I started this blog mainly to supplement my own learning but also to inspire and spread awareness of the often unseen but nonetheless highly important role that microorganisms play in human, animal and environmental health.
My BSc was in Biological Sciences, I completed my MSc in Medical Microbiology and I am presently a doctoral researcher. My work specifically focuses on investigating pathogenesis, host-pathogen interactions and and molecular biology of unusual phenotypes of Streptococcus pyogenes.
Posts will include clinically relevant topics within bacteriology, parasitology, virology and mycology as well as occasional essays, papers and reviews produced throughout my studies.
I am a member of the Microbiology Society and the British Society for Parasitology.
Questions, corrections, suggestions and requests are welcome.
The Measles virus (MV) is a pleomorphic single-stranded negative-sense RNA virus that belongs to the genus Morbillivirus within the family Paramyxoviridae. The measles virus is the causal agent of Measles, a disease that is responsible for more than 40 million infections globally each year and more than 250,000 deaths, predominantly among children (Moss and Griffin, 2009).
Like many other viruses, the measles virus has evolved an elegant repertoire of strategies to evade host immunity and has become adept at exploiting and manipulating many aspects of its normal functioning to enhance infection and facilitate transmission (Hahm et al. 2004). A number of mechanisms interplay to induce immunosuppression in measles and infection is characterised by lymphopenia, initially impaired immunoglobulin synthesis, inhibition of T cell proliferation, lymphocyte apoptosis, and NK-cell functioning and aberrant Th2- biased cytokine production (Griffin, 2010).
Transmission and entry
Measles is transmitted by aerosol or direct contact with respiratory secretions; viral particles are inhaled and establish infection at the alveolar level in the lung (Lemon et al. 2011). The measles virus is highly lymphotropic, preferentially parasitizing alveolar macrophages and dendritic cells, utilising the CD150 receptor, a member of the immunoglobulin superfamily to which the MV haemagglutinin (MV-H) protein binds with high affinity (Lemon et al. 2011). Attachment and subsequent infection is enhanced by the binding of the glycoprotein designated ‘fusion’ (MV-F) and MV-H to the C-type lectin receptor DC-SIGN, which is expressed on immature dendritic cells (Lemon et al. 2011).
Evading innate immunity
Upon entering the cytosol, the measles virus eludes recognition by RIG-1-like receptors (Nunes-Alves, 2014). These receptors constitute the first line defence against viral pathogens and when viral RNA is detected, RIG-1 and MDA5 complex with the mitochondrial antiviral signalling protein (MAVS) by associating with their caspase activation and recruitment domains (Nunes-Alves, 2014). This sequence of events culminates in the production of antiviral type 1 interferons and is negatively modulated by phosphorylation of RIG-1 and MDA5 (Davis et al. 2014). Phosphorylation prevents MAVS, RIG-1 and MDA5 from forming a complex. Conversely, PP1 phosphatase dephosphorylates the same residues, allowing these proteins to complex and thus triggering type 1 interferon production (Davis et al. 2014; Mesman et al. 2014). MV replication is known to be sensitive to type 1 interferon and has evolved numerous cell-type specific strategies to suppress their expression and evade innate immunity (Davis et al. 2014).
The non-structural V protein (MV-V) blocks the phosphatase responsible for the regulation of type 1 interferon production (PPI) and is a well-studied virulence factor (Mesman et al. 2014). When MV-V inhibits PP1, RIG-1 and MDA5 remain phosphorylated and inactive and cannot complex with MAVS; as a result the measles virus remains undetected (Mesman et al. 2014). It has been also shown that MV prevents dephosphorylation of RIG-1 and MDA5 by activating RAF1, a regulatory kinase (Davis et al. 2014). RAF-1 phosphorylates a type-1 phosphatase inhibitor, designated inhibitor-1. Inhibitor-1 in turn reduces the function of PP1 and subsequently the production of antiviral IFN-β (Davis et al. 2014; Mesman et al.2014; Nunes-Alves, 2014).
Replication within immune cellsIn the absence of antiviral type 1 interferons, the measles virus can replicate within activated CD150+ immune cells (Fontana et al. 2008; Fugier-Vivier, 1997). Dendritic cells infected with MV do not attain the mature phenotype and exhibit a marked decrease in expression of major histocompatibility complex (MHC) class II and associated co-stimulatory cytokines, such as IL-12 (Servet-Delprat et al. 2000). This down-regulation of MHC II impedes the ability of infected cells to prime specific cytotoxic CD8+ T cell responses (Yilla et al. 2003). Infected DCs also maintain expression the chemokine receptor CCR5 and antigen uptake (Servet-Delprat et al. 2000). As a result, infected DCs remain functional and are continually recruited from the luminal alveolar surface to regional lymph nodes and bronchus associated lymphoid tissue (Moss et al. 2004).
Ordinarily, maturation signals are given in the secondary lymphoid tissues by naïve T cells expressing the ligand for CD40 receptors expressed on the dendritic cell surface (Servet-Delprat et al. 2000). This ligation is fundamental to the terminal differentiation of dendritic cells and for IL-12 production. In the absence of IL-12, natural killer cells are not recruited and cannot eliminate parasitized cells in the early stages of infection (Griffin, 2010). When infected DCs interact with T cells, CD40-CD40L ligation triggers a burst of vigorous viral replication (Servet-Delprat et al. 2000). This has been demonstrated in-vitro and the absence of this signal prevents synthesis of the MV nucleoprotein (NP) (Laine et al.2005).
DC escape and dissemination: crippling adaptive immunityDCs that are parasitized by MV are observed as being markedly more sensitive to the pro-apoptotic transmembrane protein Fas ligand (FasL) (Servet-Delprat et al. 2000). FasL is expressed on activated T cells, and expression of the receptor (Fas) is upregulated on MV infected DCs (Servet-Delprat et al. 2000). When Fas interacts with FasL, infected DCs die by apoptosis, releasing vast quantities of progeny virion within secondary lymphoid organs and the circulation (Servet-Delprat et al. 2000).
It is also known that infected DCs are able to trigger apoptosis of infected and uninfected T cells (Vidalain et al. 2000). Studies have shown that this process is Fas-independent, occurring instead through the tumour necrosis factor (TNF)-related inducing apoptosis ligand (TRAIL) pathway (Vidalain et al. 2000). MV-infected dendritic cells highly express TRAIL and are cytotoxic by this mechanism (Vidalain et al. 2000). Strikingly, implementation of this death ligand to eliminate T cells has also been demonstrated in HIV-1 infection and is likely fundamental to the suppressive and evasive properties of the measles virus (Katsikis et al. 1997; Vidalain et al. 2000).
