Current Molecular Medicine - Volume 9, Issue 2, 2009

Central Nervous System (CNS) tuberculosis is a serious, often fatal form of tuberculosis, predominantly affecting young children. HIV co-infection and drug resistant strains of Mycobacterium tuberculosis are making the diagnosis and treatment of CNS tuberculosis more complicated. Current concepts about the pathogenesis of CNS tuberculosis are based on necropsy studies done in 1933, which suggest that tuberculous meningitis develops subsequent to the rupture into the cerebrospinal fluid of tuberculomas that form around M. tuberculosis deposited in the brain parenchyma and meninges during the initial hematogenous dissemination. Foreign antigens including pathogens deposited in the brain parenchyma are not detected efficiently by the immune system in the CNS. These experimental data may explain the clinical observation of delayed “paradoxical” enlargement or development of intracranial tuberculomas, observed several weeks to months in patients receiving anti-tuberculous therapy. Since severe sequelae are observed even when CNS tuberculosis is treated effectively, it is important to develop preventive strategies for this disease. Recent data utilizing animal models suggests that, in addition to host factors, M. tuberculosis genes and their encoded proteins may contribute specifically to bacterial invasion and survival in the CNS. Understanding how these microbial factors affect CNS disease would be essential to developing such preventive strategies.

Staphylococcus aureus can cause a wide variety of infections, ranging from minor skin infections to post-operative wound infections. Its adaptive power to antibiotics has resulted in the emergence of methicillinresistant S. aureus (MRSA) in the beginning of the 1960s. Resistance to methicillin and all other ß-lactam antibiotics is caused by the mecA gene, which is situated on a mobile genomic island, the Staphylococcal Cassette Chromosome mec (SCCmec). Seven main SCCmec types, I to VII, have been distinguished. The most important methods used to study the molecular epidemiology of MRSA are pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), spa typing and SCCmec typing. These methods have been used to investigate the evolution of the MRSA clones that have emerged since the 1960s, and to study their worldwide dissemination. Early MRSA clones were hospital-associated (HA-MRSA). However, from the late 1990s, community-associated MRSA (CA-MRSA) has emerged. CA-MRSA harbors SCCmec type IV, V or VII, has a genetic background that is often distinct from HA-MRSA, and is often associated with the toxin Panton- Valentine leukocidin (PVL). However, the distinction between HA-MRSA and CA-MRSA is beginning to blur, and CA-MRSA is endemic in many US hospitals nowadays. This review describes the latest developments concerning the structure of SCCmec, the methods used to investigate the molecular epidemiology of MRSA, the molecular evolution of MRSA as well as the major challenges that are awaiting researchers in the near future.

Malaria is one of today's most serious diseases with an enormous socioeconomic impact. While anti- malarial drugs have existed for some time and vaccines development may be underway, the most successful malaria eradication programs have thus far relied on attacking the mosquito vector that spreads the disease causing agent Plasmodium. Here we will review past, current and future perspectives of malaria vector control strategies and how these approaches have taken a promising turn thanks recent advances in functional genomics and molecular biology.

Highly pathogenic H5N1 avian influenza virus can infect humans and is currently the most deadly influenza virus that has crossed the species barrier. As of December 2007, the spread of H5N1 virus from human to human has been rare. Nobody can predict if H5N1 may cause a pandemic. However, the number of human cases is continuously increasing and changes in virulence and epidemiology have been detected. There are specific pathogenic features of H5N1 infection. In contrast to human-adapted influenza A strains, H5N1 preferentially infects cells of the lower respiratory tract and may spread to tissues outside the respiratory tract in humans. Moreover, H5N1 replication is prolonged in target organs and results in higher viral loads and increased tissue damage. These features will have to be considered for therapeutic protocols for H5N1 infection in humans. Rapid genetic and antigenic changes observed in H5N1 virus isolates represent a challenge for the development of vaccines. In the present review, current knowledge about epidemiology, virulence factors and pathology of H5N1 infections in humans are summarised and discussed. Moreover, the possible roles of antiinfluenza drugs in the pandemic situation as well as the development of effective vaccines are subject of this overview.

