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Staphylococcus auerus is facultative anaerobic gram positive bacteria which are mainly found in respiratory tract, intestinal tract and in the skin as the microflora (Bachert et al, 2002). S. auerus produce staphylococcal toxins which include enterotoxins and pyrogenic toxins such as toxic shock syndrome toxin 1. There are many type of enterotoxins such as staphylococcal enterotoxins A (SEA), SEB, SEC1, SEC2, SEC3, SED, SEE, SEG, SHE, SEI and SEJ. Many human diseases are caused by staphylococcal superantigens/enterotoxins such as inflammatory bowel diseases, staphylococcal food poisoning, infant cot death and respiratory disease such as chronic rhinosinusitis which will be discussed later. The general mechanism of staphylococcal superantigens involved the interaction of superantigens with MHC class II molecules on antigen presenting cells and Vβ T cell receptors which will leads to the non-specific activation and proliferation of T cells. Cytokines are then released and more immune cells such as macrophages are activated and eventually cause damaged to the cells/tissues occurs. The effects of destruction can be ranged from mild to severe. Staphylococcal food poisoning can be a mild condition with self remission whereas sudden infant death syndrome caused by staphylococcal enterotoxins (SE) can be fatal. Therefore, proper treatments or treatment strategies are required to combat these unwanted effects by staphylococcal enterotoxins caused to the body. These treatment strategies which will be discussed later include action of inhibitor molecules, inhibiting transcription/translation of superantigen genes, antibodies against staphylococcus auerus or its superantigens, using the superantigens derived peptides that interfere with immune cell signaling and production of anti-superantigens antibody, block co-stimulatory signals, receptor-based inhibitor to compete with superantigens and use of anti-inflammatory cytokine IL-10 (Hong-Geller and Gupta, 2003).
I would like to say thank you to lecturer JI Ross for his guidance on my dissertation topic. Moreover, I would like to thanks University of Bradford which provide us with information technology support such as Athen which allows us to find free and useful journals for our dissertation. Lastly, I would like to thanks MDIS for the communication support.
Title Page………………………………………………………………..Page 1
Abstract…………………………………………………………………..Page 2 to 3
Introduction………………………………………………………………Page 5 to 6
Staphylococcal food poisoning…………………………………………..Page 6 to 8
Inflammatory bowel diseases……………………………………………..Page 8 to 11
Respiratory diseases………………………………………………………Page 11 to 15
Infant cot death incidence…………………………………………………Page 15 to16
Therapeutic approaches to human diseases caused by staphylococcal enterotoxins………………………………………………………………...Page17 to 19
Conclusion…………………………………………………………………Page 19 to 20
References………………………………………………………………….Page 21 to 25
Staphylococcal enterotoxins (SE) are from a family of heat stable toxins which can cause many human diseases. Staphylococcal enterotoxins are mainly produced by S. auerus, is a human pathogen which its toxin produced are involved in diseases such as food poisoning, inflammatory bowel disease, infant cot death and respiratory diseases which will be discussed in this dissertation. S. auerus is facultative anaerobic gram positive bacteria which are mainly found in respiratory tract and in the skin as the microflora (Bachert et al, 2002). Staphylococcal infection will leads to all of the mentioned human diseases which can be either caused by the gastrointestinal enterotoxins or the toxins that act as a superantigen to cause non-specific T cells growth (Duong et al, 2002). Staphylococcal enterotoxins function as superantigens which bind to major histocompatability complex (MHC) class II molecules and result in non-specific T cell proliferation and cytokine release by the activated T cell population (Hong-Geller and Gupta, 2003). Cytokines released will leads to destruction of cells and tissues which resulted in acute diseases and eventually to chronic diseases if no treatment is given. Staphylococcal superantigens are a group of low molecular weight proteins that can activate up to 25% of all T cells (Lu et al, 2003) There are different types of staphylococcal enterotoxins such as SEA, SEB, SEC1, SEC2, SEC3, SED, SEE, SEG, SHE, SEI and SEJ. Moreover, SE also include streptococcal pyrogenic toxin such as toxic shock syndrome toxin (TSST) which are involved in toxic shock syndrome (Balaban and Rasooly, 2000). However, pyrogenic exotoxins will not be discussed further. SEA is one of the most common enterotoxins that caused staphylococcal food poisoning. Moreover, it has a structure of two protein domains and has zinc sites which is needed for MHC class II binding (Balaban and Rasooly, 2000). SEB is also one of the toxins that lead to staphylococcal food poisoning by S. aureus, is a powerful stimulator of T-cell activation. SEB can activate T cells population as it can binds directly to MHC class II molecules and the Vβ T-cell receptor (TCR) which leads to proliferation of CD4+ and CD8+ cells and results in immunological effects caused by the secretion of cytokines. SEC is classified into SEC1, SEC2 and SEC3 where all three SEC are slightly different in their nucleotide sequence. SED is similar to SEA where it requires zinc for the interaction with MHC class II (Balaban and Rasooly, 2000). The remaining of SE shall not be discussed further.