Adaptive cellular immunity is critical in the elimination of MV infected cells and clearance of the virus from the body (Slifka et al 2003). In the absence of adaptive cellular responses due pronounced lymphopenia, MV replicates in huge quantities and disseminates throughout the body to multiple organs (de Vries et al. 2012).
DC-SIGN+ DCs are able to directly infect T and B-lymphocytes in secondary lymphoid organs as well as in peripheral blood, although the former is the most common (de Vries et al. 2012). As infected DCs undergo Fas-mediated apoptosis, and lymphocytes are induced to die by the TRAIL pathway, copious amounts of progeny virion and infectious cellular debris are released into the lymphatic and circulatory systems resulting in viraemia and further infection of CD150+ DC-SIGN+ immune cells (Servet-Delprat et al. 2000; de Vries et al. 2012). It has also been demonstrated that MV-NP blocks immunoglobulin synthesis and secretion by activated B cells by binding to the Fc-Receptor II, dampening adaptive cellular immune responses further (Ravanel et al. 1997; Laine et al. 2003).
Targeting respiratory epithelia: exit, shedding and transmission
It was initially believed that respiratory epithelia constituted primary replicative sites for MV, however this has since been discredited (Lemon et al. 2011). Although establishing infection in these cells is critical to pathogenesis and transmission, in contrast to other respiratory viruses such as respiratory syncytial virus (RSV), the respiratory epithelium is the ultimate goal (de Vries et al. 2012). Hitherto, each aspect of infection has contributed to crippling host immunity to a sufficient extent so as to permit unregulated viral replication and dissemination (de Witte et al. 2006; de Vries et al. 2012). Having successfully accomplished this, the virus disseminates unrestricted, finally targeting the basolateral surface of the respiratory epithelium (Noyce, 2011).
Until recently, it was not known precisely how MV reached the luminal surface (Noyce, 2011; Muhlebach et al. 2011). However in 2011, two separate groups found that this occurs by transmission of the virus from infected lymphocytes and dendritic cells in the respiratory submucosa by utilisation of a novel attachment receptor in the immunoglobulin superfamily, now known as nectin-4 (Noyce, 2011; Muhlebach et al. 2011). At this stage, the virus is detectable at high quantities in numerous tissues including the buccal mucosa, the trachea, the nose, conjunctiva and the skin (fig.1) (Lemon et al. 2011; de Vries et al. 2012). Having finally reached these sites, virion extrude by budding from the luminal surface, facilitating copious shedding into respiratory secretions de Vries et al. 2012).
Considerable damage to the respiratory epithelium is a hallmark of measles infection, heralding the onset of symptoms that include pyrexia, coughing, rhinitis, conjunctivitis and sneezing as well as the characteristic ‘Koplik’s spots’ within the oral cavity (Schneider-Schaulies and Meulen, 2009). Around 3-7 days after the onset of these prodromal symptoms, the pathognomonic generalised maculopapular rash is observed, covering the whole body (Schneider-Schaulies and Meulen, 2009).
Figure 1: The fundamental steps in the pathogenesis of measles are illustrated using rMV expressing enhanced green fluorescent protein (EGFP) in a cynomolgus macaque model (Macaca fascicularis). MV viraemia is demonstrated using fluorescence-activated cellular sorting data plots, showing EGFP+ CD150+ cells in the peripheral circulation. Image sourced from de Vries et al. 2012.
The appearance of the rash marks the point at which the immune system finally begins to respond to the infection, mounting an adaptive immune response and subsequently allowing for the elimination of infected cells and reservoirs by natural killer cells and CD8+ T cells (Ludlow et al. 2015). Transmission and infectivity steeply decline from this point, with antibodies specific to the measles virus increasing exponentially, correlated with the decrease in viral load (Ludlow et al. 2015; Lemon et al. 2011).
Evasion is critical to virus survival and success
MV has a basic reproductive number (R0) of 15-17, among the highest of all human pathogens (de Vries et al. 2012). Unlike many other respiratory viruses, recovery from measles confers lifelong immunity (Griffin et al. 2012). This is a hindrance for the measles virus, which must subsequently implement a number of strategies to maximise potential for transmission to new susceptible hosts (de Vries et al. 2012).
As discussed, this is achieved by inducing pronounced, transient immunosuppression, disabling host immunity and buying the virus enough time to replicate to sufficient numbers, promoting infection and thus transmission (Lemon et al. 2011). Peak levels of viral replication occur prior to the onset of symptoms due to these strategies as MV paralyses the antiviral action of both innate and adaptive immunity (Ludlow et al. 2015; de Vries et al. 2012).
MV immune evasion is essential to the survival of the virus, which has circulated in human populations since antiquity (Schneider-Schaulies and Meulen, 2009). It is evident that not only is there still much to learn from measles, but it also seems pertinent to re-examine what we think we know about this unique Morbillivirus. Learning from practical experience (de Swart et al. 2012), the virus is seems very much a step ahead; evading not only human immunity, but also our comprehension and our control efforts.
REFERENCES
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The pathogenesis of measles. Current opinion in virology, 2(3), 248-255.- de Witte, L., Abt, M., Schneider-Schaulies, S., van Kooyk, Y., & Geijtenbeek, T. B. (2006).
Measles virus targets DC-SIGN to enhance dendritic cell infection.Journal of virology, 80(7), 3477-3486.- Fontana, J. M., Bankamp, B., Bellini, W. J., & Rota, P. A. (2008).
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Interleukin-1β converting enzyme–like protease involvement in Fas-induced and activation-induced peripheral blood T cell apoptosis in HIV infection. TNF-related apoptosis-inducing ligand can mediate activation-induced T cell death in HIV infection.The Journal of experimental medicine, 186(8), 1365-1372.- Laine, D., Trescol-Biémont, M. C., Longhi, S., Libeau, G., Marie, J. C., Vidalain, P. O., ... & Valentin, H. (2003).
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Measles virus nucleoprotein induces cell-proliferation arrest and apoptosis through NTAIL–NR and NCORE–FcγRIIB1 interactions, respectively. Journal of general virology, 86(6), 1771-1784.- Lemon, K., de Vries, R. D., Mesman, A. W., McQuaid, S., van Amerongen, G., Yuksel, S., ... & de Swart, R. L. (2011).
