There is a large and productive tobacco research literature that focuses on epidemiology, behavior, addiction and quitting. However, despite the wealth of epidemiological evidence of the profound ill-effects of smoking on human health, studies that set out to understand the mechanisms of how
cigarette smoke induces disease are limited, as we have recently commented [89
]. It is not the intent of this review to provide comprehensive data on why tobacco use leads to increased rates of infectious disease in smokers. Rather, we will introduce some of the key potential mechanisms underlying this increased susceptibility and provide the reader with links to more exhaustive literature reviews.
Cigarette smoking can, theoretically, increase the risk of infection by pathogenic or opportunistic bacteria by three general mechanisms:
• Tobacco-induced physiological and structural changes in humans.
• Tobacco-induced increase in bacterial virulence.
• Tobacco-induced dysregulation of immune function.
Such mechanisms are not mutually exclusive and all three may occur simultaneously. For example, tobacco smoke exposure may play a direct role in bacterial colonization of the respiratory tract by hindering mucociliary clearance of bacteria [19
]; while inducing bacterial components that aid in the binding of microbes to respiratory epithelial cells ([7
] and our own, unpublished data); and concurrently decreasing the ability of respiratory phagocytic cells to detect and destroy pathogenic microbes [91
]. Tobacco-induced physiological and structural changes in humans have focused primarily on the vasculature and respiratory tract. The vasoactive effects of cigarette smoke and nicotine appear to vary in different vascular beds. For example, smoking induces vasoconstriction in peripheral arteries [92
] but vasodilation in cerebral blood vessels [93
]. In periodontal tissues smoking does not seem to exert an acute vasoactive (constriction or dilation) influence on the microvasculature [94
]. Rather, smoking results in a suppression of periodontal angiogenesis [95
] in a manner that is rapidly reversible on smoking cessation [96
]. Thus, the negative influence of smoking on mucociliary function most likely contributes to increased risk of bacterial infection by reducing the ability of the respiratory tract to clear pathogens, while the vasoconstrictive or anti-angiogenic influence of tobacco may contribute to increased susceptibility to bacterial infection by decreasing the effectiveness of inflammatory responses to pathogenic bacteria.
Several research groups have examined the interactions between infectious agents and cigarette smoke components. For example, Sayers et al. have demonstrated the potentiating influence of low levels of nicotine on staphylococcal and enterobacter toxins in studies addressing why passive exposure to cigarette smoke is a risk factor in sudden infant death syndrome [86
]. The same group has also shown that both nicotine and cotinine exhibit lethal synergy with toxins produced by several periodontal pathogens (Prevotella
species) in the chick embryo toxicity model. Wiedeman et al. have suggested that tobacco smoke exposure may represent a risk for establishment of a chronic reservoir of C. pneumoniae
infection within respiratory epithelium [97
]. Other groups have shown that exposure to cigarette smoke affects the growth of bacteria which may facilitate populational shifts in the microbial communities that colonize some human tissues. Zonuz et al reported that the growth of Streptococcus mutans
and S. sanguis
, two common oral bacteria, was stimulated by cigarette smoke [99
]. In contrast, Ertel et al. showed that cigarette smoke inhibited the growth of Gram positive organisms, e.g., S. pneumoniae
and S. aureus
, but had little effect on Gram negative enteric bacteria such as Klebsiella, Enterobacter
]. Consistent with this observation, they report that smokers have a propensity to develop heavy Gram negative colonization of the oral cavity relative to non-smokers. Interestingly, women who smoke are at higher risk of contracting bacterial vaginosis, as discussed above. Pavlova and Tao showed that the trace amounts of benzo [a]pyrene diol epoxide that are present in the vaginal secretions of women who smoke promotes the induction of bacteriophages in resident lactobacilli [101
]. This may lead to a reduction in lactobacilli populations and facilitate overgrowth of anaerobes that are associated with vaginosis. In general, however, mechanistic studies to examine the direct influence of tobacco smoke on bacterial physiology and their pathogenic potential are lacking in the literature.
Dysregulation of innate immune function
Several innate cell receptor-tobacco agonist couples have been identified, suggesting that tobacco smoke is capable of effecting neutrophil and monocyte function both directly and indirectly [54
]. Indeed, multiple effector functions of professional phagocytic and antigen presenting innate cells (neutrophils, monocytes, macrophages and dendritic cells) are compromised by tobacco smoke. For example, in neutrophils, tobacco smoke and/or nicotine have been shown to reduce key anti-microbial activities including phagocytosis (the engulfment and uptake of bacteria) [54
]; the generation of a respiratory burst (the combined oxygen-dependent processes by which neutrophils kill phagocytosed bacterial cells) [102
]; and, ultimately, the ability to kill specific bacterial species [102
]. Compared to unexposed monocytic cells, tobacco-exposure suppresses general responsiveness to bacteria and lipopolysaccharide (LPS) [108
], reflected in a down-regulation of surface pathogen recognition receptors (TLR-2 and MARCO) [109
]; with reduced phagocytic, reactive-oxygen species generating, and bacterial killing capacities also reported [105
]. Dendritic cells, whose primary function is to process antigen and present them to adaptive immune cells thus bridging innate and adapative immune responses, are also negatively influenced by tobacco smoke and smoke constituents. For example, nicotine exposure suppresses the maturation dendritic cells that, subsequently, exhibit a reduced expression of antigen presenting and costimulatory molecules (MHC Class II, CD80 and CD86), reduced capacity for antigen uptake and reduced production of T cell stimulating cytokines in response to the archetypal Gram-negative pro-inflammatory stimulus, LPS [112
Dysregulation of adaptive immune function
The potential effects of smoking on lymphocyte function are not well understood. However, while IgE levels are increased in smokers compared to non-smokers, concentrations of anti-bacterial IgG levels are reduced [114
]. This may represent a key underlying mechanism of increased susceptibility to bacterial infection in smokers. Furthermore, in order to mount a successful humoral immune response, B cells require T helper cell-derived cytokines to proliferate and differentiate into plasma cells and to promote immunoglobulin class switching. However, it has been shown by several groups that tobacco smoke reduces T cell proliferative responses to mitogen/antigen [119
], with similar tobacco-induced reductions in B cell proliferative responses also reported [122
]. For further details of the influence of tobacco smoke on the immune system, we point the reader to several extensive reviews [54