Staphylococcal food poisoning
Staphylococcal food poisoning is mainly caused by bacteria S.auerus which are the second most common food-borne diseases (Archer and Young, 1988; Balaban and Rasooly, 2000). The most common cause for the incidence of staphylococcal food poisoning is caused by SEs such as SEA and SEB which are produced by S. auerus. Beside SEA and SEB, SED is the second most common staphylococcal enterotoxins associated with food poisoning outbreak where small amount of SED present can cause food poisoning (Pinchuk et al, 2010). Moreover, a newly discovered staphylococcal-like protein SEH is detected to have association with food poisoning ( Argudín et al, 2010). In addition, there is one case in France where SEE that was found in cheese to be the cause of food poisoning outbreak (Ostyn et al, 2009) Thus, different enterotoxins produced by S. aureus can play a part in food poisoning incidences. However, SEA and SEB is still the major cause for staphylococcal food poisoning. SEB consists of 239 amino acid residues and has two tightly-packed domains that have a very compact tertiary structure which makes SEB to be highly resistant to proteases such as trypsin, chymotrypsin, and papain that are found in the lumen of intestine (Gleason and Huebner, 2009). Moreover, SEB is relatively stable and moderately resistant to temperature changes and acid so they may not be completely denatured by mild cooking (Pinchuk et al, 2010). Thus, SEs are highly resistant to denaturation which allow them to be intact in contaminated food which leads to food poisoning outbreaks (Pinchuk et al, 2010) Staphylococcus organisms usually survive and produce toxins in unrefrigerated foods such as meats, bakery and dairy products (Gleason and Huebner, 2009). Example of foods that are commonly contaminated with SEs are meat and meat products; poultry and egg products; potato salad and sandwich fillings; bakery products such as cream-filled puff; milk and dairy products (Normanno et al, 2006). Thus, foods that normally required handling are at high risk for contamination with SEs. Moreover, S. aureus also multiply well in cooked foods that are rich in protein, low in acid, sugar or salt, and also food with slightly wet fillings (Hocking et al, 2001).The high incidence rate for staphylococcal food poisoning is mainly due to the inadequate heat treatment/decontamination of originally contaminated product source or individuals who are carriers of the organism transfer the contaminants to the food during preparation and handling (Scherrer et al, 2004). In order to cause staphylococcal food poisoning, toxin level of less than 1.0 μg is required (Bremer et al, 2004). The normal symptoms for staphylococcal food poisoning are diarrhea, vomiting, abdominal pain and nausea which have a fast onset starting from less than an hour and have spontaneous recovery after 1 day (Yves et al, 2003). In some cases, more severe symptoms such as headache and; blood pressure and pulse rate changes can be seen in affected individuals where the degree of severity depend mainly on the amount of contaminated food ingested and the general health of individuals. Normally, staphylococcal food poisonings do not results in death but elderly are more prone to enterotoxins- induced gastroenteritis than younger individuals. However, food poisoning may leads to death when rare complication occurs (Balaban and Rasooly, 2000). Based on the World Health Organization (WHO), many deaths in the world are due to staphylococcal enterotoxins-related food poisoning associated with diarrhoea. Large amount of medical costs were needed per year to treat the food poisoning outbreak (Pinchuk et al, 2010). SEs are usually in the form of superantigens which cause many non-specific T cell activation and proliferation. Superantigens will recognize specific T cell receptor (TCR) Vβ which will cross interact with MHC class II on the antigen presenting cells. Thus, activation and proliferation of T cells occurs (Kappler et al, 1994). Activation of T cells will leads to large amount of interleukins (IL) secreted out and resulted in the intestinal epithelium and the nervous system being affected which cause the food poisoning symptoms (Yves et al, 2003). However, the mechanism mode of SEs entering the body to the intestine which will leads to food poisoning is not well known (Balaban and Rasooly, 2000). There are some studies