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Methamphetamine enhances Cryptococcus neoformans pulmonary infection and dissemination to the brain.

Patel D, Desai GM, Frases S, Cordero RJ, DeLeon-Rodriguez CM, Eugenin EA, Nosanchuk JD, Martinez LR - MBio (2013)

Bottom Line: In addition to functioning as a central nervous system stimulant, METH has diverse effects on host immunity.Notably, C. neoformans modifies its capsular polysaccharide after METH exposure, highlighting the fungus's ability to adapt to environmental stimuli, a possible explanation for its pathogenesis.The findings may translate into new knowledge and development of therapeutic and public health strategies to deal with the devastating complications of METH abuse.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, Long Island University Post, Brookville, New York, USA.

ABSTRACT

Unlabelled: Methamphetamine (METH) is a major addictive drug of abuse in the United States and worldwide, and its use is linked to HIV acquisition. The encapsulated fungus Cryptococcus neoformans is the most common cause of fungal meningitis in patients with AIDS. In addition to functioning as a central nervous system stimulant, METH has diverse effects on host immunity. Using a systemic mouse model of infection and in vitro assays in order to critically assess the impact of METH on C. neoformans pathogenesis, we demonstrate that METH stimulates fungal adhesion, glucuronoxylomannan (GXM) release, and biofilm formation in the lungs. Interestingly, structural analysis of the capsular polysaccharide of METH-exposed cryptococci revealed that METH alters the carbohydrate composition of this virulence factor, an event of adaptation to external stimuli that can be advantageous to the fungus during pathogenesis. Additionally, we show that METH promotes C. neoformans dissemination from the respiratory tract into the brain parenchyma. Our findings provide novel evidence of the impact of METH abuse on host homeostasis and increased permissiveness to opportunistic microorganisms.

Importance: Methamphetamine (METH) is a major health threat to our society, as it adversely changes people's behavior, as well as increases the risk for the acquisition of diverse infectious diseases, particularly those that enter through the respiratory tract or skin. This report investigates the effects of METH use on pulmonary infection by the AIDS-related fungus Cryptococcus neoformans. This drug of abuse stimulates colonization and biofilm formation in the lungs, followed by dissemination of the fungus to the central nervous system. Notably, C. neoformans modifies its capsular polysaccharide after METH exposure, highlighting the fungus's ability to adapt to environmental stimuli, a possible explanation for its pathogenesis. The findings may translate into new knowledge and development of therapeutic and public health strategies to deal with the devastating complications of METH abuse.

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METH alters the size of C. neoformans capsular polysaccharide fractions. Capsular polysaccharide obtained from untreated (A) and METH-treated (B) strain H99. The x axis represents size distribution by particle diameter; the y axis corresponds to the values of percentage intensity-weighted sizes obtained with the nonnegative least-squares (NNLS) algorithm. (C) METH promotes capsular polysaccharide release from cryptococcal cells. After coincubation with 25 µM METH, the cells were washed and incubated with Uvitex and MAb 18B7-FITC-conjugated goat anti-mouse IgG1 stain to label the cell wall (blue) and capsular polysaccharide (green), respectively. Bar, 2 µm.
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fig4: METH alters the size of C. neoformans capsular polysaccharide fractions. Capsular polysaccharide obtained from untreated (A) and METH-treated (B) strain H99. The x axis represents size distribution by particle diameter; the y axis corresponds to the values of percentage intensity-weighted sizes obtained with the nonnegative least-squares (NNLS) algorithm. (C) METH promotes capsular polysaccharide release from cryptococcal cells. After coincubation with 25 µM METH, the cells were washed and incubated with Uvitex and MAb 18B7-FITC-conjugated goat anti-mouse IgG1 stain to label the cell wall (blue) and capsular polysaccharide (green), respectively. Bar, 2 µm.

Mentions: We analyzed the size distribution of polysaccharide from C. neoformans capsule molecules cultivated with or without METH (Fig. 4). The capsular polysaccharide molecules of METH-treated yeast cells exhibited, on average, a smaller diameter (941.0 ± 11.9 nm) (Fig. 4B) than those of untreated cells (1,203.8 ± 33.2 nm) (Fig. 4A). Treatment with METH yielded two homogeneous populations of reduced capsular polysaccharide. The size distribution range for each population was 181.1 to 273.9 and 1,590.5 to 2,405.8 nm, with the highest values at 222.7 and 1,956.1 nm, respectively (Fig. 4B). Similarly, two different populations with respect to polysaccharide size were present in untreated cells (Fig. 4A). The size range for each population was 2.03 to 288.1 and 1,405.9 to 3,786.7 nm, with the highest values at 193.8 and 2,089.7 nm, respectively. Using immunofluorescence, we demonstrated a significant reduction in capsule-specific monoclonal antibody (MAb) 18B7 binding to cryptococcal cells treated with METH relative to that of control yeast cells (Fig. 4C), suggesting that METH might be capable of altering capsular polysaccharide synthesis and/or structure, resulting in a different capsular surface with altered epitope density and/or accessibility. METH-induced alterations of the cryptococcal cell surface might have adverse implications on host-pathogen interactions and enhance pathogenesis.


