TLR3 in antiviral immunity: key player or bystander?

Toll-like receptor 3 (TLR3), which recognizes double-stranded (ds)RNA, was the first identified antiviral TLR and, because dsRNA is a universal viral molecular pattern, TLR3 has been assumed to have a central role in the host response to viruses. However, this role has recently been questioned by in vivo studies and the discovery of several other antiviral pattern-recognition receptors. In this review, the function of TLR3 in the context of these other receptors, namely TLR7, 8 and 9 and the newly identified dsRNA-receptor retinoic-acid inducible gene-I (RIG-I) is discussed. Also, recent research concerning the expression profile of TLR3, its evasion by viruses and a potential role in crosspriming is addressed, which reveals a clearer appreciation of the contribution of TLR3 to antiviral immunity.     

CMV in critically ill patients: pathogen or bystander?

Despite broad variability in study populations, methodologies for CMV detection, and analytic methods used, multiple studies have documented frequent CMV infection in non-immunocompromised adults with critical illness due to a variety of causes. Higher rates of CMV infection in studies of seropositive patients suggest that reactivation of latent infection rather than primary infection is the main mechanism in this setting. Risk factors for CMV reactivation (other than seropositivity) have not been clearly defined and there does not appear to be a consistent association with severity of illness. Furthermore, CMV reactivation in this setting has been associated with important adverse clinical outcomes, including increased duration of mechanical ventilation, longer length of stay and all-cause mortality. There are several biologically plausible mechanisms that could link CMV reactivation with adverse outcomes, including: direct lung injury (CMV pneumonia), amplification of inflammation systemically and within the lung, or predisposition to other nosocomial infections, but clinical data in the ICU setting are limited. Further observational studies are unlikely to significantly advance our understanding of the role of CMV in critically ill patients. Given the significant impact of critical illness, limited current therapeutic options, the availability of generally well-tolerated antiviral options for CMV, and the clinical data supporting a possible pathogenic role for CMV, there is a strong rationale for a randomised controlled trial of CMV prevention as a novel means of improving the outcomes of critically ill patients.     

Is uric acid itself a player or a bystander in the pathophysiology of chronic heart failure?

Uric acid (UA) is the end product of purine metabolism in humans. Hyperuricemia is often found in patients with chronic heart failure (CHF). The increase of serum UA level is inversely associated with disease severity, cardiac function and prognosis of CHF. Some researchers found that UA had detrimental impact on the cardiovascular system, including mediating immune response upon cell injury, increasing endotoxin-stimulated tumor necrosis factor-alpha production and hence proinflammatory immune activation, increasing blood pressure, and so on. Other researchers found that UA had important antioxidant properties by scavenging various reactive oxygen species. So far, there is no evidence suggest that UA has detrimental effect on the pathophysiology of CHF. Xanthine oxidase (XO) is an enzyme that produces uric acid during purine metabolism. XO activity is up-regulated in failing heart, and serum UA levels reflect the degree of XO activation in CHF. XO plays an important role in the pathophysiology process of CHF, including myocyte apoptosis, endothelial dysfunction and cardiac mechanoenergetic uncoupling. The therapeutic effect of long-term XO inhibition has been confirmed in animal models and partly in human bodies. We hypothesize that UA itself is not a player but a bystander associated with the activation of XO in the pathophysiology of CHF.     

Autoantibodies in atrial fibrillation: actor, biomaker or bystander?

Atrial fibrillation (AF) is one of the most common arrhythmias in patients with congestive heart failure, although the underlying mechanism has still to be determined. There is increasing evidence to suggest that autoimmunity may play an important role in the pathogenesis of AF. To date, at least three types of autoantibody have been found in AF: the anti-myosin heavy chain autoantibody, the anti-M2 muscarinic receptor autoantibody and the anti-heat shock protein autoantibody. The question is: are these autoantibodies actors, biomakers or merely bystanders? How much knowledge do we have?     

Homocysteine in cardiovascular disease: a culprit or an innocent bystander?