stating that SEB are capable of transcytose via the epithelial cells and cause immunological effect when it enter the bloodstream to interact with the activated T cell population (Hamad et al, 1997). SEA and SEB are the two most common staphylococcal enterotoxins which involved in food poisoning, hence by finding the mode of mechanism of these enterotoxins can reduce the pathophysiological impact by these toxins to our body. In a study, it is found out that glycosphingolipid (GSL) receptor which is made up of sugar, sphingosine and fatty acids is the receptor for SEB and is found in human kidney (Subroto et al, 1995). Human kidney proximal tubule cells have many specific binding sites for SEB but not for SEA (Subroto et al, 1995). Human are prone to SEB as our kidney consist of GSL receptor for SEB. However, in some studies, rat kidney do not have GSL receptor so rat are not as susceptible as human to SEB when expose with this toxins (Subrto et al, 1995). Moreover, it is specific that SEB will only bind to the GSL receptor on the human kidney but not other part of the body which also have GSL receoptors (Subroto et al, 1995). In the same study, there is a maximum binding of SEB with GSL receptors before further binding are inhibited. It can be due to that many layers formed by GSL receptors which prevent receptor binding further (Subroto et al, 1995). With the high affinity binding sites for SEB in the human kidney, many of SEB will accumulate in the kidney which will resulted in the damage of kidney by SEB toxicity and eventually SEB will infiltrate to other part of the body via the bloodstream. Therefore, normal staphylococcal food poisoning may leads to complications which may be fatal to the individuals.
Inflammatory bowel diseases
Inflammatory bowel disease (IBD) is a chronic inflammation disease of gastrointestinal tract which involved both ulcerative colitis (UC) and Crohn's disease (CD) (Liu et al, 2009). The peak incidence of IBD is at 15 to 30 years old (Abraham and Cho, 2009) and both CD and UC seem to occur more in countries like Europe, North America and United Kingdom. The cause of IBD is not known but it seems to be related to the malfunction of T cell apoptosis and intestinal epithelial cells which leads to the inability to provide barriers (Tsianos and Katsanos, 2009). Moreover, it seems that macrophages are also involved in IBD where activated macrophage increased its secretion of cytokines such as TNF-α, IL-1 and IL-6 (Tsianos and Katsanos, 2009). In addition, IBD also involved the action caused by the presence of chemokine which can leads to many inflammatory effects such as induction of chemo-attraction and activation of white blood cells such as the CD4+ T cells (Tsianos and Katsanos, 2009). Thus, the intestinal wall will be damage due to the inflammation reactions caused by cytokines and chemokines which leads to abdominal pain and diarrhoea with blood. IBD results in large accumulation of neutrophils in the intestinal area and the balance of the normal microflora are affected (Tsianos and Katsanos, 2009). In some studies, the results showed that IBD can be found in genetically prone individuals with abnormal inflammatory activities to intestinal microorganisms (Abraham and Cho, 2009). For example, nucleotide oligomerization domain 2 (NOD 2) and helper T-cell (Th17) pathway are involved in the inflammatory responses in susceptible individuals (Cho and weaver, 2007; Barrett et al, 2008). The NOD 2 proteins look out for bacterial murein and are autophagy genes that regulate and degrade cellular components. Example of an autophagy gene is ATG16L1 which is involved in CD (Abraham and Cho, 2009).The Th17 pathway where many genes regulate is associated with both CD and UC which involve in prevention of intestinal inflammation and microbial invasion (Abraham and Cho, 2009). Beside genetic factors, other factors such as smoking, change in diet and usage of antibiotics can also increase the risk of IBD (Eckburg and Relman, 2007). IBD can results in many different symptoms depending on the location of the intestinal tract involved. Beside bloody diarrhoea and abdominal pain, fever, weight loss, loss of appetite and anaemia can be seen in affected individuals. In IBD, there are some differences between UC and CD. CD is a chronic in inflammation of gastrointestinal tract with granulomatous characteristics (Lakatos et al, 2006). UC