Dengue is a very rapidly growing public health problem being currently faced by ∼40% of the global population living in more than a hundred tropical and sub-tropical countries. It is a viral disease, caused by four types of dengue viruses, transmitted by mosquitoes, to an estimated 50 million people each year. Vector control methods to contain transmission have not been successful and there is currently no useful diagnostic test, drug or vaccine to combat dengue disease. However, as a result of the heightened awareness of its magnitude and its potential to spread beyond the tropical world, dengue has begun to emerge out of the list of neglected diseases in recent years. New interest in this disease has drawn scientists from multiple disciplines into the dengue arena. This has resulted in novel insights into several aspects of dengue virus biology and identified potential drug targets. Several tetravalent vaccines are being developed. Newer animal models that mirror some of the salient features of dengue disease are becoming available to investigate the mechanism of pathogenesis and to aid in drug and vaccine discovery efforts. The realization that therapeutic and prophylactic intervention can be cost-effective has resulted in vigorous industry-driven translational initiatives to develop drugs and vaccines. Dengue research is at a critical juncture and the implementation of existing knowledge supplemented by a better understanding of pathogenesis promises to make a tangible impact in the combat against dengue in the coming years.

The filoviruses, Ebola (EBOV) and Marburg (MARV), are among the deadliest of human pathogens, causing acute diseases typified by rapidly fatal hemorrhagic fevers. Upon filoviral infection, innate immune cells become paralyzed and lose the capacity to properly co-stimulate and activate filovirus-specific, T-cell responses. Deleterious inflammation and upregulation of co-inhibitory molecules expressed by monocytic lineage cells (e.g., dendritic cells) and their co-inhibitory receptors on T- and B-cells may lead to incomplete humoral and T-cell immunity, anergy, exhaustion, apoptosis, and subsequent immune subversion. Hence, the dysregulation of inflammatory and co-inhibitory molecules may be exploited by filoviruses to further deteriorate host immune responses, ultimately leading to fulminant infections in susceptible species. Thus, in light of accumulating scientific observations, the challenge is now to characterize the molecular mechanisms that may result in rational strategies leading to new therapeutics and vaccines.

Hemichannels are transmembrane channels that represent the functional subunits of gap junctions. Each hemichannel is composed of a connexin or pannexin hexamer and, after being transported to the membrane, remains unpaired until it is incorporated in a gap junction. Several studies have already provided evidence that gap junction-mediated intercellular diffusion of ions and small molecules during ischemia represents an important mechanism through which necrotic, apoptotic, or even protective signals are transported between cells. Although initially hemichannels were supposed to be functional only in gap junctions, recent findings indicate that unpaired hemichannels also display a large array of activities that can be modulated under several pathophysiological conditions, including ischemia. Open hemichannels in ischemia dramatically alter the permeability properties of membranes and lead to cell death through ionic dysregulation, loss of metabolites, and changes in intracellular ATP. This review focuses on the properties and possible functions of unpaired connexin and pannexin hemichannels and the implications this has for a variety of events, such as cell death, glutamate release, oxidative stress, cortical spreading depression, that occur during an ischemic insult and may affect its outcome.

The interaction between the brain and immune system has been intensely studied in patients with several central nervous system (CNS) disorders including brain trauma and brain tumours. Pioneering studies described cellular immune changes after human stroke more than three decades ago but the potential existence of a CNS- mediated immunodepression syndrome has obtained renewed attention only recently. The CNS and the immune system are extensively interconnected through neural pathways, hormonal cascades and cell-to-cell interactions orchestrated primarily by cytokines. Indeed, the balance between pro- and anti-inflammatory cytokines determines the prowess of the immunological response but could also influence the fate of the injured brain tissue and the threshold to develop complications including systemic infection. Prominent changes in primary and secondary lymphoid organs and increased susceptibility to infections and pneumonia have been described in a mouse model of transient focal cerebral ischemia in support of the existence of a stroke induced immunodepression syndrome. Yet, the intrinsic characteristics of secondary lymphoid organs located in areas that receive direct signals from the CNS could mediate anti-inflammatory responses after stroke. In human stroke, the balance between pro-inflammatory and anti-inflammatory cytokines is an important prognostic clinical factor. Recent data also suggest that the appearance infections early after stroke could be the manifestation of a stroke-induced immunodepression syndrome, characterized by strong adrenergic activity and excessive anti-inflammatory drive. Overall, current research suggests that a better understanding of the reciprocal effects between the CNS and the immune system could pave the way to more effective therapies for this devastating condition.

