- freely available
Pharmaceuticals 2010, 3(6), 1873-1886; doi:10.3390/ph3061873
Published: 9 June 2010
Abstract: Exogenous cannabinoids or receptor antagonists may influence many cellular and systemic host responses. The anti-inflammatory activity of cannabinoids may compromise host inflammatory responses to acute viral infections, but may be beneficial in persistent infections. In neurons, where innate antiviral/pro-resolution responses include the activation of NOS-1, inhibition of Ca2+ activity by cannabinoids, increased viral replication and disease. This review examines the effect(s) of cannabinoids and their antagonists in viral infections.
Both endogenous and exogenous cannabinoids can influence the course of infections in vitro and in vivo. This review will focus on viral infections of mammals, but will also describe what is known about other infections. Readers are directed to the excellent accompanying reviews in this issue which expertly discuss the clinical trials, cell biology, mechanisms of action, impact on inflammation, clinical applications, and so forth.
Cannabinoids may act either through the CB1 or the CB2 receptor, which are found on distinct cell types. The CB1 receptor is found on neurons as well as some astrocytes and skeletal muscle cells; neurons are frequently the target of viral infection. Engagement of the CB1 receptor by its endogenous or exogenous agonists may inhibit the release of Ca2+ from intracellular or extracellular stores. Since many important intracellular proteins are Ca2+-dependent for activation, signal transduction through the CB1 receptor may impair these secondary pathways and have a profound influence on the ability of viruses to replicate in neurons.
In contrast, the response of cells expressing the CB2 receptor may influence not only the responses in that cell, but may alter the course of the host innate and adaptive immune response to the pathogen, suppressing inflammation and the development of virus-specific cellular and humoral responses. The outcome on the viral infection will depend on whether inflammation is beneficial or pathogenic in the specific case.
When a host is infected with a virus, there is a dynamic competition between the ability of the host to first marshal innate (hours to days) and then adaptive immunity (>7 days post infection) vs. the replication and spread of the virus first within the host and then to additional susceptible individuals. When a virus is able to out-pace the containment efforts, the host may succumb. Pathology may result from damage to tissues by viral-induced cellular apoptosis or necrosis, or alternatively, host immune responses may result in immunopathology or the perceived symptoms of the infection. If, however, innate and adaptive immunity successfully suppress viral replication, specific life-long immunity may result.
In order to understand the influences on the host response which may be the result of cannabinoids, it is important to examine some of the cellular pathways which are dependent on Ca2+-dependent enzymes. Table 1 indicates some of the well characterized pathways involved and their potential impact on viral infections.
The common recurring impact of Ca2+-dependent enzymes is a role in inflammation. This ranges from regulation of many signal transduction pathways, production of pro-inflammatory and pro-resolving lipid mediators downstream of arachidonic acid, to activation of Nitric Oxide Synthase and the production of reactive nitrogen intermediates, to proteolytic enzymes which remodel the cytoskeleton or extracellular matrix, and apoptosis.
Inflammation is essential for recruitment of both innate and adaptive immune cells to the site of infection to control virus production and limit spread, and then to promote recovery. Inflammation is comprised not only of non-specific cells (sequentially these are polymorphonuclear leukocytes, natural killer cells, macrophages) and then pathogen-specific T lymphocytes recruited from circulation, and activation of antibody-secreting B lymphocytes, but also induction of production and secretion of cytokines, chemokines, interferons, complement components, acute phase reactants, reactive oxygen and nitrogen intermediates, and other mediators [24,25,26]. Readers are referred to the accompanying review by Bani, Mannaioni, Passani, and Masini . Thus, many of these critical pathways may be impaired or compromised when endogenous or exogenous cannabinoids are present during an infection .
Cannabinoids have been used both recreationally by groups of people who have viral infections, and experimentally by scientists investigating their impact in vitro or in animal models. Table 2 presents what has been published about these populations in peer reviewed journals. In most of the infections studied (Table 2), it is apparent that cannabinoid treatment, whether in vitro or in vivo, had profound impact on the virus-host (cell) interactions. For HSV-2, HIV-1, KSHV, influenza and VSV viral replication, or surrogate measures of infection, were found to be substantially increased upon cannabinoid treatment [30,34,39,50,52,63]. In HIV-1 infection, syncytia formation was enhanced, and monocytes were stickier on endothelial cells [57,58]. In one study, KHSV was more likely to exit latency and enter lytic infection when transformed cells were treated with THC , however, another study found the opposite result in several herpesvirus infections .