is also a chronic disease but it involved the growth of inflammatory lesion which affects the colon and rectum (Shiobara et al, 2007; Abraham and Cho, 2009). In a population-based study in Denmark, the results showed that there is a significant increase in the trend of IBD patients suffering from CD than UC, median age seems to increase at diagnosis of UC, but time of onset of symptoms to diagnosis of CD seem to decrease (Jess et al, 2007). Intestinal mucosa of UC individual has the sign of infiltration of activated cells such as T cells, macrophages or monocytes. Moreover, SEs produced by S. auerus which is a superantigens seems to play a part in UC where bind to α-chain of the MHC class II and Vβ of TCR that results in the activation of T cells which leads to secretion of cytokines that allows recruitment of cells such as monocytes or macrophages and granulocyte, hence the intestinal mucosal tissues will be damage (Shiobara et al, 2007). Moreover, there are studies showing that SEs are superantigens which will have an impact on gut structures and functions where animal models such as mice were used in the experiment to received intraperitoneal injection of SEB which resulted in an increase of T cell population but there was a decrease in epithelial cells responsiveness to pro-secretory stimuli (Lu et al, 2003). A study showed that SEs such as SEB which come from rhinosinusitis may be involved in the pathogenesis of UC (Yang et al, 2005). Moreover, it showed that an immune response change toward the normal microflora may be involved which leads to its pathology (Yang et al, 2005). In the same study, it showed that chronic rhinosinusitis (CRS) which is normally caused by bacterial infection and its products such as SEB may associate with UC as SEB from CRS can be released into the nasal cavity and swallowed which then goes into gastrointestinal tract where SEB interact with intestinal mucosa to affect its function (Yang et al, 2005). S. auerus which is normally present in the nasal cavity and sinus can produce SEB that may leads to the normal microflora being disturbed and eventually may linked with UC which had mentioned earlier on (Yang et al, 2005). Moreover, the same study showed that there is a degranulation of mast cells in individual with both CRS and UC resulting in an increase in the released of histamine and tryptase; and there is an increased in serum SEB specific immunoglobulin E antibody which seems to play a role in the inflammation in UC (Yang et al, 2005). However, it does not proved that all CRS individual which caused by staphylococcus enterotoxins will have UC (Yang et al, 2005). In other study, it showed that the presence of SEB increase the permeability of the intestinal epithelium which results in efficient uptake of potent antigens which trigger the immune cells to secrete out the cytokines such as IL-4, IL-13 and IL-5 which intensify antigen-specific immune responses against the intestinal epithelium (Chen and Yang, 2009). In addition, SEB seem to cause maturation of dendritic cells which can help in the antigen presentation by antigen presenting cells (APCs) (Chen and Yang, 2009). Beside SEs, the involvement of IL-21 and its receptor may also cause IBD. In CD, there is an increased in Th1 type cytokines secretion such as TNF and IFN-γ. In UC, there is an increased in Th2 type secretion instead such as IL-13 and IL-5 (Liu et al, 2009). CD4+ T cells expressed cytokine IL-21 where they may be involved in the differentiation of Th17 cells whereas IL-21 receptors can be found in natural killer cells, dendritic cells, B cells and T cells (Liu et al, 2009). In IBD, the inflamed mucosa has increased amount of IL-21 receptors which are responsible for T cell proliferation and cytokine secretions when IL-21 interact with it. IL-21 and its receptor is said to be one of the causes in IBD as blockage of IL-21 receptors results in the improvement of the condition (Liu et al, 2009). In conclusion, the etiology of inflammatory bowel disease is little known. Most of the investigations done did not prove the real cause for the disease so further research is still required. SEB which is involved in respiratory diseases and food poisoning also do play a role in IBD as it has the same pathology where it leads to mucosal T cells activation and its cytokines are released to cause damage to the tissues involved (Spiekerman and Anderson, 2010).
