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Author Topic: Impact of Methamphetamine on Infection and Immunity  (Read 3401 times)

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Impact of Methamphetamine on Infection and Immunity
« on: October 20, 2018, 09:50:48 AM »
source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4290678/

So i have developed another non-IV Cellulitis infection, courtesy of ....



Impact of methamphetamine on infection and immunity

Abstract

Quote
The prevalence of methamphetamine (METH) use is estimated at ~35 million people worldwide, with over 10 million users in the United States.

METH use elicits a myriad of social consequences and the behavioral impact of the drug is well understood. However, new information has recently emerged detailing the devastating effects of METH on host immunity, increasing the acquisition of diverse pathogens and exacerbating the severity of disease.

These outcomes manifest as modifications in protective physical and chemical defenses, pro-inflammatory responses, and the induction of oxidative stress pathways.

Through these processes, significant neurotoxicities arise, and, as such, chronic abusers with these conditions are at a higher risk for heightened consequences. METH use also influences the adaptive immune response, permitting the unrestrained development of opportunistic diseases.

In this review, we discuss recent literature addressing the impact of METH on infection and immunity, and identify areas ripe for future investigation.

some excerpts for y'all (and me) !


METH and adaptive immunity

T-cells play critical roles in orchestrating immune responses (Anderton, 2006) because their activation and proliferation are characteristic of adaptive immune responses. The mechanisms underlying the interplay between cells of the adaptive immune system and METH are currently unclear. However, the data firmly establishes that METH adversely impacts adaptive responses that render the host more susceptible to progressive diseases, particularly HIV (In et al., 2005; Martinez et al., 2009).

Murine models show that METH modifies thymic and splenic cellularity and alters peripheral T lymphocyte populations (In et al., 2005). High dose METH intake induces apoptotic death in rat thymic and splenic lymphocytes and produces severe immunosuppression, which could contribute to the higher rate of infections observed in chronic METH users (Harms et al., 2012; Peerzada et al., 2013). For instance, rodent studies demonstrate that METH alters cytokine response in retroviral-infections (Yu et al., 2002; Liang et al., 2008), alters gene expression of immune cells (Mahajan et al., 2006), and disturbs thymic CD4+/CD8+ T-cell ratios (Yu et al., 2002; In et al., 2005).

METH reduces T cell infiltrates in the lungs, inhibiting T cell proliferation and reducing the capacity of these cells to maintain a protective immune response against respiratory pathogens (Martinez et al., 2009). Similarly, METH-exposed mice demonstrated elevated levels of early response IL-6 and IL-10 in tissue homogenates, which could indicate the development of a non-protective Th2 response against bacterial and fungal pathogens in the respiratory tract, even when Th1 cytokines are present (Peerzada et al., 2013).

An alternative mechanism for altered T-cell function is that METH modifies oxidative stress responses. As discussed earlier, the effects of oxidative stress on suppressed signal transduction, transcription factor activities, and diminished cytokine production in response to antigen stimulation in T cells has been documented in several model systems (Flora et al., 2003; Shah et al., 2012). The ability of reactive oxidative free radicals to impair T lymphocyte function has been documented in various human pathologic conditions, specifically AIDS, in which oxidative stress can hamper host control of retroviral replication (Potula et al., 2010).

Interestingly, a recent finding suggests that METH alters intracellular calcium mobilization in T cells, resulting in subsequent production of oxidative free radicals, a phenomenon associated with mitochondrial damage and weakened T cell function (Potula et al., 2010). Mitochondria serve as a source of both intracellular ROS and ATP production, a process regulated by the second messenger, calcium. METH exposure elevates levels of cytosolic calcium, however, and leads to the saturation of the electron transport chain, which contributes to the acute production of oxidative free radicals and ultimately results in oxidative alteration of proteins, loss of intracellular ATP levels in T cells and mitochondrial dysfunction (Potula et al., 2010). A compensatory down-regulation of mitochondrial proteins from chronic METH treatment can incite a long-term cellular redox imbalance, weakening T cells' ability to effectively respond to opportunistic pathogens (Potula et al., 2010; Chandramani Shivalingappa, 2012; Martins et al., 2013).