|Table 1. Some Ca2+-dependent enzymes which may be inhibited by Cannabinoids and speculated role in host responses relevant for viral infections.|
|Enzyme primary/secondary||Pathways||Ref.||Role(s) in viral infection-host responses|
|cPhospholipase A2||Arachidonic acid metabolites (prostaglandins, leukotrienes, lipoxins, resolvins) and inflammation||[1,2]||Inflammation and its resolution|
- Receptor-mediated tyrosine kinase
|Production of Inositol 1,4,5-triphosphate from phosophotidylinositol||||Signal transduction|
|Phospholipase D1||Exocytosis in neuroendocrine cells||||Neurotransmission|
|Calcineurin||Activation of NFAT—gene expression||[5,6]||Signal transduction|
- Nitric oxide synthase-1
- Nitric oxide synthase-3
|Conversion of argenine to NO in neurons and endothelial cells; production of ONOO-, -SNO, -R-NO2|
Inhibition of viral infection
|[7,8,9,10,11,12]||Anti-viral; NO2-decoration of viral proteins; capillary dilation; inflammation|
|Ca2+-Calmodulin dependent protein kinases
- CaMKK activation of AMPK
|Wnt-2-dependent dendrite growth & cardiomyogenesis
Energy, epithelial cell polarity
T cell activation
|[13,14,15,16,17]||Adaptive immune responses; inflammation|
|Calpains [Ca2+-dependent proteases]||Neutral proteases [many tissues]
Cell membrane fusion, synaptic remodeling, activating PKC, remodeling cytoskeleton, transcription factors
|[18,19,20]||Cytoskeletal plasticity, cell migration, inflammation|
|Matrix metalloproteinases||Extracellular matrix remodeling, inflammation||||Inflammation|
|Calpastatin||Cell fusion in fertilization||||Formation of heterokaryons /giant cells|
|Transglutaminases||Cross-linking/deamination of proteins –wound healing, tissue repair, apoptosis, cell cycle control, inflammation and fibrosis||||Inflammation, fibrosis, cell cycle and programmed cell death|
|Table 2. Cannabinoids and Viral Infections.|
|Viral pathogen||In vivo In vitro||Agonist / Antagonist||Titer change||Pathogenesis||Inflammation Immunoregu-lation||Comments||Ref.|
|In vivo||Δ9-THC||decreased resistance to LD50||systemic infection|||
|HSV-2||In vivo||Δ9-THC||increased shedding||increased severity of lesions & mortality||delayed onset of DTH response||vaginal model B6C3H F1 mouse|||
|HSV-2||In vivo||Δ9-THC||decreased Type I IFN response||i.v. infection|||
|HSV-2||In vivo||Δ9-THC||decreased resistance to infection; increased severity of lesions||vaginal guinea pig model|||
|HSV-1,-2||In vitro||Δ9-THC||failed to replicate||antiviral effect in human & monkey cells|||
|HSV-2||In vitro||Δ9-THC||100-fold increase in released virus||Vero cells, increased CPE|||
|HSV-2||both||Δ9-THC||decreased T cell proliferation||B6C3H F1 mice immunized then T cells cultured|||
|HSV||In vitro||Δ9-THC||decreased infectivity in TC||virus incubated with THC|||
|HSV-1||both||Δ9-THC||decreased CD8 CTL activity||C3H mice immunized, L929 targets|||
|EBV, KSHV, HVS, HSV-1, MHV-68||In vivo||Δ9-THC||Immediate early ORF promoter activity inhibited||reactivation from latency inhibited||latently infected B cells in tissue culture|||
|KSHV||In vivo||Δ9-THC||increased viral load||increased efficiency of infection, activation of lytic switch||increased transformation of endothelial cells||primary human dermal microvascular cells|||
|Cowpox||In vivo||Marijuana cigarettes||generalized infection||weak Ab production, no neutralizing Abs||Case report|||
|TMEV||In vitro||Anandamide||decreased release of NO2- and TNF-α||NO is antiviral for TMEV||[41,42]|
|TMEV||In vitro||Anandamide||increased IL-6 production||astrocyte culture B6 and SJL mice|||
|TMEV||In vivo||WIN-55,212||ameliorates progression of autoimmune disease TMEV-IDD||decreased DTH, decreased IL-1, IL-6, IFN-γ , TNF-α,||TMEV-IDD a mouse model of MS|||