S. auerus is normally found as normal microflora in the intestinal tract as well as upper respiratory tract (Bachert et al, 2002). Thus, when there is a trigger from internal or external stimuli, homeostasis of normal S. aureus in the respiratory tract will be affected and become harmful which causes respiratory diseases. As the respiratory tract is the most common site for S. aureus colonization, and more than 50% of these harmful S. aureus produce SEs, it is therefore common for the nasal passage to be infected with staphylococcal superantigens (O'Brien et al, 2006). S. aureus may carry numerous of enterotoxins genes such as SEA and SEB. SEB is the major cause for staphylococcal related respiratory diseases. SEB can be used as biological toxin weapon since many years ago as low dose of inhalation of SEB can results in large impact to the body. However, SEB is not likely to cause mortality as a biological weapon; it may only results in most exposed individual to become ill for 1 to 2 weeks (Relman and Olson, 2006). Besides serving as biological toxin weapon, it may also harm healthcare staffs as they may be potentially expose to SEB due to their job nature. For example, there is an increase in laboratory research on SEB so the amounts of exposure to this agent for laboratory personnel tend to increase (Rusnak et al, 2004). Normally, individuals with respiratory diseases have symptom signs shown from 3 to 12 hours. Respiratory disease caused by low dose of SEB may result in symptoms such as fever, non-productive cough, chest pain and shortness of breath (Rusnak et al, 2004). The symptoms may worsen to elevated respiratory distress and failure; and pulmonary edema. When the respiratory tract is exposed to high-dose of SEB, symptoms such as hypotension, shock, many organs failure, and death may occurs (Relman and Olson, 2006). SEB in the respiratory tract may affect gastrointestinal tract as the toxin can be swallowed during muco-ciliary clearance (Relman and Olson, 2006). Thus, gastrointestinal symptoms such as vomiting and diarrhoea can be seen in affected individuals too. The pathology of respiratory disease is mainly due to SEs activating the pro-inflammatory cytokine pathways in the lungs which resulted in pulmonary edema, pulmonary capillary leak and other symptoms as mentioned earlier on. There are many studies showing the relationship between the exposures of SEB and the severity of the respiratory diseases. In one of the studies, SEB exposure is given to non-human model and the results showed that SEB can trigger fatal acute respiratory distress syndrome (ARDS) (Liu et al, 2009). As for humans model, CA-MRSA or HA-MRSA can produces SEs to cause necrotizing pneumonia which can increase the risk of ARDS too (Liu et al, 2009). The effects of CA-MRSA or HA-MRSA and how to prevent their activity shall not discuss further (For more information about the study, refer to Journal on Suppression of Acute Lung Inflammation by Intracellular Peptide Delivery of a Nuclear Import Inhibitor). Example for respiratory diseases caused by S. aureus can be staphylococcal pneumonia and Wegener's granulomatosis. Staphylococcal pneumonia is mainly occur in young children, infant and weak patients. It is a rapidly progressive condition where mortality can be 50%. Wegener's granulomatosis is granulomatous inflammation of the respiratory tract (Popa et al, 2007). Both respiratory conditions mentioned may not caused by SEs but they have association with S. aureus superantigens activities. Other toxins produced by S. aureus shall not be discussed further as the main focus is on SEs. In the same study mentioned in inflammatory bowel disease section, SEB which is produced by S. auerus is involved in chronic rhinosinusitis, a respiratory disease. The pathology of staphylococcal superantigens involved T cell proliferation which results in the