Obstructive Sleep Apnea (OSA) is a prevalent disease that has emerged as a new cerebrovascular disease (CVD) risk factor, which is independent of its association to hypertension, age and other known conditions that increase CVD. The mechanisms involved in this relation are most likely induced by the periodic hypoxia/ reoxygenation that characteristically occurs in OSA, which results in oxidative stress, endothelial dysfunction and activation of the inflammatory cascade, all of which favor atherogenesis. Numerous markers of these changes have been reported in OSA patients, including increased circulating free radicals, increased lipid peroxidation, decreased antioxidant capacity, elevation of tumor necrosis factor and interleukines, increased levels of proinflammatory nuclear transcription factor kappa B, decreased circulating nitric oxide, elevation of vascular adhesion molecules and vascular endothelial growth factor. In addition, several authors have described that Continuous Positive Airway Pressure, the standard OSA therapy, reverts these abnormalities. Further research is needed in order to better clarify the complex mechanisms that underlie the relation between OSA, atherogenesis and CVD which most likely will have significant clinical impact.

A predisposing weakness of the vessel wall has been assumed in patients with spontaneous cervical artery dissections (sCAD). Skin biopsies from many patients with sCAD show mild connective tissue alterations. However, their assessment depends on an invasive and highly specialized technique. Clinical signs of connective tissue disease are absent in the majority of CAD patients. In this review we document that only very few CAD patients are affected by known inherited connective tissue disorders like Ehlers-Danlos syndrome, Marfan syndrome or Osteogenesis Imperfecta. In a second part of this review we discuss the possible role of unrecognized or unknown forms of connective tissue disorders in the etiology of CAD.

Strong epidemiological evidence indicates that migraine, especially migraine with aura, is associated with increased risk of ischemic stroke. However, the precise mechanisms of such a relation are currently not fully elucidated and are still a matter of speculation. Migraine may directly cause an ischemic event (i.e, migrainous infarct), by inducing cerebral microcirculatory vasoconstriction (cortical spreading depression-related oligemia), intracerebral large vessels spasm, and vascular endothelium-related hypercoagulability. On the other hand, migraine may predispose to cerebral ischemia outside of a migraine attack by affecting endothelial function, alone or in combination with traditional vascular risk factors, or by interacting with pre-existent stroke susceptibility conditions (i.e, patent foramen ovale). At least theoretically, the migraine-stroke link may be the consequence of the unfavourable effect of migraine-specific drugs (i.e, triptans or ergot alkaloids). Finally, migraine and ischemic vascular events may be linked via genetic pathways, certain genes playing a role on both diseases and influencing their relation. The coexistence of ischemic stroke and migraine in the context of specific syndromes (i.e, CADASIL) characterized by peculiar phenotype, proven inherited background and chronic alterations of the wall of cerebral small vessel arteries suggests that migraine and ischemic stroke may be the end phenotype of common pathogenic mechanisms. How to identify those migraineurs at highest risk of ischemic stroke and whether stroke can be prevented by specific therapeutic strategies are the goals of future research.

Hyperbaric (HBO) or normobaric oxygen (NBO) therapy applied in acute ischemic stroke aims to increase oxygen supply to the ischemic tissue and to reduce the extent of irreversible tissue damage. Over the past decade, multiple studies have clarified the potential and limitations of oxygen therapy in preclinical stroke models. Considering that the reduction of the infarct size amounts to 30-40%, the cerebroprotection induced by HBO is moderate. In the experimental setting, the effective time window of HBO initiation is only a few hours. Higher pressures (2.5-3 ATA) are more effective. Even though oxygen therapy has some effectiveness in permanent cerebral ischemia without vascular recanalization, it appears more promising for bridging of a transient ischemic period until reperfusion of the penumbra takes place. Compared to HBO, the implementation of NBO to the clinical setting would be substantially less demanding. Although recent experimental NBO-studies are promising, significant effectiveness of NBO was only shown in transient cerebral ischemia and if started within a narrow time window of maximum 30 minutes. Some studies suggest that the effect of HBO is superior to NBO both during transient and permanent cerebral ischemia, even if treatment initiation is delayed. Limited experimental studies do not support an additive effect of a sequential combination of both therapies at present. While the therapeutic potential of oxygen therapy in ischemic stroke was considerably better defined over the past years, the underlying cerebroprotective mechanisms of oxygen therapy remain to be fully elucidated. Recent studies have demonstrated that physical oxygen therapy indeed improves oxygen supply of the ischemic penumbra as well as the cellular bioenergetic metabolism. Therefore, the mitochondria including their role in apoptotic cell death pathways as well as the modification of the cellular hypoxia sensor HIF-1α are considered as potential “downstream pathways” of oxygen therapy. Finally, its beneficial effects on the ischemic microcirculation suggest an important modification of various cell types within the neurovascular unit.