|TMEV||In vivo||OMDM1, OMDM2||ameliorated motor symptoms||decreased MHC II, inhibited NOS-2, reduced proinflammatory cytokines||TMEV-IDD proposed MS therapy with cannabinoids|||
|TMEV||In vitro||JWH-133 SR144558||role of CB2 receptors in anti-inflammatory actions||reduced IL-12p40, reduced ERK1/2 signaling|||
|TMEV||In vitro||WIN-55,212||CB2-dependent COX-2 induction increased vs. TMEV-alone||role of PI3 kinase pathway in CB2 but MAPK for TMEV signaling||proposed role on blood-flow and immune activity|||
|TMEV||In vivo||Palmitoyl-ethanol-amine||reduction in motor disability in TMEV-IDD||anti-inflammatory effect||TMEV-IDD|||
|TMEV||both||WIN-55,212||inhibited ICAM & VCAM on endothelium; role for PPAR-γ receptors in mechanism||reduced inflammation||TMEV-IDD|||
|Influenza||In vivo||Δ9-THC||HA mRNA increased||inflammation, metaplasia of mucous cell||decreased CD4, CD8, and macrophage recruitment|||
|Influenza||In vivo||Δ9-THC||HA mRNA decreased in CB1/CB2KO mice||THC-mediated airway pathology +/- CB1/CB2||KO mice had increased CD4 and IFN-γ recruitment||CB1/CB2 KO mice|||
|VSV||In vitro||WIN-55,212||increased viral titers||CB1-dependent; decreased NOS-1 activity||antagonized IFN-γ-mediated antiviral pathway||suggested disease progression likely in neurons/viral encephalitis|||
|BDV||In vivo||WIN-55,212||protected BrdU-positive neural progenitor cells in striatum||suppressed microglial activation||suggested treatment of encephalitis with microglial inflammation and neuro-degeneration|||
|HCV||In vivo||Marijuana cigarettes||progression of liver fibrosis||epidemiological study|||
|HCV||In vivo||Oral cannabinoids||improved weight||no viral markers or immune markers studied||7 week clinical trial for anorexia and nausea|||
|HCV||In vivo||Marijuana cigarettes||progression of liver fibrosis; increased disease severity||clinical pathological survey of 204 HCV patients|||
|HIV-1||In vitro||Δ9-THC, CP-55,940, WIN-55,212||increased syn-cytia formation MT-2 cells (CB1 & CB2+)||speculate cannabinoids enhance HIV-1 infection|||
|HIV-1||In vitro||anandamide||increased adherence for monocytes||uncoupled NO release, inhibited NO||human saphenous vein or internal thoracic artery; speculate higher titers in vivo|||
|HIV-1 Tat||In vitro||WIN-55,212||reduced tat-induced cytotoxicity||inhibited NOS-2 activity||C6 rat glioma cell line|||
|HIV-1||In vivo||Marijuana cigarettes||increased appetite||insufficient numbers of individuals||3 week trial|||
|HIV-1||In vivo||Marijuana cigarettes||mRNA unchanged||CD4+ and CD8+ cells unchanged||3 week trial, placebo-controlled|||
|HIV-1||WIN-55,212||inhibited expression||CD4 and microglial cultures|||
|HIV-1||In vivo||THC||increased viral replica-tion 50-fold||decreased CD4 IFN-γ-producing cells, increased co-receptor expression||scid-Hu mouse model|||
|HIV-1 Gp120||In vitro||2-AG, CP55940||inhibited Ca+2-flux-induced substance P, decreased permeability||model of BBB, co-culture of Human brain microvascular endothelial cells and astrocytes|||
|HIV-1||In vivo||WIN-55,212||dose-related hypothermia in mouse pre-optic anterior hypothalamus infusion||WIN-55,212 is antagonist for SDF-1a/ CXCL12/ CXCR4 [HIV-1 coReceptor] pathway||mouse model for HIV-thermoreg-ulation by direct injection of WIN-55,212 to brain POAH center|||
|HIV-1 Tat||In vitro||CP55940, Δ9-THC||CB2-dependent inhibition of U937 migration to Tat||possible anti-inflammatory mechanism||U937 cells in culture|||
Legend: BDV, Borna disease virus; EBV, Epstein-Barr virus; HCV, Hepatitis C virus; HIV, Human immunodeficiency virus; HSV, Herpes simplex virus; HVS, Herpes virus samirii; KO, knock-out mice; KSHV, Kaposi's sarcoma herpes virus; L. monocytogenes, Listeria monocytogenes; MHV-68, Murine herpes virus-68; TMEV, Theiler's murine encephalomyelitis virus; VSV, Vesicular stomatitis virus.