Early target cells of measles virus after aerosol infection of non-human primates. PLoS Pathog, 7(1), e1001263.- Ludlow, M., McQuaid, S., Milner, D., de Swart, R. L., & Duprex, W. P. (2015).
Pathological consequences of systemic measles virus infection. The Journal of pathology, 235(2), 253-265.- Mesman, A. W., Zijlstra-Willems, E. M., Kaptein, T. M., de Swart, R. L., Davis, M. E., Ludlow, M., ... & Geijtenbeek, T. B. (2014).
Measles virus suppresses RIG-I-like receptor activation in dendritic cells via DC-SIGN-mediated inhibition of PP1 phosphatases. Cell host & microbe, 16(1), 31-42.- Moss, W. J., Ota, M. O., & Griffin, D. E. (2004).
Measles: immune suppression and immune responses. The international journal of biochemistry & cell biology,36(8), 1380-1385.- Moss, WJ. Griffin, DE. (2012).
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The Gundi (or gondi) (family Ctenodactylidae) was the first organism from which Toxoplasma gondii was isolated, specifically the common Gundi (Ctenodactylus gundi). They’re a little like guinea pigs or chinchillas! Gundi can serve as intermediate hosts for T. gondii, just like other rodents such as mice or rats. T. gondii was also observed in rabbits around the same time, and despite having been observed in almost all warmblooded animals since, (even Beluga whales in the Arctic!), the organism was named after the noble Gondi. n____n
Scanning electron microscopy of Toxoplasma gondii tachyzoites
Toxoplasma gondii is an obligate intracellular protozoan parasite responsible for the human disease Toxoplasmosis. Over a billion people worldwide are believed to carry the coccidian parasite and Toxoplasmosis is classified as a neglected parasitic disease by the Centers for Disease Control and Prevention (Boothroyd and Grigg, 2002; Hotez and Kamath, 2009). Toxoplasma gondii has a uniquely vast host range and is able to invade virtually all nucleated cells in virtually any warm-blooded host, however felids such as the domestic cat constitute the only definitive hosts (Dubey and Beattie, 1988; Werk, 1985). Incidences of human Toxoplasmosis are often subclinical with few, if any generalized symptoms and rates of infection are highly dependent on cultural and social practices that expose humans to food and water contaminated with infective oocysts (Pappas et al. 2009). However, in instances of congenital infection or infection among those with compromised immunity, such as HIV/AIDS patients or those undergoing chemotherapy, the effects can be catastrophic (Havelaar et al. 2007; Israelski and Remington, 1993). Despite its name, Toxoplasma gondii, the only member of the genus Toxoplasma was so named not due to its toxic or malign nature, but as a reference to its crescent morphology; (Toxo, from Greek τόξον (toxon); arc, bow). Interestingly however, a number of recent studies have implicated the organism in human psychopathology and risk taking behaviour.
A generalised lifecycle of Toxoplasma gondii
Schizophrenia is a severe psychiatric disorder, or cluster of disorders characterised by disturbances in cognitive processes, perception, emotion and sociality and is one of the most burdensome and costly illnesses globally despite affecting only 1% of the population (Sawa and Snyder, 2006; Goldner et al. 2002). The cause of schizophrenia and associated disorders are unknown and are likely complex and multifactorial (Goldner et al. 2002). Following the completion of the Human Genome Project and subsequent genome wide association studies (GWAS), a genetic basis for the development of schizophrenia and similar disorders was not found, sparking renewed interest in infective agents such as Toxoplasma gondii as potential etiologic factors (Gershon et al. 2012; Torrey et al. 2012).
Although infection has classically been considered innocuous among otherwise healthy human hosts, more recent evidence appears to highlight this as an oversight, hinting at a less benign disease process. In light of recent evidence, a relationship has been suggested between Toxoplasmosis and psychiatric disturbances as well as a variety of long-term alterations to individual personality (Webster, 2001; Gaskell et al. 2009; Torrey et al. 2007; Torrey et al. 2003), these are discussed herein.
Pathogenicity and host manipulation
The affinity of Toxoplasma gondii tachyzoites for neural tissues, particularly astrocytes and microglial cells is fundamental to the pathogenicity of the organism (Hermes et al. 2008). Upon establishing a chronic infection within skeletal muscle and the CNS, the parasite is able to induce significant alterations in the mood and behaviour of intermediate hosts and has been associated with risk taking and combative behaviour in humans (Torrey et al. 2012; Flegr et al. 2002; Flegr et al. 2007). These effects are most pronounced in rodents and studies have demonstrated that rats infected with the parasite exhibit not only markedly modified risk perception but also developed an imprudent attraction to felid predators such as the domestic cat facilitating the transmission of the organism (Berdoy et al. 2000). Although the risk of a human being consumed by a felid are astronomically small, historically this was not always the case and other primates such as chimpanzees still constitute significant portion of prey items for felid predators such as leopards (Zuberbuhler et al. 2002) and therefore are not, as is the case for humans, dead end hosts for the parasite. From an evolutionary perspective, it is therefore reasonable to assume that human infection with Toxoplasma gondii would have a similar effect to those observed among our primate ancestors (Brain, 1981).
Serological analyses of samples obtained from mothers before and after birth elucidated a significantly elevated proportion of IgM antibodies raised against T. gondii in those women whose children developed schizophrenia in later life (Torrey and Yolken, 2003). Torrey and Yolken also carried out meta-analyses on the 18 studies conducted since 1953 that reported evidence of a relationship between T. gondii antibody titres and the emergence of schizophreniform characteristics in first-time psychiatric patients. The analyses revealed that 11 of these demonstrated statistically significant associations between antibody titres and the development of schizophrenia. Another study conducted by Yolken et al. found that among patients suffering from first-episode schizophrenia, EIA and Western blotting analysis of CSF and serum samples revealed significantly greater proportions of IgG, IgM and/or IgA antibodies to Toxoplasma proteins compared to a matched control group (Yolken et al. 2001).
Leweke et al. also found that among individuals with recent onset schizophrenia, serum and CSF samples displayed significantly higher levels of antibodies to T. gondii-associated antigens when compared with those obtained from controls with no history of psychiatric disease (Leweke et al. 2004).