Whether hyperhomocysteinemia is a cardiovascular risk factor or is just an epiphenomenon is a subject of debate. More than 20 prospective and 30 retrospective studies on the topic have been published. Despite huge literature available, an unequivocal view has not been firmly established. Medical fraternity is still witnessing differing opinions regarding need to treat hyperhomocysteinemia. A medical practitioner needs to be well informed of developments and current opinion on this subject as it has a strong bearing on a major emerging public health problem of cardiovascular disease (CVD). This review presents the two views - for and against the acceptance of association between hyperhomocysteinemia and cardiovascular disease - and their basis. The two views are examined in the light of clinical, epidemiologic and genetic studies, reviews and meta-analyses available. Following conclusion was drawn from the exercise: The available evidence indicates that homocysteine is not an innocent bystander; it is an independent risk factor for CVD. The need for homocysteine-lowering therapy is however not yet unequivocally established. Physicians need to be vigilant of the updates on this much-debated topic thrusted on them time and again.     

Human bocavirus in stool: A true pathogen or an innocent bystander?

Human bocavirus (HBoV) is a parvovirus that was discovered only a decade ago and currently includes four genotypes. HBoV-1 is predominantly found in the respiratory tract, whereas HBoV-2, HBoV-3, and HBoV-4 are mainly detected in stool. HBoV-1 is known to be associated with respiratory tract infections. In stool, the prevalence of HBoV (1–4) is similar between patients with gastro-intestinal symptoms and healthy controls in most studies. Furthermore, often other viruses are concurrently present. Both findings suggest that HBoV in stool is an innocent bystander rather than a true pathogen. Nevertheless, several gaps in knowledge on the role of HBoV in stool remain to be addressed. All studies were performed in primarily immunocompetent patients. The role of HBoV in immunocompromised patients remains unknown.     

Role of T-type channels in vasomotor function: team player or chameleon?

Low-voltage-activated T-type calcium channels play an important role in regulating cellular excitability and are implicated in conditions, such as epilepsy and neuropathic pain. T-type channels, especially Cav3.1 and Cav3.2, are also expressed in the vasculature, although patch clamp studies of isolated vascular smooth muscle cells have in general failed to demonstrate these low-voltage-activated calcium currents. By contrast, the channels which are blocked by T-type channel antagonists are high-voltage activated but distinguishable from their L-type counterparts by their T-type biophysical properties and small negative shifts in activation and inactivation voltages. These changes in T-channel properties may result from vascular-specific expression of splice variants of Cav3 genes, particularly in exon 25/26 of the III–IV linker region. Recent physiological studies suggest that T-type channels make a small contribution to vascular tone at low intraluminal pressures, although the relevance of this contribution is unclear. By contrast, these channels play a larger role in vascular tone of small arterioles, which would be expected to function at lower intra-vascular pressures. Upregulation of T-type channel function following decrease in nitric oxide bioavailability and increase in oxidative stress, which occurs during cardiovascular disease, suggests that a more important role could be played by these channels in pathophysiological situations. The ability of T-type channels to be rapidly recruited to the plasma membrane, coupled with their subtype-specific localisation in signalling microdomains where they could modulate the function of calcium-dependent ion channels and pathways, provides a mechanism for rapid up- and downregulation of vasoconstriction. Future investigation into the molecules which govern these changes may illuminate novel targets for the treatment of conditions such as therapy-resistant hypertension and vasospasm.     

Crohn's disease and the mycobacterioses: a quarter century later. Causation or simple association?

It has been more than 25 years since Mycobacterium paratuberculosis was first proposed as an etiologic agent in Crohn's disease based on the isolation of this organism from several patients. Since that time, a great deal of information has been accumulated that clearly establishes an association between M. paratuberculosis and Crohn's disease. However, data are conflicting and difficult to interpret and the field has become divided into committed advocates and confirmed skeptics. This review is an attempt to provide a thorough and objective summary of current knowledge from both basic and clinical research from the views and interpretations of both the antagonists and proponents. The reader is left to draw his or her own conclusions related to the validity of the issues and claims made by the opposing views and data interpretations. Whether M. paratuberculosis is a causative agent in some cases or simply represents an incidental association remains a controversial topic, but current evidence suggests that the notion should not be so readily dismissed. Remaining questions that need to be addressed in defining the role of M. paratuberculosis in Crohn's disease and future implications are discussed.