Prior Exposure to Live Mycobacterium bovis BCG Decreases Cryptococcus neoformans-Induced Lung Eosinophilia in a Gamma Interferon-Dependent Manner

ABSTRACT Some common childhood infections appear to prevent the development of atopy and asthma. In some Mycobacterium bovis BCG-vaccinated populations, strong delayed-type hypersensitivity responses to mycobacterial antigens are associated with a reduced risk of atopy. Although BCG exposure decreases allergen-induced lung eosinophilia in animal models, little attention has been given to the effect of immunity to BCG on responses against live pathogens. We used the murine Cryptococcus neoformans infection model to investigate whether prior BCG infection can alter such responses. The present study shows that persistent pulmonary BCG infection of C57BL/6 mice induced an increase in gamma interferon, a reduction in interleukin-5, and a decrease in lung eosinophilia during subsequent Cryptococcus infection. This effect was long lasting, depended on the presence of live bacteria, and required persistence of mycobacterial infection in the lung. Reduction of eosinophilia was less prominent after infection with a mutant BCG strain (ΔhspR), which was rapidly cleared from the lungs. These observations have important implications for the development of vaccines designed to prevent Th2-mediated disease and indicate that prior lung BCG vaccination can alter the pattern of subsequent host inflammation.

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Immune Responses to Defined Antigens of Mycobacterium bovis in Cattle Experimentally Infected with Mycobacterium kansasii

Clinical and Vaccine Immunology ◽

10.1128/cvi.00054-06 ◽

2006 ◽

Vol 13 (6) ◽

pp. 611-619 ◽

Cited By ~ 45

Author(s):

W. R. Waters ◽

M. V. Palmer ◽

T. C. Thacker ◽

J. B. Payeur ◽

N. B. Harris ◽

...

Keyword(s):

Mycobacterium Bovis ◽

Bovine Tuberculosis ◽

Nontuberculous Mycobacteria ◽

Gamma Interferon ◽

Delayed Type Hypersensitivity ◽

Enzyme Linked Immunosorbent Assay ◽

Serum Antibodies ◽

Specific Serum ◽

Specific Proteins

ABSTRACT Cross-reactive responses elicited by exposure to nontuberculous mycobacteria often confound the interpretation of antemortem tests for Mycobacterium bovis infection of cattle. The use of specific proteins (e.g., ESAT-6, CFP-10, and MPB83), however, generally enhances the specificity of bovine tuberculosis tests. While genes for these proteins are absent from many nontuberculous mycobacteria, they are present in M. kansasii. Instillation of M. kansasii into the tonsillar crypts of calves elicited delayed-type hypersensitivity and in vitro gamma interferon and nitrite concentration responses of leukocytes to M. avium and M. bovis purified protein derivatives (PPDs). While the responses of M. kansasii-inoculated calves to M. avium and M. bovis PPDs were approximately equivalent, the responses of M. bovis-inoculated calves to M. bovis PPD exceeded their respective responses to M. avium PPD. The gamma interferon and nitrite responses of M. kansasii-inoculated calves to recombinant ESAT-6-CFP-10 (rESAT-6-CFP-10) exceeded corresponding responses of noninoculated calves as early as 15 and 30 days after inoculation, respectively, and persisted throughout the study. The gamma interferon and nitrite responses of M. bovis-inoculated calves to rESAT-6-CFP-10 exceeded the corresponding responses of M. kansasii-inoculated calves beginning 30 days after inoculation. By using a lipoarabinomannan-based enzyme-linked immunosorbent assay, specific serum antibodies were detected as early as 50 days after challenge with M. kansasii. By a multiantigen print immunoassay and immunoblotting, serum antibodies to MPB83, but not ESAT-6 or CFP-10, were detected in M. kansasii-inoculated calves; however, responses to MPB83 were notably weaker than those elicited by M. bovis infection. These findings indicate that M. kansasii infection of calves elicits specific responses that may confound the interpretation of bovine tuberculosis tests.

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Evaluation of Gamma Interferon (IFN-γ)-Induced Protein 10 Responses for Detection of Cattle Infected with Mycobacterium bovis: Comparisons to IFN-γ Responses

Clinical and Vaccine Immunology ◽

10.1128/cvi.05657-11 ◽

2012 ◽

Vol 19 (3) ◽

pp. 346-351 ◽

Cited By ~ 24

Author(s):

W. R. Waters ◽

T. C. Thacker ◽

B. J. Nonnecke ◽

M. V. Palmer ◽

I. Schiller ◽

...