A similar survey assessed 105 individuals seeking psychiatric help using Brief Psychiatric Rating Scale and Scale for the Assessment of Negative Symptoms measures, followed by immunoassays with a view to determine whether an association between seropositivity for IgG antibodies against T. gondii and psychotic symptoms could be demonstrated. Amminger et al. concluded that seropositive individuals with higher levels of serum IgG against T. gondii exhibited more severe psychotic symptoms and subsequently identified these individuals as being ‘ultra-high risk for psychosis’ (Amminger et al. 2007).
Skallova et al. carried out personality profiles and serological analysis on 290 blood donors with a view to demonstrate an association between Toxoplasma gondii infection and altered dopamine neuromodulatory processes. Using Cloninger’s Temperament and Character inventory, 290 subjects, were assessed and evaluated predominately for novelty-seeking behavioural traits, which correlate negatively with dopamine production and the subject’s samples were then assayed for anti-Toxoplasma antibodies. The study demonstrated that novelty-seeking behaviour was significantly reduced in both male and female subjects with latent Toxoplasmosis when compared to those whose samples were not positive for serological evidence of T. gondii (Skallova et al. 2005).
Toxoplasma gondii and behaviour
Elevated levels of dopamine in various areas of the brain is known to play an important role in the emergence of schizotypal symptoms and schizophrenia among patients with certain forms of the disease (Sawa and Snyde, 2002). Many countries have also identified cat breeders as an at risk group for the development of schizophrenia (Etheredge and Frenkel, 1995; Fan et al. 2001). Similarly, contact with cats has also been demonstrated as an important etiologic factor in the development of schizophrenia (Torrey and Yolken, 2002; Torrey et al. 2002). Numerous independent studies have demonstrated recurrent associations between acute Toxoplasmosis and schizophrenia; evidence of latent infection is also significantly more prevalent among patients with schizophrenia than is observed among groups of uninfected individuals (Yolken et al. 2001; Minto and Roberts, 1959; Robertson 1965; Kramer, 1966; Ladee et al. 1966).
In the immune competent host, immunity appears to be sufficient in suppressing the emergence of pronounced psychiatric alterations. Studies have highlighted IFN- γ and TNF as key mediators in maintaining T. gondii bradyzoites in their latent or dormant state. If the immune system becomes compromised however, such as in HIV/AIDS patients, latent bradyzoites may become reactivated and patients often display psychotic symptoms and may be misdiagnosed as having schizophrenia (Wang et al. 2006). Similarly, when the TNF-α is blocked, for instance as a result of therapeutics used in the treatment of arthritis, Toxoplasma reactivation is observed – leading to complications such as chorioretinitis (Rodrigues et al. 2013; McGregor et al. 2008).
A negative association has been observed between schizophrenia and rheumatoid arthritis, the latter of which is characterised by excessive inflammation largely mediated by TNF- α overproduction. This could explain the association between the two diseases as well as lend support to the importance of TNF in the maintenance of Toxoplasma latency and reactivation (Eaton et al. 1992; Eaton et al. 2010).
Toxoplasma gondii mediated alterations to neurochemistry
Increased levels of catecholamines such as dopamine, known to mediate novelty-seeking and neurotic behaviours in humans have been observed in chronically infected rodents (Stibbs et al. 1985; Benjamin et al. 1996; Ebstein et al. 1996; Lee et al. 2005). Skallova et al. conducted a study using a mouse model to demonstrate the link between Toxoplasmosis and changes in dopaminergic neuromodulatory systems. Measuring dopamine-mediated behaviours such as locomotion and exploration, the group found that among mice infected with the parasite exhibited marked reduction in trepidation with the opposite being observed in control mice. Treatment with a selective dopamine uptake inhibitor GBR 12909 reversed these effects but had no effect on the control group, suggesting a potential link between observed alterations in dopamine modulation and Toxoplasmosis (Skallova et al. 2006).
Analyses of the Toxoplasma gondii genome have identified two dual action tyrosine hydroxylases, enzymes known to drive the catabolism of phenylalanine to L-tyrosine and L-tyrosine to L-3, 4-dihydroxyphenylalanine (L-DOPA), a precursor to dopamine and antibodies to these enzymes have also been described (Gaskell et al. 2009). These dopaminergic enzymes have been studied in-vitro using artificially infected cultures of PC12 cells. One study found that dopamine release among infected cells was up to 350% greater than was observed in the uninfected PC12 cultures, with neurotransmitter release increasing in a dose-dependent manner, correlated with parasites per cultured cell (Prandovszky et al. 2011). Immunostaining of parasitized cells containing both bradyzoites and tachyzoites highlighted the parasite membrane and parasitophorous vacuole but no organelles, which is consistent with secretory processes (Prandovszky et al. 2011). The activity of the aromatic amino acid hydroxylases is dependent on the presence of a tetrahydrobiopterin cofactor, which also serves as a cofactor for the synthesis of the neurotransmitter serotonin (Broadle-Biber, 1993). Toxoplasma gondii is able to synthesize some amino acids, but is auxotrophic for others such as tryptophan and arginine and thus must salvage or scavenge these (Chaudhary and Roos, 2005; Krug et al. 1989). L-tryptophan is a vital precursor to the biosynthesis of serotonin; among other compounds and dramatic depletion of this neurotransmitter and its precursor have been observed in brain tissues obtained from mice experimentally infected with Toxoplasma gondii (Fujigaki et al. 2002). Deficiencies of serotonin and its precursory compounds are highly depressogenic and classically associated with a myriad of psychiatric sequela, for which numerous conventional therapies have been designed (Holmes et al. 2003; Ressler and Nemeroff, 2000).
Toxoplasma gondii infection has also been shown to stimulate the production of IFN- γ in immunecompetent hosts, which serves to catalyse the conversion of L-tryptophan to kynurenine, by indoleamine 2,3-dioxygenase (IDO) in-vitro and in-vivo (Giese et al. 1999; Silva et al. 2002) and thus inhibiting the parasites replicative machinery (Dai et al. 1994). Studies have shown that the parasite is also able to stimulate the degradation of L-tryptophan along the kynurenine pathway (KP), which comprises many neuroactive metabolites – “kynurenines”, such as 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN) and kynurenic acid (KYNA) (Notarangelo et al. 2014). 3-HK is a potent endogenous free radical generator and neurotoxin, elevated levels of which have been observed in numerous neurodegenerative disorders (Okuda et al. 1998). QUIN is an agonist of the N-methyl-D-aspartate (NMDA) receptor agonist and also potent neurotoxin, described as a key mechanistic mediator in the pathology of various neurodegenerative and psychiatric disorders such as depressive disorders and schizophrenia (Guillemin, 2012). KYNA is a glycine-site NDMA receptor antagonist and has also been identified as a neuroactive substance and high levels of this compound are also associated with schizophrenia and other major neurological disorders (Erhardt et al. 2003; Erhardt et al. 2007). These endogenous substances have strong influences over normal and aberrant neurophysiological processes and are predominately synthesised by astrocytes and glial cells, which incidentally are also preferentially parasitized by Toxoplasma gondii tachyzoites and bradyzoites, providing a possible link between the parasite and the pathophysiology of various psychiatric disorders (Rozenfeld et al. 2003; Espey et al. 1997; Schwarcz and Hunter, 2007).