Disease was more severe in HSV-2-infected guinea pigs which were treated with THC [29,30,32]. In HCV infections, clinical studies have shown a profound co-morbidity of recreational cannabinoid use, for disease progression [54,56]. One case report of Cowpox infection, a very rare human pathogen, indicated that recreational use of cannabinoids was associated with generalized infection and very poor immune responses to the virus .
In contrast, in those infections where host inflammatory responses are often associated with pathology, and not with clearance and recovery, cannabinoid treatment of hosts was beneficial. These included one mouse model of multiple sclerosis, the Theiler's murine encephalomyelocarditis virus (TMEV)-induced demyelinating disease (IDD), where progression towards the paralysis and disability were ameliorated [44,45,48] and in Borna disease virus (BDV) where neural progenitors were protected from proinflammatory cytokine-mediated damage  infections. TMEV-IDD is characterized by microglial activation in the spinal cord of mice and a T cell-mediated autoimmune demyelinating disease, triggered by the viral infection [42,67,68,69]. Persistent BDV infection of the central nervous system is associated with immunopathology associate with inflammation and production of pro-inflammatory cytokines, induction of NOS-2 in microglia, and breakdown of the blood-brain barrier [70,71,72,73]. In both BVD and TMEV-IDD, the targets for the anti-inflammatory effects of the cannabinoid treatment are lymphocytes and mononuclear cells.
Two excellent reviews of the impact of cannabinoids on bacterial, yeast, and protozoan infections were published in the same issue of Journal of Neuroimmunology [26,74]. These infections included Treponema pallidum (Syphilis), Legonella pneumophila (Legionnaires' disease), Staphylococci aureus and S. albus, Listeria monocytogenes, Candida albicans (Thrush), and Naegleria fowleri. Both reviews concluded that THC significantly reduced host resistance to infection of experimental animals, and speculated that similar host compromise would be found in man. In the more than 12 years since those reviews were published, additional findings have extended the serious consequences of cannabinoids on host responses to pathogens and opportunistic infections. Marijuana use is a risk factor for Mycobacterium tuberculosis (TB) infections [75,76,77]; this author speculates the suppression of host innate immune responses by THC contributes to the increased severity of TB in users. Similarly, more serious exacerbations central nervous system infection by Acanthamoeba among HIV-infected patients has been attributed to marijuana consumption , possibly by inhibiting macrophage chemotaxis . However, the antiinflammatory effects of cannabinoids have been found to be beneficial in attenuating fever induced by bacterial endotoxin [65,80], inhibiting cytokine responses to Corynebacterium parvum endotoxin . These drugs may also offer therapeutic efficacy in meningitis caused by Streptococcus pneumoniae  and in irritable bowel syndrome [83,84].
Cannabinoids may relieve pain and may induce hyperphagia, which could be beneficial in cancer [85,86]. However, these physiological characteristics are not relevant to most viral, bacterial fungal or parasitic infections, where the regulation of inflammation is central to controlling pathogen replication and immunopathology. However, the same anti-inflammatory properties of cannabinoids just described are detrimental to the host in handling the other infections. In most cases, a rapid and robust inflammatory response, associated with production of proinflammatory cytokines and effect T lymphocytes capable of eliminating infected cells is essential to recovery and survival.
Cannabinoids are profoundly anti-inflammatory and impair many Ca2+-dependent enzyme systems which are central to inflammatory and cell-autonomous antiviral responses. When viral-induced host responses lead to immunopathology, as is seen in a rodent model of multiple sclerosis, TMEV-IDD, or in a persistent infection of the central nervous system caused by a non-lytic virus, BDV, cannabinoid treatment was beneficial.
In all other virus infections, both in vitro and in vivo, cannabinoid treatment led to disease progression, increased pathology, and sometimes to host death. Therefore, in many clinical settings, including latent infections caused by HIV-1 or HSV-1, and persistent infection of the liver caused by HCV, cannabinoids lead to worsened disease outcome.
The generous support of the U.S. National Institutes of Health, both grants DC039746 and NS039746, enabled my lab to perform these studies, and to summarize the work of many other labs. Two former students, Ramon Antonio Herrera and Joseph H. Oved, contributed published  and unpublished data, provided stimulating discussions and critically read this manuscript.
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