Keyword(s):

Mycobacterium Bovis ◽

Similar Pattern ◽

Gamma Interferon ◽

Content Type ◽

Purified Protein Derivative ◽

Testing Protocol ◽

Archived Samples ◽

Ifn Γ ◽

Highly Correlated ◽

Mycobacterial Antigens

ABSTRACTGamma interferon (IFN-γ)-induced protein 10 (IP-10) has recently shown promise as a diagnostic biomarker ofMycobacterium tuberculosisinfection of humans. The aim of the current study was to compare IP-10 and IFN-γ responses uponMycobacterium bovisinfection in cattle by using archived samples from two aerosol inoculation studies. In the first study (104CFUM. bovisby aerosol,n= 7),M. bovispurified protein derivative (PPDb)-specific IP-10 and IFN-γ gene expression was detected as early as 29 days after challenge. PPDb-specific IP-10 and IFN-γ mRNA responses followed a similar pattern of expression over the course of this study and were highly correlated (r= 0.87). In the second study (105CFUM. bovisby aerosol,n= 5), IP-10 and IFN-γ (protein) responses to mycobacterial antigens were compared following challenge. IFN-γ responses to mycobacterial antigens were detected at 29 days after challenge and were sustained during the remainder of the study. IFN-γ responses to mycobacterial antigens exceeded corresponding responses in nonstimulated cultures. IP-10 responses to mycobacterial antigens exceeded preinfection responses at 7, 29, and 63 days after challenge. In contrast to IFN-γ responses, IP-10 responses to mycobacterial antigens generally did not exceed the respective responses in nonstimulated cultures. IP-10 responses to medium alone and to mycobacterial antigens followed a similar pattern of response. Correlations between IP-10 and IFN-γ (protein) responses were modest (r≈ 0.50 to 0.65). Taken together, these findings do not support the use of IP-10 protein as a biomarker for bovine tuberculosis using the current testing protocol and reagents; however, mRNA-based assays may be considered for further analysis.

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Immune Responses in Cattle Inoculated with Mycobacterium bovis, Mycobacterium tuberculosis, or Mycobacterium kansasii

Clinical and Vaccine Immunology ◽

10.1128/cvi.00442-09 ◽

2009 ◽

Vol 17 (2) ◽

pp. 247-252 ◽

Cited By ~ 49

Author(s):

W. R. Waters ◽

A. O. Whelan ◽

K. P. Lyashchenko ◽

R. Greenwald ◽

M. V. Palmer ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Immune Responses ◽

Mycobacterium Bovis ◽

Antibody Responses ◽

Delayed Type Hypersensitivity ◽

Mycobacterium Kansasii ◽

Purified Protein Derivative ◽

Cellular Immune ◽

Mycobacterial Antigens ◽

Interferon Responses

ABSTRACT Cattle were inoculated with Mycobacterium bovis, Mycobacterium tuberculosis, or Mycobacterium kansasii to compare the antigen-specific immune responses to various patterns of mycobacterial disease. Disease expression ranged from colonization with associated pathology (M. bovis infection) and colonization without pathology (M. tuberculosis infection) to no colonization or pathology (M. kansasii infection). Delayed-type hypersensitivity and gamma interferon responses were elicited by each mycobacterial inoculation; however, the responses by the M. bovis- and M. tuberculosis-inoculated animals exceeded those of the M. kansasii-inoculated animals. Specific antibody responses were detected in all M. tuberculosis- and M. bovis-inoculated cattle 3 weeks after inoculation. From 6 to 16 weeks after M. tuberculosis inoculation, the antibody responses waned, whereas the responses persisted with M. bovis infection. With M. kansasii inoculation, initial early antibody responses waned by 10 weeks after inoculation and then increased 2 weeks after the injection of purified protein derivative for the skin test at 18 weeks after challenge. These findings indicate that antibody responses are associated with the antigen burden rather than the pathology, cellular immune responses to tuberculin correlate with infection but not necessarily with the pathology or bacterial burden, and exposure to mycobacterial antigens may elicit an antibody response in a presensitized animal.