release of pro-inflammatory cytokines, T cell apoptosis or T cell anergy (Bachert et al, 2002). In order for T cell to be activated and proliferate in the presence of superantigens, it also required the presence of co-stimulators such as CD28. Without co-stimulators, T cells will not proliferate (Bachert et al, 2002). Therefore, there is likely that staphylococcal superantigens have association with respiratory disease such as asthma and chronic rhinosinusitis. In a study, specific immunoglobulin E to SEA and SEB was detected in the inflamed nasal tissues and there is a high level of eosinophils present too (Bachert et al, 2002). After knowing the effect of superantigens to the immune responses, we shall look into the role of staphylococcal enterotoxins in the pathogenesis of respiratory diseases such as asthma. Staphylococcal enterotoxins is a potent superantigens because they bypass the normal antigen recognition pathway by interaction with MHC class II molecules on the surface of antigen presenting cells which will cross link Vβ T cells and activate the T cells (Argudín et al, 2010). Lung epithelium serve as a barrier between the internal and the external. Asthma tends to be due to damage of epithelial cells and airway hyper-responsiveness (Brien et al, 2006). It is common that nasal cavity is filled with bacterial superantigens as it is the common site where S. aureus can be found. Moreover, secreted cytokine IFN-γ will leads to the enhanced expression of MHC class II on the bronchial epithelial cells in respiratory disease such as asthma where the bronchial epithelial cells can play a role as antigen presenting cells to interact with T cells (Brien et al, 2006). Cytokines such as IL-8 play an inflammatory role in the lung as they function as chemo-attractant to recruit eosinophils and neutrophils (Brien et al, 2006). Asthmatic pathogenesis is possible due to the attraction of neutrophils into the inflamed airway which is induced by SEA and SEB. Based on the Brien et al studies, we know that asthma has unknown etiology and SEs may play an important role in pathogenesis of asthma; hence we may link chronic rhinosinusitis with asthma since SEB may be the possible cause for CRS. There are many evidences stating that the pathogenesis of asthma is contributed by CD4+ T helper 2 (Th2) cells as there are high level of IL-4 and IL-13 detected which are necessary for immunoglobulin E production to result in asthma (Liu et al, 2006). There is a possible link between asthma and CRS because individual with both CRS and asthma have rather high level of SEA and SEB detected in their nasal secretion where SEB can cause effects such as increase the permeability of airway epithelial barrier which then allows the antigens to cross the epithelium to interact with the immune cells (Liu et al, 2006). Interaction between antigens and the immune cells will leads to T cell activation and proliferation which caused cytokines such as IL-13, IL-4 and IL-5 to be secreted out and results in unwanted effects (Okano et al, 2005). These unwanted effects can be seen in CRS and asthma. Thus, the asthmatic condition improved after individuals with both CRS and asthma undergo treatment as the immunoglobulin E level and eosinophils activity have gradually decrease due to the absence of cytokines release (Liu et al, 2006; O'Byrne et al, 2001). SE plays an important role in asthma where it secretes cytokine such as IL-4 and Il-5. Therefore, without SEB stimuli, Th 2 is unable to release cytokines so the absence of SEB can actually improve the condition of asthma (Dejima et al, 2005). In many cases, individuals that undergo treatment result in better conditions of their illness but there are cases where the individuals with CRS and asthma undergo treatment, their asthmatic condition did not improve even though they actually felt better (Uri et al, 2002).