Toxoplasma gondii deregulates kynurenine and serotonin synthesis
Implications for the treatment of mental illness?
The discovery that some medications used to treat schizophrenia are also able to efficaciously ameliorate T. gondii-associated behaviours has lent further support to the theory of a potential link between the parasite and elements of neurological disorders (Torrey and Yolken, 2003). Webster et al. evaluated the impact and efficacy of the anti-parasitic medication pyrimethamine with Dapsone, typically used to treat Toxoplasmosis, as well as medications commonly used to treat schizophrenia and other disorders; the antipsychotic haloperidol and valproic acid, a mood stabilizer. Using a rat model, Webster et al. found that when feline attraction and other risk-behaviours were monitored in test-pens, haloperidol outperformed the conventional pyrimethamine with Dapsone treatment in reducing Toxoplasma-associated behaviours among infected rats. Infected yet untreated rats spent proportionately more time in the area treated with cat urine and stayed 175% longer on average than the uninfected untreated rats. Infected treated rats were, following all three treatments, less likely to enter the area treated with cat urine and spent significantly less time in the same area when compared to the untreated infected group and the uninfected treated group (Webster et al. 2006).
The identification and characterisation of specific patterns of pathogenicity among T. gondii strains may prove very useful as studies in humans have been unable to suitably describe the symptomatology of either of the 3 identified strains in humans (Fuentes et al. 2001).
While rodent models have proven helpful to conduct preliminary research into the effect of Toxoplasmosis on human neurochemistry, as more sinister aspects of human pathology are elucidated a different model would most definitely prove beneficial. The effects of the parasite on rodent neurochemistry are considerably more distinct and some strains are even fatal (Fuentes et al. 2001). Furthermore, if the efficacy of both novel and existing therapies were to be properly assessed, the use of various model rodent lines in the development of anxiolytic and antipsychotic medications for human consumption would skew the outcome of such studies. For example, the response of a rat to stimuli such as bedding treated with cat urine is a well-established test model to determine the efficacy of novel compounds proposed for use as to treat anxiety (Adamec et al. 1990).
It is an oversimplification and an error to assume that any one factor is solely responsible for all instances of schizophrenia and other disorders with psychotic features, but the implication of an infective agent, particularly one as widely distributed, as Toxoplasma gondii would represent a discovery of significant gravitas. If a link could be definitively demonstrated, modifications to existing therapeutic and diagnostic standards, as well as novel approaches could provide relief for those affected by the debilitating symptoms of the disorder.
References
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Sorry i haven’t posted in forever, the past few months have been absolutely insane but I have finished my undergrad now and have a lot of free time to play with before I start my MSc in September. I’m going to be posting a lot more frequently and I have a few ideas but if anybody has any requests or questions then hit me up. Peace!
Hysteria about the latest Ebola virus (EBOV) outbreak in West Africa has reached new heights this week with the World Health Organisation declaring it an international health emergency. To put this into perspective, the WHO has made similar declarations in the past with reference to Swine influenza (H1N1) and Poliomyelitis in Pakistan. Margaret Chan, the Director-General of the World Health Organization has said of the most recent outbreak that it is "the most severe and the most complex" outbreak in the history of the disease which spans almost four decades.
Severity and complexity are particularly useful when one considers whether or not this EBOV outbreak is a personal threat or indeed a probable threat to a particularly community or country.
Complexity indeed feeds the severity of the disease in the remote villages in West Africa wherein Ebola virus is at its most destructive. This is due to a vast number of factors. For example, many of the afflicted communities in the more recent outbreaks either; do not understand the health risks associated with the disease; do not understand the viruses and fatally, do not trust or are understandably unwilling to cooperate with health officials.
Ebolavirus outbreaks are not purely virological problems, but rather sociological problems. Past outbreaks of Ebola (and indeed the presently raging outbreak) are not fuelled by a miraculous gain in function by EBOV which infects the cells that line human blood vessels, as well as some immune cells and liver cells. Nor are they likely to be cured by a technological magic bullet such as a vaccine or a novel medication.
Ebolaviruses are now believed to originate in bats, and somehow, probably through either consumption of the meat or consumption of foods that have been contaminated, the viruses are able to enter hapless populations of other species, including humans. Outbreaks seem to be occurring with increasing frequency and severity which is unsurprising when one considers the extent of localised deforestation and habitat destruction that has forced Bats and innumerable other animals closer to human populations which expand without relent. Ebolaviruses are transmitted between populations of humans by contact with the bodily fluids of the infected. However, the virus is actually unable to survive for any appreciable period of time on a clean, dry surface.
N.B. While this image calls Zaire ebolavirus “Ebola virus,” this isn’t how the International Committee on the Taxonomy of Viruses actually recommends you refer to the virus, which is why this article does not follow the CDC convention. Also, the “(non-human)” note on Reston ebolavirus is not entirely accurate. Reston ebolavirus does not cause disease or death in humans, but it can still infect humans. Reston ebolavirus, for this reason, could potentially be used to develop ebolavirus vaccines.
All of the recorded outbreaks of Ebola Hemorrhagic Fever, including this, the largest, have been in areas wherein the available healthcare is unfortunately many, many realms below the standard with which the majority of those concerned about the spread of the disease are familiar. Further gumption is afforded to the spread of Ebola due to the systemic distrust in the local governments that is commonplace in many of the areas affected by the outbreaks, due to the numerous civil wars; corruption and genocides that have ravaged them. It is through such lenses that epidemiologists and other such prying eyes can begin to make sense of the apparent chaos.
