within AMs. This study highlights the hypothesis that AMs may exacerbate C. neoformans infection in conditions in which there is severe host immunodeficiency.

scholarly journals THE ROLE OF HUMORAL ANTIBODIES IN REJECTION OF SKIN HOMOGRAFTS IN RABBITS

1961 ◽  
Vol 114 (4) ◽  
pp. 509-520 ◽  
Author(s):  
Roberto R. Kretschmer ◽  
Ruy Peréz-Tamayo
Keyword(s):  
Immune Responses ◽  
Skin Graft ◽  
Local Administration ◽  
Cellular Immune Responses ◽  
Humoral Antibodies ◽  
Skin Homograft ◽  
Cellular Immune ◽  
Control Skin

Gross and microscopic observations of skin homograft rejection carried out in cortisone-conditioned and non-conditioned rabbits seem to indicate that humoral antibodies play an important role in the phenomenon. Thus, local administration of isoimmune serum to animals bearing skin homografts resulted in a significantly earlier rejection of that particular test graft without modifying the course of a neighboring control-skin graft. This result appears to support the idea that homograft rejection is not only due to cellular antibodies but to a combination of both humoral and cellular immune responses, which should not be regarded as completely unrelated.

scholarly journals Detection of a gamma interferon-induced protein IP-10 in psoriatic plaques.

1988 ◽  
Vol 168 (3) ◽  
pp. 941-948 ◽  
Author(s):  
A B Gottlieb ◽  
A D Luster ◽  
D N Posnett ◽  
D M Carter
Keyword(s):  
Immune Responses ◽  
Cdna Probe ◽  
Gamma Interferon ◽  
Activated T Cells ◽  
Cellular Immune Responses ◽  
Hla Dr ◽  
Pathologic Features ◽  
Dermal Infiltrate ◽  
Cellular Immune

The pathologic features of psoriatic plaques are inflammation and increased epidermal turnover. IP-10, a cytokine the expression of which is induced by gamma-interferon, is a member of a family of soluble mediators with inflammatory and growth-promoting activities. IP-10 protein was detected in keratinocytes and the dermal infiltrate from active psoriatic plaques using an affinity-purified rabbit anti-IP-10 antibody in immunoperoxidase studies. Successful treatment of active plaques decreased IP-10 expression in plaques. These results were corroborated by Northern blot analysis with an IP-10 cDNA probe. We have previously detected activated T cells and HLA-DR keratinocytes in active psoriatic plaques. Since IP-10 is detected in delayed cellular immune responses, the present study further points to the role of ongoing cellular immune responses in the pathogenesis of psoriasis.

scholarly journals CD171 multi‑epitope peptide design based on immunoinformatics approach as a cancer vaccine candidate for glioblastoma

2021 ◽  
Author(s):  
Seyed Amir Hossein Mohammadzadeh Hosseini Moghri ◽  
Arefeh Abbasian
Keyword(s):  
Tertiary Structure ◽  
Vaccine Development ◽  
T Cell Epitopes ◽  
Epitope Peptide ◽  
Primary Malignancy ◽  
Cellular Immune Responses ◽  
The Central Nervous System ◽  
Cellular Immune ◽  
Informatics Tools ◽  
The Brain

Abstract Glioblastoma (GB) is a common primary malignancy of the central nervous system, and one of the highly lethal brain tumors. GB cells can promote therapeutic resistance and tumor angiogenesis. The CD171 is an adhesion molecule in neuronal cells that is expressed in glioma cells; it is a regulator of the brain development. CD171 is one of the immunoglobulin-like CAMs (cell adhesion molecules) families that can be associated with prognosis in a variety of human tumors. The multi-epitope peptide vaccines are based on synthetic peptides with a combination of both B-cell epitopes and T-cell epitopes, which can induce specific humoral or cellular immune responses. In the present study, several immune-informatics tools were used for analyzing the CD171 sequence and studying the important characteristics of a designed vaccine. The results included the prediction and validation of the secondary and tertiary structure, physicochemical properties, solubility, conservancy, toxicity as well as antigenicity and allergenicity of the promising candidate for a vaccine against CD171. The immunoinformatic analysis suggested 12 predicted multi-epitope peptides, whose construction consists of 582 residues long. Therewith, cloning adaptation of designed vaccine was performed and eventually sequence was inserted into pET30a (+) vector for the application of the anti-glioblastoma vaccine development.

scholarly journals Next-Generation Pertussis Vaccines Based on the Induction of Protective T Cells in the Respiratory Tract

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 621 ◽  
Author(s):  
Caitlín Ní Chasaide ◽  
Kingston H.G. Mills
Keyword(s):  
Respiratory Tract ◽  
Protective Immunity ◽  
Membrane Vesicle ◽  
Secretory Iga ◽  
Nasal Colonization ◽  
Next Generation ◽  
Previous Infection ◽  
Cellular Immune

Immunization with current acellular pertussis (aP) vaccines protects against severe pertussis, but immunity wanes rapidly after vaccination and these vaccines do not prevent nasal colonization with Bordetella pertussis. Studies in mouse and baboon models have demonstrated that Th1 and Th17 responses are integral to protective immunity induced by previous infection with B. pertussis and immunization with whole cell pertussis (wP) vaccines. Mucosal Th17 cells, IL-17 and secretory IgA (sIgA) are particularly important in generating sustained sterilizing immunity in the nasal cavity. Current aP vaccines induce potent IgG and Th2-skewed T cell responses but are less effective at generating Th1 and Th17 responses and fail to prime respiratory tissue-resident memory T (TRM) cells, that maintain long-term immunity at mucosal sites. In contrast, a live attenuated pertussis vaccine, pertussis outer membrane vesicle (OMV) vaccines or aP vaccines formulated with novel adjuvants do induce cellular immune responses in the respiratory tract, especially when delivered by the intranasal route. An increased understanding of the mechanisms of sustained protective immunity, especially the role of respiratory TRM cells, will facilitate the development of next generation pertussis vaccines that not only protect against pertussis disease, but prevent nasal colonization and transmission of B. pertussis.

Sign in / Sign up

Export Citation Format

Share Document