Infant cot death incidence
Infant cot death is also known as sudden infant cot death syndrome (SIDS) which characterized by sudden death of infant with unexplained etiology. SIDS is the major cause of death in infants aged between 1 month and 1 year old in most industrialized areas but it may vary in different countries. (Courts and Madea, 2010; Mitchell, 1997). There are many researches on SIDS and many conclude that it can be caused by multifactorial factors (Goldwater, 2003). The incidence rate for SIDS is rather high as it accounts for one third of all infant death populations per year. Normally, the peak incidence is from 2 to 4 months of age for healthy full-term infants (Courts and Madea, 2010). Normally, maturation of autonomic control for respiratory and cardiovascular systems require at least 6 months so within this period, it is where most of the SIDS death occurs as these systems are still immature (Horne et al, 2010). Moreover, more than 90% of incidences of SIDS seem to occur in these infants especially when they reach 6 to 8 months. United States seem to have the highest rate of SIDS occurrence (Ottaviani, 2010; Willinger et al, 1998). There are many studies showing that SIDS is mainly due to three main reasons such as unusual temperature control, unusual sleep control and unusual cardio-respiratory control. Infants with abnormal sleep control tend to have less response to sleep associated hypoxia while infants with irregular temperature control such as elevated body temperature can be associated with abnormal autonomic nervous systems and abnormal cardio-respiratory control. Infants with abnormal cardiorespiratory regulation tend to have a decrease in chemoreceptor sensitivity to less surrounding gases such as oxygen and carbon dioxide. All of the above may results in extended bradycardia in infants which then eventually leads to SIDS. In addition, there are preventable risk factors such as exposure to tobacco smoke (Blair et al, 1996), the position of sleep for infant (Kemp et al, 2000) and whether the infants have been breastfeed (Gordon et al, 1999; McVea et al, 2000) which can contribute to the incidences of SIDS. New Zealand population studies showed that these preventable risk factors account for about 79% of SIDS death (Mitchell, 2009). Thus, reducing these preventable risk factors can reduce the chance of SIDS in infants. There are some unpreventable risk factors such as mother's age and maternal age,
n the age of the mother at the period of conception. , angestational age which can also leads to SIDS (Leach et al, 1999). Based on the SIDS mortality data, it showed that higher risk is observed in male infants, low birth weight or pre-mature babies and those infants come from communities such as Maori (Mitchell, 2009). In addition, mortality is more often in area with higher latitudes and during winter (Mitchell, 2009).There are studies showing that SIDS may be derived from minor respiratory infection which was complicated to become SIDS in infants (Mitchell, 2009). Respiratory infection caused by especially toxins from S. aureus will induce proinflammatory cytokines which resulted in abnormal respiratory and cardiac function, fever, shock and sensitivity defects (Blackwell et al, 1994). Infants with wrong sleeping position tend to increase in small collection of nasal secretions which may leads to increased bacterial colonization (Harrison et al, 1999). Normally, liable position may increase the temperature in the nasopharynx where the temperature (between 37°C and 40°C) allows the colonized S. aureus to produce its toxins (Blackwell and Weir, 1999; Molony et al, 1999). Thus, there is a close relationship between staphylococcal related respiratory infection and SIDS as infants do not have mature immune response against pathogens (Quan et al, 2000). In SIDS, there is an increased in the mast cell numbers in the lung tissues where the degranulation of mast cells increases which results in the released of typtase. Degraulation of mast cells can be possible due to a bacterial infection which then leads to the increased regulation of mast cells MHC class II antigens (Goldwater, 2003). There are many studies which link bacterial toxins to SIDS where staphylococcal enterotoxins are one of them (Siarakas et al, 1995). In Siarakas et al studies, all the high level of bacterial toxins including staphylococcal enterotoxins can caused effects such as decreased in breathing rate, pulse rate, blood pressure or even death. SIDS seems to happen during the period when maternal antibodies start to decline and the infants have to rely on their immature immune system (Saadi et al, 1993). Infants that died from sudden infant death syndrome have history of upper respiratory tract infection (Saadi et al, 1993). S. auerus which produce superantigens such as toxic shock syndrome toxin 1 (TSST-1) may be involved in the infant cot death as S. auerus is found in respiratory tract whose superantigens can react with the immune cells to cause adverse effects such as respiratory shock and cardiac shock (Saadi et al, 1993). Bacterial infection may leads to inflammatory responses which can results in the sudden death of the infants. Many of the proinflammatory cytokines such as TNFα are secreted which will leads to many unwanted effects such as vascular shock and irregular beating of heart (Moscovis et al, 2004) Moreover, SIDS infants have IL-10 polymorphism detected. IL-10 is an anti-inflammatory cytokines which can prevent the activity caused by proflammatory cytokines (Moscovis et al, 2004). In addition, smoking tends to be one of the high risk factors for SIDS (Saadi et al, 1993; Crawford, 2010). IL-10 which play an important role in controlling the proinflammatory cytokine activities that is stimulated by staphylococcal toxins seems to decrease in individual that smoke (Moscovis et al, 2004). In SIDS, there are evidences that staphylococcal infection which produced enterotoxins is one of the risk factor. Staphylococcal infection is not the only possible cause. As the infants have immature immune system, further reduction of anti-inflammatory cytokine IL-10 production will leads to infant's immune system is unable to cope with the toxins attack. Thus, the infants will soon die due to the adverse effects on its cardiac and respiratory systems.