Although previously unseen in West Africa, isolated villages have become particularly vulnerable to outbreaks of EHF not simply due to the aforementioned social issues but also owing to deep rooted traditional practices for the management and burial of corpses. Such practices often include ceremonial rites such as washing, bathing and kissing the corpse prior to their burial during which time the body is at its most infectious. Corpses are then buried in graves which are not contained, are not shallow enough and are ill prepared to restrict further transmission which may occur for up to three months following death.
Furthermore, if individuals do develop symptoms of Ebola hemorrhagic fever, cooperation between these villages and health officials is paramount to not only to provide necessary medical support to the patients but to contain the outbreak swiftly and effectively. This has proven to be incredibly difficult and it is reported that villages commonly conceal or deny the existence of infected individuals for fear of their isolation to the extent that in Liberia alone, figures estimating how many may have been infected by Ebola may be as much as half of the true count.
Isolation is a concern for villagers for fear that loved ones and fellow villagers will perish alone, surrounded only by the daunting shrouded figures of aid workers, reeking of chlorine, draped in plastics and sheets. Patients that perish in quarantine are also denied ceremonial funeral rites.
Despite being an international issue, as ever, the disease is not an immediate threat to the entire planet by virtue of the highly complicated 'perfect storm' scenarios that have allowed the emergence of Ebola hemorrhagic fever past and present. In fact, several countries have thus far demonstrated their ability to quell outbreaks of related, highly dangerous pathogens.
For instance, the outbreak of related viruses such as Marburg virus in Germany in the 1960's and the outbreak of Reston virus in Washington DC in the 90's to name just two. Even past outbreaks of Ebolaviruses in Africa have been effectively quashed by global efforts.
A media frenzy erupted when American doctors who contracted the disease during aid efforts in the most recent outbreaks have been safely transported back to the United States and are undergoing treatments in designated facilities. The swift recognition of Ebola cases and the proper management of those infected in appropriately controlled facilities is key in preventing the spread of this disease and effectively diffuse the threat of pandemic. Such facilities in the field are sadly becoming overwhelmed, are faced with low compliance and are often ill equipped to deal with the growing number of people breaking with Ebola on a weekly basis.
The CDC however, is far from ill equipped and once patients are transferred to appropriate facilities for medical attention, it becomes apparent quite how strongly the disease is dependent on the bleak 'perfect storm' of social issues observed in the areas where the virus has prevailed.
Also, Dr. Stephan Monroe of the CDC had this to say of the current outbreak:
"The mortality rate in some outbreaks can be as high as 90 percent, but in this outbreak, it is currently around 60 percent, indicating that some of our early treatment efforts may be having an impact."
The ongoing outbreak in West Africa as Ebola is extremely easy to write about with a view to sell papers. Sources such as the WHO and the CDC are much more useful and more reliable. Eye popping buzz words such as 'haemorrhage!' and 'quarantine!' coupled with the tropical, mysterious and very Hollywood backdrops of Sierra Leone and Bundibugyo enable journalists to make light work of painting a terrifying apocalyptic picture, the likes of which fuels the industry.
Ebola viruses are not stand alone etiologic agents of viral hemorrhagic fevers (VHF's). In fact, the VHF's represent a large and diverse group of illnesses which affect both humans and other animals and are often zoonotic. Viral hemorrhagic fevers may be caused by a great number of RNA viruses spanning five diverse families:
Filoviridae
Arenaviridae
Bunyaviridae
Flaviviridae
Rhabdoviridae
The very term viral hemorrhagic fever instantly sends out a sensationally jarring message and in the case of Ebola this is somewhat deserved. However, at the risk of sounding deluded and defensive, it is important to remember that not all VHF's are life threatening. In fact, some such agents may produce only mild symptoms; this is true of Nephropathia epidemica, a VHF caused by the Puumala virus.
Nephropathia epidemica, although capable in some instances of inducing a more severe, internal hemorrhagic phase, often only produces relatively mild symptoms such as fever, headaches and gastrointestinal upset. Predominantly found in Finland and Scandinavia. the Puumala virus' natural reservoir is the noble Bank vole (Myodes glareolus). Unlike other hantaviruses, the Puumala virus is thought to be potentially fatal in rodent hosts.
The following is a white blood cell chasing a bacterium. It eventually ends up swallowing it. The following white blood cell is specifically a neutrophil. They end up ingesting the microbe a process known as phagocytosis.
EMB agar is used to identify coliforms and fecal coliforms (the bacteria they are looking for when testing water quality at the beach, for example). Coliforms are gram negative lactose fermenting bacteria that can indicate the presence of fecal mater. EMB agar is selective for gram negative bacteria (the methylene blue dye prevents the growth of gram positive bacteria) and differential for lactose fermentation (eosin dye turns black/purple when acids are produced during lactose fermentation). The reason this is one of my favorite microbiological media is what happens when you grow a vigorous fermenter like E. coli on the plate (upper picture) - you get this beautiful green sheen to the colonies! The lower picture on the left shows a regular lactose fermenter (K. pneumoniae), where the colonies have turned a dark purple color, and the lower right picture shows a gram negative, non-lactose fermenter (P. aeruginosa)
This picture shows human epithelial cell infected with Chlamydia trachomatis (green) and it was taken with ZEISS FE-SEM.
Chlamydia trachomatis is an obligate intracellular human pathogen (the bacterium lives within human cells), a gram-negative bacterium, and it can appear as either coccoid or rod shape.
C. trachomatis can cause numerous disease states in both men and women. Both sexes can display urethritis, proctitis (rectal disease and bleeding), trachoma, and infertility. The bacterium can cause prostatitis and epididymitis in men. In women, cervicitis, pelvic inflammatory disease (PID), ectopic pregnancy, and acute or chronic pelvic pain are frequent complications. It is the single most important infectious agent associated with blindness.
So the bacteria that I am currently working with is called C.perfringens and is a common soil bacteria that is also found in association with mammals as a commensal and sometimes as a pathogen. There are five serotypes (A-E), each associated with a set of different diseases and target organism which is either a mammal or poultry. C.perfringens is capable of producing up to 16 different toxins, although these are rarely expressed all at once. It is a saprophyte, so decays dead matter - hence most of its toxins are hydrolytic enzymes. The most common diseases caused by C.perfringens is food poisoning and necrotic enteritis (chickens).
It is also the fastest growing bacteria, with a doubling time of 10 minutes (E.coli’s doubling time is 20 minutes). It is an obligate anaerobe which makes it tricky to grow. I have to essentially streak it out onto TSC agar and then add a second layer of agar on top of that to create a highly anaerobic microenvironment. I also need to leave these microbes in an anaerobic chamber over night to completely remove any possible source of oxygen from their surroundings.
