Methamphetamine Enhances Histoplasmosis by Immunosuppression of the Host

Abstract

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-1 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.

Agglutination ofHistoplasma capsulatumby IgG Monoclonal Antibodies against Hsp60 Impacts Macrophage Effector Functions

“…This is also consistent with the hypothesis that internalization of yeast by macrophage strictly via CR3 inhibits the respiratory burst (5,36,47). These findings are also supported by our recent observation that IgG2b levels were significantly increased in histoplasmosis in mice treated with methamphetamine, and these mice have accelerated disease and increased mortality (24). Hence, certain antibodies may be detrimental, especially compromising the capacity of macrophages to combat this intracellular invader.…”

The Complex Interaction Between Methamphetamine Abuse and HIV-1 Pathogenesis

“…METH’s ability to alkalize acidic organelles may inhibit antigen presentation, impairs phagocytosis, and likely compromises the immune response to pathogen inactivation [60–62]. For example, it has been showed that METH inhibits endosomal acidification in macrophages [60–62]. A neutral pH of endosomes has been shown to have beneficial effects for pathogens during infection of macrophages [63].…”

“…A neutral pH of endosomes has been shown to have beneficial effects for pathogens during infection of macrophages [63]. In addition, METH has also been reported to destabilize the capacity of infected macrophages to regulate their intracellular milieu [60–62]. In macrophages endosomal trafficking plays critical roles in HIV-1 replication [64].…”

IntracellularHaemophilus influenzaeinvades the brain

“…High TNF-α production in the blood directly alters the permeability of the BBB suggesting that this cytokine plays an important role in the induction of meningitis by inhibiting the expression of TJs. Although previous studies have shown that elevated TNF-α levels increase the BBB permeability [12][13][14] and the essential role of zyxin on bacterial dissemination, 15,16 this is the first study that shows that TNF-α reduces zyxin expression on the surface of brain endothelial cells exacerbating Hi CNS transmigration using the TH mechanism leading to increased mortality.…”