METH alterations of natural physical and chemical barriers

The skin acts as a primary physical barrier to prevent the entrance of pathogens, thereby serving as one of the innate immune response's first lines of defense (Proksch et al., 2008). Sweat glands in the skin release various bactericidal and regulatory peptides, restricting the development of pathogenic microbiota (Rieg et al., 2006). METH has been detected in sweat 2 h after ingestion, with traces remaining for periods of more than a week in cases wherein multiple doses were administered (Barnes et al., 2008). No previous studies exist, however, aiming to understand the effect of METH on microbiota and metabolites present in the skin (e.g., lactate, glycerol, pyruvate, ammonium cation, urea) (Kutyshenko et al., 2011). In this regard, the administration of drugs such as METH via injection is associated with the development of necrotizing fasciitis. Significantly, heavy daily users of METH frequently develop neurological manifestation of formication, a sensation akin to insects crawling on or under the skin. The result of formication is that users engage in constant skin “picking,” often causing the formation of ulcers that frequently scar. A marked lack of hygiene among users may also be correlated to higher rates of skin infections, abscess, and cellulitis (Rusyniak, 2013).


Conclusion and future perspectives

METH use has become increasingly prevalent in recent years, creating a severe public health epidemic and societal burden. The drug adversely changes user behavior, including putting METH users at high risk for the acquisition of diverse infectious diseases. Recent studies have identified a causal linkage between METH and immune dysfunction in mature mammals. METH immunosuppression may underlie the mechanism for the rapid development of AIDS in METH users, progressing from HIV to AIDS within only a few months (CDC, 2007). Investigators are just beginning to decipher the complex effects of METH in the context of HIV infection, but the limited nature of available information suggests that this drug dramatically impacts disease. Understanding the specific mechanisms of METH abuse and HIV will require large epidemiological studies as well as the utilization of relevant animal models that reproduce salient features of HIV infection in humans and are devoid of numerous confounding factors present in human studies.

Another important question yet to be answered is how METH disarms the adaptive immune system, further rendering the host more susceptible to opportunistic infections. We recently showed that the impairment of adaptive immunity by METH diminishes the ability of mammalian hosts to mount and maintain efficient immune responses to pathogens (Martinez et al., 2009). However, the mechanisms responsible for altered regulation of T- and B-cells in METH-exposed hosts require further study. Identification of these underlying mechanisms will highlight new therapeutic and prophylactic methods to improve immunity in the context of drug abuse. These goals are of considerable significance in the fields of immunity, host-pathogen interactions and drug abuse.

There is an urgent need for innovative METH treatment interventions to prevent the acquisition and transmission of infectious diseases. Through utilization of drug abuse treatment and community-based outreach programs, drug abusers can change their HIV risk behaviors (Garfein et al., 2010; Miller et al., 2010; Naar-King et al., 2010). Through targeted outreach and awareness programs, the prevalence of drug abuse and drug-related risk behaviors, such as needle-sharing and unsafe sexual practices, can be reduced significantly, thus decreasing the risk of disease acquisition. This is a challenge because due to recent reduction in healthcare funding usually compromises the viability of these preventive programs. Healthcare providers should be trained to recognize signs of METH addiction, and work openly and honestly with their patients to address the detrimental effects of METH addiction.

At this time, cognitive behavioral and contingency management interventions are the most effective treatments for METH addiction (Rawson et al., 2004; Roll et al., 2006). For example, the Matrix Model is a comprehensive behavioral treatment approach for the reduction of METH abuse that merges cognitive therapy, drug testing, family education, 12-Step support, individual counseling and reinforcement for nondrug-related activities (Rawson et al., 2004). Contingency management interventions also offer tangible incentives in exchange for participating in therapy and sustaining abstinence. (Roll et al., 2006) Currently, no specific medications exist that counteract the effects of METH or that prolong abstinence from the abuse of METH by an addict. However, novel anti-METH immunotherapies, primarily in the form of monoclonal antibodies and lipid-based vaccines, are in early clinical trial phases and act as pharmacokinetic antagonists, isolating METH and its metabolites from vulnerable areas in the brain and minimizing the toxic effects of the drug (Peterson et al., 2013; Rüedi-Bettschen et al., 2013; Collins et al., 2014; Hambuchen et al., 2014).

Finally, the research described to date is likely to be only the tip of the proverbial iceberg, such that numerous other diseases, especially infectious diseases, are likely to be significantly modified by METH. The propagation of this disease, along with many other viral and bacterial contagions, demonstrates the necessity for continued studies in this area of healthcare and substance abuse. Until the use of METH is strictly curtailed, the impact of METH on our society will continue to be severe.


Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

« Last Edit: October 20, 2018, 10:07:32 AM by Chip »
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