The final thing I want to mention is the TSC media I use to grow them. This media contains a source of sulphite which C.perfringens is able to reduce which is what causes the bacteria to show up black on these plates. They are one of the few Clostridia that can reduce sulphite, so this media acts as a differential media for C.perfringens.
Earlier this month, a team of Moroccan scientists isolated two previously undiscovered strains of catalase- and oxidase-negative Streptococcus-like strains from raw camel milk. Published in the Journal of Systematic Evolutionary Microbiology, Streptococcus moroccensis and S. rifensis join over 50 others in the growing Streptococci genus, with Streptococcus rupicaprae as their nearest phylogenetic neighbour. 16S rRNA sequencing placed similarity of the two strains to to S. rupicaprae at 95.9 % and 95.7 %, respectively.
Although these novel strains are believed presently to be relatively benign, this is not the case for all members of this fascinating genus which although are commensal in many instances, are capable of producing an array of symptoms ranging from annoying to deadly in ways that are not always easy to predict.
Classification
Phylum Firmicutes
Class Bacilli
Order Lactobaciliales
Family Streptococcaceae
Genus Streptococcus
Streptococci are spherical Gram-positive bacteria and are classified in accordance with their metabolism on blood agar; their ability to induce haemolysis (nonspecific killing of blood cells by metabolic by-products) of red blood cells on 5% sheep blood agar; inducing a visible change in the growth medium. This process is known as hemedigestion. They are also described according to the presence or absence of Lancefield carbohydrate group antigens on their cell walls.
Using these methods, Streptococci are organised thus:
Pyogenic (beta-haemolytic) including Groups A, B, C, E, F & G
Viridans group
Lactococci (generally not pathogenic)
Alpha-haemolytic Streptococci induce only partial haemolysis of red blood cells and thus turn blood agar green (see image below). An example of an alpha-haemolytic Streptococci is S. pneumoniae which forms part of the commensal flora of the nasopharynx in healthy individuals. Despite this, S. pneumoniae is associated with disease in some individuals particularly the elderly, neonates and the immunocompromised and is a leading cause of meningitis in adults and young adults. S. pneumoniae is not restricted to respiratory infection however and may induce septic arthritis, endocarditis, rhinitis and brain abscesses among other disease states.
The late microbiologist Rebecca Lancefield, established the system of Lancefield grouping over the course of her esteemed career, working extensively on beta-haemolytic Streptococci; placing them into one of 11 groups based on their immunochemical properties.
Group A (GAS) - S. pyogenes is of clinical importance as it is responsible for an array of infections which may be invasive or noninvasive. Non invasive infections are generally not severe and include impetigo, pharyngitis, the now uncommon scarlet fever and also rheumatic fever. More severe invasive Group A streptococcal infections include toxic shock syndrome, pneumonia as well as gruesome and disfiguring necrotising fasciitis.
Group B (GBS) - Such as S. agalactiae; a common cause of pneumonia and meningitis in neonates and the elderly. Group B Streptococci are also known to colonise the intestines and the birth canal wherein it may threaten the integrity of the amniotic membrane and infect the baby. To prevent this occurring, women in some countries are screened for Group B Streptococci and treated with prophylactic antibiotics during labour.
Group C (GCS) - GCS are generally animal pathogens. S. equi is not pathogenic in humans but certainly a bacteria of consequence in veterinary medicine and is responsible for the equine upper-respiratory tract infection known as strangles. Other GCS have been known, albeit rarely, to cause severe disease in humans such as meningitis.
Group D (GDS) - Many of the species that were previously thought to comprise the Group D Streptococci have largely been reclassified and allocated to the genus Enterococcus. An example of a GDS since reallocated is Enterococcus faecalis. Strep. bovis is an example of a true GDS and is a coliform common in the alimentary canals of ruminants although this bacterium has been linked to cancers and endocarditis in humans. Other members are associated with food borne disease.
Group F (GFS) - S. anginosus, also known as S. milleri is commonly associated with highly purulent abscesses. In previous years it was postulated that this microorganism is more common than previously thought as a pathogen due to misidentification in clinical laboratories, this seems to have been true to some degree but with the refinement of technology and understanding, misidentification is greatly reduced.
Group G (GGS) - Streptococcus canis is an example of a GGS and is a part of the natural flora of the oral mucosa in cats and dogs. Although not widely considered to be a common pathogen among humans, incidences of toxic shock syndrome and necrotising fasciitis attributable to S. canis are known. S. canis is also reported to complex albumin in human hosts as well as other animals and thus is highly likely to be vertically transferred.
Gamma-haemolytic (non-haemolytic) Streptococci do not induce haemolysis of red blood cells and thus do not alter the appearance of blood agar. Group D Streptococci such as Enterococcus faecalis are gamma haemolytic and as aforementioned are typically commensal coliforms also associated with food borne disease.
Other species discovered this month
Rebecca Lancefield
Streptococci
More on Biochemical and Molecular methods in bacteriology
Information and indeed misinformation about Ebola spread with speed and vigour comparable to the disease itself, but with such a deluge of often misleading news in light of the recent outbreaks in West Africa, it can be difficult to discern the valuable from the reactionary.
Classification
To fully appreciate both the threat of disease and the beauty of the etiologic agents, it is useful to start at the beginning. Ebola Virus disease (EVD), also known as Ebola hemorrhagic fever (EHF) first emerged in Yambuku, Zaire, home to the Ebola river after which the disease is named. Ebola viruses are Group V ((-)ssRNA) viruses; Order: Mononegavirales; Family: Filoviridae; Genus: Ebolavirus.
The Ebolavirus genus is comprised of 5 species each named after the location of their initial emergence. Of the 5, Zaire ebolavirus is the type species:
Species: Tai Forest ebolavirus
Virus: Tai Forest virus (formerly Cote d’Ivoire ebolavirus)
Species: Reston ebolavirus
Virus: Reston virus
Species: Sudan ebolavirus
Virus: Sudan virus
Species: Zaire ebolavirus
Virus: Ebola virus
Species: Bundibugyo ebolavirus
Virus: Bundibugyo virus
A virus species is defined as a polythetic class of viruses which constitute a replicating lineage, occupying a specific ecological niche. To contextualise this, the virus behind the recent ongoing Ebola outbreak in Guinea and elsewhere in West Africa is Ebola virus (Zaire ebolavirus) (found to be 97% identical to those found previously in the Congo and Gabon by Baize et al.) Whereas the virus responsible for the 2012 Ebola outbreak in Orientale Province, Democratic Republic of the Congo was Bundibugyo virus. Understandably, this can cause confusion among both the public and experts and can make it difficult to understand the epidemiology and virology of Ebola outbreaks.