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Role of Eosinophils in the Pathogenesis ofMycobacterium bovis BCG Infection in Gamma Interferon Receptor-Deficient Mice

Infection and Immunity ◽

10.1128/iai.68.5.2976-2978.2000 ◽

2000 ◽

Vol 68 (5) ◽

pp. 2976-2978 ◽

Cited By ~ 25

Author(s):

Joanna Kirman ◽

Zamsyari Zakaria ◽

Kathy McCoy ◽

Brett Delahunt ◽

Graham Le Gros

Keyword(s):

Monoclonal Antibody ◽

Mycobacterium Bovis ◽

Gamma Interferon ◽

Eosinophil Infiltration ◽

Interleukin 5 ◽

Interferon Receptor ◽

Mycobacterial Growth ◽

Deficient Mice

ABSTRACT A profound eosinophil infiltration of granulomas is observed in the lungs of Mycobacterium bovis bacillus Calmette Guérin-infected gamma interferon receptor-deficient mice. Blockade of eosinophil proliferation and recruitment into the lung by treatment with anti-interleukin-5 monoclonal antibody marginally reduced mycobacterial growth within the lung but did not affect dissemination of the infection to other tissues.

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Faculty Opinions recommendation of Protection against cryptococcosis by using a murine gamma interferon-producing Cryptococcus neoformans strain.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1059076.511051 ◽

2007 ◽

Author(s):

Arturo Casadevall

Keyword(s):

Cryptococcus Neoformans ◽

Gamma Interferon

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Antifungal activity of dendritic cell lysosomal proteins against Cryptococcus neoformans

Scientific Reports ◽

10.1038/s41598-021-92991-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Benjamin N. Nelson ◽

Savannah G. Beakley ◽

Sierra Posey ◽

Brittney Conn ◽

Emma Maritz ◽

...

Keyword(s):

Antifungal Activity ◽

Cryptococcus Neoformans ◽

Mammalian Cells ◽

Cysteine Proteases ◽

Dependent Manner ◽

Life Threatening ◽

Opportunistic Fungal Pathogen ◽

Dose Dependent ◽

Lysosomal Proteins

AbstractCryptococcal meningitis is a life-threatening disease among immune compromised individuals that is caused by the opportunistic fungal pathogen Cryptococcus neoformans. Previous studies have shown that the fungus is phagocytosed by dendritic cells (DCs) and trafficked to the lysosome where it is killed by both oxidative and non-oxidative mechanisms. While certain molecules from the lysosome are known to kill or inhibit the growth of C. neoformans, the lysosome is an organelle containing many different proteins and enzymes that are designed to degrade phagocytosed material. We hypothesized that multiple lysosomal components, including cysteine proteases and antimicrobial peptides, could inhibit the growth of C. neoformans. Our study identified the contents of the DC lysosome and examined the anti-cryptococcal properties of different proteins found within the lysosome. Results showed several DC lysosomal proteins affected the growth of C. neoformans in vitro. The proteins that killed or inhibited the fungus did so in a dose-dependent manner. Furthermore, the concentration of protein needed for cryptococcal inhibition was found to be non-cytotoxic to mammalian cells. These data show that many DC lysosomal proteins have antifungal activity and have potential as immune-based therapeutics.

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Investigation of Antifungal Mechanisms of Thymol in the Human Fungal Pathogen, Cryptococcus neoformans

Molecules ◽

10.3390/molecules26113476 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3476

Author(s):

Kwang-Woo Jung ◽

Moon-Soo Chung ◽

Hyoung-Woo Bai ◽

Byung Yeoup Chung ◽

Sungbeom Lee

Keyword(s):

Cryptococcus Neoformans ◽

Fungal Pathogens ◽

Reverse Genetics ◽

Mapk Pathway ◽

Global Climate ◽

Mitogen Activated Protein Kinase ◽

Ergosterol Biosynthesis ◽

Thymus Vulgaris ◽

Dependent Manner ◽

Expression Levels

Due to lifespan extension and changes in global climate, the increase in mycoses caused by primary and opportunistic fungal pathogens is now a global concern. Despite increasing attention, limited options are available for the treatment of systematic and invasive mycoses, owing to the evolutionary similarity between humans and fungi. Although plants produce a diversity of chemicals to protect themselves from pathogens, the molecular targets and modes of action of these plant-derived chemicals have not been well characterized. Using a reverse genetics approach, the present study revealed that thymol, a monoterpene alcohol from Thymus vulgaris L., (Lamiaceae), exhibits antifungal activity against Cryptococcus neoformans by regulating multiple signaling pathways including calcineurin, unfolded protein response, and HOG (high-osmolarity glycerol) MAPK (mitogen-activated protein kinase) pathways. Thymol treatment reduced the intracellular concentration of Ca2+ by controlling the expression levels of calcium transporter genes in a calcineurin-dependent manner. We demonstrated that thymol decreased N-glycosylation by regulating the expression levels of genes involved in glycan-mediated post-translational modifications. Furthermore, thymol treatment reduced endogenous ergosterol content by decreasing the expression of ergosterol biosynthesis genes in a HOG MAPK pathway-dependent manner. Collectively, this study sheds light on the antifungal mechanisms of thymol against C. neoformans.