Methamphetamine enhances Cryptococcus neoformans pulmonary infection and dissemination to the brain.

Patel D, Desai GM, Frases S, Cordero RJ, DeLeon-Rodriguez CM, Eugenin EA, Nosanchuk JD, Martinez LR - MBio (2013)

METH alters the size of C. neoformans capsular polysaccharide fractions. Capsular polysaccharide obtained from untreated (A) and METH-treated (B) strain H99. The x axis represents size distribution by particle diameter; the y axis corresponds to the values of percentage intensity-weighted sizes obtained with the nonnegative least-squares (NNLS) algorithm. (C) METH promotes capsular polysaccharide release from cryptococcal cells. After coincubation with 25 µM METH, the cells were washed and incubated with Uvitex and MAb 18B7-FITC-conjugated goat anti-mouse IgG1 stain to label the cell wall (blue) and capsular polysaccharide (green), respectively. Bar, 2 µm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3735193&req=5

fig4: METH alters the size of C. neoformans capsular polysaccharide fractions. Capsular polysaccharide obtained from untreated (A) and METH-treated (B) strain H99. The x axis represents size distribution by particle diameter; the y axis corresponds to the values of percentage intensity-weighted sizes obtained with the nonnegative least-squares (NNLS) algorithm. (C) METH promotes capsular polysaccharide release from cryptococcal cells. After coincubation with 25 µM METH, the cells were washed and incubated with Uvitex and MAb 18B7-FITC-conjugated goat anti-mouse IgG1 stain to label the cell wall (blue) and capsular polysaccharide (green), respectively. Bar, 2 µm.
Mentions: We analyzed the size distribution of polysaccharide from C. neoformans capsule molecules cultivated with or without METH (Fig. 4). The capsular polysaccharide molecules of METH-treated yeast cells exhibited, on average, a smaller diameter (941.0 ± 11.9 nm) (Fig. 4B) than those of untreated cells (1,203.8 ± 33.2 nm) (Fig. 4A). Treatment with METH yielded two homogeneous populations of reduced capsular polysaccharide. The size distribution range for each population was 181.1 to 273.9 and 1,590.5 to 2,405.8 nm, with the highest values at 222.7 and 1,956.1 nm, respectively (Fig. 4B). Similarly, two different populations with respect to polysaccharide size were present in untreated cells (Fig. 4A). The size range for each population was 2.03 to 288.1 and 1,405.9 to 3,786.7 nm, with the highest values at 193.8 and 2,089.7 nm, respectively. Using immunofluorescence, we demonstrated a significant reduction in capsule-specific monoclonal antibody (MAb) 18B7 binding to cryptococcal cells treated with METH relative to that of control yeast cells (Fig. 4C), suggesting that METH might be capable of altering capsular polysaccharide synthesis and/or structure, resulting in a different capsular surface with altered epitope density and/or accessibility. METH-induced alterations of the cryptococcal cell surface might have adverse implications on host-pathogen interactions and enhance pathogenesis.

Bottom Line: In addition to functioning as a central nervous system stimulant, METH has diverse effects on host immunity.Notably, C. neoformans modifies its capsular polysaccharide after METH exposure, highlighting the fungus's ability to adapt to environmental stimuli, a possible explanation for its pathogenesis.The findings may translate into new knowledge and development of therapeutic and public health strategies to deal with the devastating complications of METH abuse.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, Long Island University Post, Brookville, New York, USA.

ABSTRACT

Unlabelled: Methamphetamine (METH) is a major addictive drug of abuse in the United States and worldwide, and its use is linked to HIV acquisition. The encapsulated fungus Cryptococcus neoformans is the most common cause of fungal meningitis in patients with AIDS. In addition to functioning as a central nervous system stimulant, METH has diverse effects on host immunity. Using a systemic mouse model of infection and in vitro assays in order to critically assess the impact of METH on C. neoformans pathogenesis, we demonstrate that METH stimulates fungal adhesion, glucuronoxylomannan (GXM) release, and biofilm formation in the lungs. Interestingly, structural analysis of the capsular polysaccharide of METH-exposed cryptococci revealed that METH alters the carbohydrate composition of this virulence factor, an event of adaptation to external stimuli that can be advantageous to the fungus during pathogenesis. Additionally, we show that METH promotes C. neoformans dissemination from the respiratory tract into the brain parenchyma. Our findings provide novel evidence of the impact of METH abuse on host homeostasis and increased permissiveness to opportunistic microorganisms.

Importance: Methamphetamine (METH) is a major health threat to our society, as it adversely changes people's behavior, as well as increases the risk for the acquisition of diverse infectious diseases, particularly those that enter through the respiratory tract or skin. This report investigates the effects of METH use on pulmonary infection by the AIDS-related fungus Cryptococcus neoformans. This drug of abuse stimulates colonization and biofilm formation in the lungs, followed by dissemination of the fungus to the central nervous system. Notably, C. neoformans modifies its capsular polysaccharide after METH exposure, highlighting the fungus's ability to adapt to environmental stimuli, a possible explanation for its pathogenesis. The findings may translate into new knowledge and development of therapeutic and public health strategies to deal with the devastating complications of METH abuse.

Show MeSH
Related in: MedlinePlus