The family Filoviridae to which Ebolaviruses belong are so named due to their characteristic thread-like appearance and are not a welcome sight for any virologist, even those operating within the stringent confines of a Biosafety Level-4 containment facility. These images and indeed the catastrophic symptoms they herald in those infected have crystallised Ebola in the nightmares of many.
Symptoms
A staggering 90% of those suffering with Ebola die within days of the onset of symptoms and there are no treatments or preventative measures beyond containment due to the relative rarity of outbreaks. On July 6, 2014, the Guinea Ministry of Health announced a total of 408 suspect and confirmed cases of Ebola hemorrhagic fever (EHF), including 307 fatal cases.
Incubation periods of Ebola hemorrhagic fever may range from as little as one day to several weeks, making it wildly unpredictable and difficult to control. Furthermore, initial symptoms of Ebola are ambiguous and similar to those observed in other tropical fevers, including headaches, joint and muscle pain and a high fever; this further serves to delay control efforts and quarantines. For the unfortunate majority, these initial stages generally progress to the catastrophic haemorrhagic stage for which the disease is infamous. Victims frequently suffer from bloody vomit and diarrhoea as well as a haemorrhagic rash which covers the skin, eyes and mucous membranes. Dramatic blood loss occurs from every orifice and this disastrous final stage leads to death from exsanguination and multiple organ failure within hours.
This dramatic haemorrhaging is not entirely under the control of the virus but rather results from the hosts immune response to the disease. Host antibodies flood the circulation, clogging the blood stream and attacking blood vessels leading to sustained, heavy internal bleeding.
Vectors and Transmission
Both the dead and the surviving Ebola victims remain contagious for over a month, shedding the viruses in their tears, blood, saliva, faeces and even semen. It is for this reason that outbreaks of Ebola are not considered to be over unless there have been no further cases for a 2 month period following the death or recovery of the last victim.
Little is known about the natural reservoirs of Ebolaviruses, nor is there any clear evidence to suggest a definitive vector. With each outbreak of the disease scientists are able to learn more, but certainly in the case of the most recent outbreak, the virus, as ever, appears without constraint and several steps ahead as we scramble to keep up.
River Blindness, also known as Onchocerciasis is a parasitic infection caused by the filarial worm Onchocerca volvulus, the immature microfilariae of which are spread between humans by female flies in the family Simuliidae, as they bite to take a blood meal.
Once deposited in a human host, the microfilariae form nodules in subcutaneous tissue where they mature and sexually reproduce. A fertilised Onchocerca volvulus female may produce up to a thousand larval worms daily which give rise to the numerous rashes, lesions and other disfiguring skin conditions such as 'Leopard skin' (shown above) as they mature and die.
River Blindness affects 17-25 million yearly and is classified as one of seventeen neglected tropical diseases, by the World Health Organisation and is characterised by disfiguring skin conditions such as those shown above, visual impairment which often progresses leaving those infected permanently blind, shown above being guided by children.
A curious and little understood complication of Onchocerciasis is Nodding Disease, which manifests in children as partial or completely stunted growth which extends to the brain leading to severe handicapping. Perhaps the most bizarre symptom of Nodding Disease is the occurrence of non-responsive nodding seizures which manifests when afflicted individuals are presented with food that is unfamiliar to them.
Bacteria of the genus Wolbachia are known to infect a plethora of insect species as well as some nematodes and in the case of Onchocerciasis, is known to play an important but highly complex role in the symptoms observed in patients with River Blindness and Wolbachia remain a target for chemotherapeutics such as doxycycline which appears to weaken the worms.
Diagnosing River Blindness is possible through a number of avenues such as taking subcutaneous tissue biopsies which are placed in saline, and monitored closely for the emergence of larval worms. Nodules may also be dissected to detect the presence of adult worms, which may also be present in the eye.
River Blindness is endemic to central Africa and South America and as there is no vaccine, prevention relies on avoiding the bite of Simulium spp. by wearing repellants and treating the fast flowing rivers and streams in which they breed.
A new disease has arrived in the US following its gradual spread across the western hemisphere. Although not new to science, the Chikungunya Virus (CHIKV), discovered in Tanzania in 1955 was previously confined to sub-saharan Africa, Asia and in small footholds in southern Europe. The Chikungunya virus is a relatively small (60-70nm) arthropod-borne group IV ((+)ssRNA) virus, belonging to the family Togaviridae and the genus Alphavirus.
CHIKV attacks primarily the joints and causes debilitating nausea, swelling, joint and muscle pain, rashes and headaches and it is these symptoms that have earned the virus its unusual name, which translates literally as 'to bend up'-- a reference to the pained posture of people whom are infected. The stiffness, inflammation and pain associated with Chikungunya infection may persist for several months after the other symptoms have relented, although a single infection generally confers lifelong immunity.
Two viral glycoprotein heterodimers known as E1 (shown red) and E2 (yellow) enable the virus to invade susceptible host cells and are the main antigenic determinants, arranged as a beautiful piece of functional architecture in the icosahedral shell of 80 'spikes', encapsulating the virion. The CHIKV E1 glycoprotein is responsible for membrane fusion whereas E2 binds to surface receptors on target cells, following the successful binding of these glycoproteins the virus enters the hosts cell wherein it undergoes an acid triggered conformational change.
It was previously thought that Chikungunya had only one vector, the mosquito Aedes aegypti which is also the vector for Dengue and Yellow Fever among other diseases and prefers a warm tropical climate. However, it has recently been discovered that the Tiger mosquito (Aedes albopictus) which tolerates cooler climes is also capable of spreading the disease, expanding the distributional range to now include central america and Europe and making it possible for local infection to occur in new countries where Chikungunya had previously never been seen.
There is no vaccine or cure for Chikungunya and treatment is limited to analgesics such as naproxen or paracetamol for the symptoms. Of course, prevention is better than treatment so avoiding mosquitos by wearing insect repellant (including during the day as the Tiger mosquito feeds during the daylight hours) and reducing habitat wherein mosquitos can breed by draining standing water and treating other such bodies appropriately.
