TY - JOUR
T1 - Methamphetamine enhances histoplasmosis by immunosuppression of the host
AU - Martinez, Luis R.
AU - Mihu, Mircea Radu
AU - Gácser, Attila
AU - Santambrogio, Laura
AU - Nosanchuk, Joshua D.
N1 - Funding Information:
Received 9 September 2008; accepted 21 October 2008; electronically published 27 May 2009. Potential conflicts of interest: none reported. Financial support: Molecular pathogenesis training grant (to L.R.M.); National Institutes of Health (grant AI056070–01A2 to J.D.N.). Reprints or correspondence: Joshua D. Nosanchuk, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461 (nosanchu@aecom.yu.edu).
PY - 2009/7/1
Y1 - 2009/7/1
N2 - The effect of methamphetamine on the host response to an opportunistic pathogen has not been extensively described. Methamphetamine is a major public health and safety problem in the United States. Chronic methamphetamine abuse is associated with a 2-fold higher risk of human immunodeficiency virus infection and, possibly, additional infections. Histoplasma capsulatum is a dimorphic fungus that is endemic in the Midwest of the United States and that causes respiratory and systemic disease, particularly in individuals with impaired immunity. We showed that methamphetamine abrogates normal macrophage function, resulting in an inability to control histoplasmosis. Methamphetamine decreased phagocytosis and killing of yeast by primary macrophages by alkalization of the phagosome. Furthermore, mice that received methamphetamine prior to H. capsulatum infection were immunologically impaired, with increased fungal burden, increased pulmonary inflammation, and decreased survival. Immunosuppression by methamphetamine may be associated with deregulation of cytokines in the lungs of infected mice, aberrant processing of H. capsulatum within macrophages, and immobilization of MAC-I receptors on the surface of macrophages that are involved in phagocytosis. Additionally, methamphetamine inhibits T cell proliferation and alters antibody production, which are important components of adaptive immunity. With use of a murine model of histoplasmosis, this study establishes that methamphetamine may alter the immune system of the host and enhance fungal pathogenesis.
AB - The effect of methamphetamine on the host response to an opportunistic pathogen has not been extensively described. Methamphetamine is a major public health and safety problem in the United States. Chronic methamphetamine abuse is associated with a 2-fold higher risk of human immunodeficiency virus infection and, possibly, additional infections. Histoplasma capsulatum is a dimorphic fungus that is endemic in the Midwest of the United States and that causes respiratory and systemic disease, particularly in individuals with impaired immunity. We showed that methamphetamine abrogates normal macrophage function, resulting in an inability to control histoplasmosis. Methamphetamine decreased phagocytosis and killing of yeast by primary macrophages by alkalization of the phagosome. Furthermore, mice that received methamphetamine prior to H. capsulatum infection were immunologically impaired, with increased fungal burden, increased pulmonary inflammation, and decreased survival. Immunosuppression by methamphetamine may be associated with deregulation of cytokines in the lungs of infected mice, aberrant processing of H. capsulatum within macrophages, and immobilization of MAC-I receptors on the surface of macrophages that are involved in phagocytosis. Additionally, methamphetamine inhibits T cell proliferation and alters antibody production, which are important components of adaptive immunity. With use of a murine model of histoplasmosis, this study establishes that methamphetamine may alter the immune system of the host and enhance fungal pathogenesis.
UR - http://www.scopus.com/inward/record.url?scp=67650751411&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67650751411&partnerID=8YFLogxK
U2 - 10.1086/599328
DO - 10.1086/599328
M3 - Article
C2 - 19473099
AN - SCOPUS:67650751411
SN - 0022-1899
VL - 200
SP - 131
EP - 141
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
IS - 1
ER -