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Early Antibody Responses to Experimental Mycobacterium bovis Infection of Cattle

Clinical and Vaccine Immunology ◽

10.1128/cvi.00061-06 ◽

2006 ◽

Vol 13 (6) ◽

pp. 648-654 ◽

Cited By ~ 90

Author(s):

W. R. Waters ◽

M. V. Palmer ◽

T. C. Thacker ◽

J. P. Bannantine ◽

H. M. Vordermeier ◽

...

Keyword(s):

Mycobacterium Bovis ◽

Skin Testing ◽

Rapid Test ◽

Kinetic Studies ◽

Immunoblot Analysis ◽

Immunoglobulin M ◽

Serum Samples ◽

Mycobacterial Antigens ◽

New Generation ◽

And Control

ABSTRACT Bovine tuberculosis persists as a costly zoonotic disease in numerous countries despite extensive eradication and control efforts. Sequential serum samples obtained from Mycobacterium bovis-infected cattle were evaluated for seroreactivity to mycobacterial antigens. Animals received M. bovis by aerosol, intratonsil, intranasal, or intratracheal inoculation. Assays included the multiantigen print immunoassay for determination of antigen recognition patterns, immunoblot analysis for sensitive kinetic studies, and the VetTB STAT-PAK test, a novel, rapid test based on lateral-flow technology. Responses to MPB83 were detected for all M. bovis-infected animals regardless of the route or strain of M. bovis used for inoculation. Other less commonly recognized antigens included ESAT-6, CFP-10, and MPB70. Responses to MPB83 were detectable as early as 4 weeks after inoculation, were boosted upon injection of purified protein derivatives for skin testing, and persisted throughout the course of each of the four challenge studies. MPB83-specific immunoglobulin M (IgM) was detected prior to MPB83-specific IgG detection; however, early IgM responses rapidly waned, suggesting a benefit of tests that detect both IgM- and IgG-specific antibodies. The VetTB STAT-PAK test detected responses in sera from 60% (15/25) of the animals by 7 weeks after challenge and detected responses in 96% (24/25) of the animals by 18 weeks. These findings demonstrate the potential for new-generation antibody-based tests for the early detection of M. bovis infection in cattle.

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Enhanced Antigen-Specific Delayed-Type Hypersensitivity and Immunoglobulin G2b Responses after Oral Administration of ViableLactobacillus casei YIT9029 in Wistar and Brown Norway Rats

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.8.4.762-767.2001 ◽

2001 ◽

Vol 8 (4) ◽

pp. 762-767 ◽

Cited By ~ 21

Author(s):

R. de Waard ◽

J. Garssen ◽

J. Snel ◽

G. C. A. M. Bokken ◽

T. Sako ◽

...

Keyword(s):

Trichinella Spiralis ◽

Active Role ◽

Lymphoid Organ ◽

Delayed Type Hypersensitivity ◽

Brown Norway ◽

Infection Model ◽

Cell Mediated Immunity ◽

Th1 Cell ◽

Inflammatory Reactions ◽

Norway Rats

ABSTRACT In this study, the effects of orally administered viableLactobacillus casei Shirota strain YIT9029 on the immunity parameters of Wistar and Brown Norway rats were examined. For this purpose, we used the Trichinella spiralis host resistance model. Two weeks before and during T. spiralisinfection, rats were fed 109 viable L. casei bacteria 5 days per week. The T. spiralis-specific delayed-type hypersensitivity (DTH) response was significantly enhanced in both Wistar and Brown Norway rats given L. casei. In both rat strains fedL. casei, serum T. spiralis-specific immunoglobulin G2b (IgG2b) concentrations were also significantly increased. In the model, no significant effects ofL. casei on larval counts or inflammatory reactions in the tongue musculature, body weights, or lymphoid organ weights were observed. Serum specific antibody responses, other than IgG2b, were not changed by feeding of L. casei. In contrast toL. casei, it was shown that orally administeredBifidobacterium breve or Bifidobacterium bifidum had no influence on the measured infection and immunity indices in the rat infection model. Since the rat DTH response is considered to be a manifestation of Th1 cell-mediated immunity and the IgG2b isotype has been associated with Th1 activity, it was concluded that Th1 cells could play an active role in the immunomodulatory effects of orally administered L. casei. Furthermore, our data do not indicate that the effect of oral supplementation withL. casei is dependent on the genetic background of the host.

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