Therapeutic approaches to human diseases caused by staphylococcal enterotoxins
As mentioned earlier on, there are indeed many human diseases caused by staphylococcal enterotoxins or superantigens which may result in adverse conditions or even death. The treatments such as antibiotic, blood transfusion and fluid administration are given to individuals with staphylococcal superantigens derived human disease. Antibiotic treatment is the most common in clinical practice, hence as a result, the development of antibiotic resistant strain of S. auerus occurs where the bacteria mainly resistant to methicillin (Kreiswirth et al, 1993). Many of the researchers know that staphylococcal superantigens can leads to a cascade of pathogenesis where the superantigens bind to the MHC class II molecule on the antigen presenting cells which leads to T cell activation and proliferation. T cell activation and proliferation will eventually leads to the released of cytokines which will have adverse effects to the human tissues. Based on this series of events mentioned, it is important to have therapeutic approach designed to prevent the staphylococcal superantigens to activate the T cells and the secretion of the cytokine occur to cause inflammatory effects. Thus, Hong-Geller and Gupta studies come out with possible approaches to combat with the pathological effects of superantigens. These approaches are production of antibodies against S. auerus or its superantigens, using thesuperantigens derived peptides that interfere with immune cell signaling and production of anti-superantigens antibody, prevent superantigens genes from transcription or translation, block co-stimulatory signals, using of inhibitor molecules, receptor-based inhibitor to compete with superantigens and use of anti-inflammatory cytokine IL-10 (Hong-Geller and Gupta, 2003). Antibodies against S. auerus or its superantigens will prevent them from activating the immune system and leads to cytokines released. In Hong-Geller and Gupta studies, one example used by them is StaphVax vaccine which requires a short time to reach its protection immunity. It is suggested to be used in patients who may exposed to S. auerus infection during a surgery (Hong-Geller and Gupta, 2003). Moreover, peptides derived from superantigens can disturb the binding of superantigens to T cells receptors and MHC class II. At the same time, production of antibodies can remove those superantigens from the body (Hong-Geller and Gupta, 2003). However, not all the peptide derived from the superantigens is effective to disturb the interaction between the superantigens with T cell receptor and MHC class II molecules. RNA III activating protein (RAP), RNA III inhibiting protein (RIP) and TRAP protein play a role in the inhibition of transcription or translation of superantigens genes. High level of inhibition of RAP and activation of RIP will prevent production of superantigens by S. auerus (Hong-Geller and Gupta 2003). In addition, TRAP protein seems to be involved with RAP activation so upregulation of TRAP protein may increase the production of staphylococcal superantigens (Hong-Geller and Gupta, 2003). Thus, there are studies stating that antibodies against TRAP proteins can prevent superantigen production (Vieira-da-Motta et al, 2001). In order to compete with the secreted staphylococcal superantigens binding to the T cell receptor and MHC class II molecules, a protein is produced which can be used as an inhibitor against superantigens (Lehnert et al, 2001). T cell activation requires not only the superantigens but also the co-stimulator CD28. The presence of CD28 will interact with B7 co-stimulator on antigen presenting cells which is necessary for activation and proliferation of T cells so without CD28, T cell may not proliferate. IL-10 is an anti-inflammatory cytokine which is needed for the inhibition of superantigen activity which involve cytokine secretion. Thus without cytokines secretion, unwanted effects will not occurs. Lastly, inhibitor molecules such as drug niacinamide can be used to prevent cytokine production caused by staphylococcal superantigens (LeClaire et al, 1996).
In conclusion, Staphylococcus auerus produced staphylococcal toxins which can act in the form of enterotoxins, pyrogenic type such as toxic shock syndrome toxin 1 or superantigenic type. In this dissertation, the actions of staphylococcal enterotoxins or superantigens caused in human diseases are discussed. There are many type of human diseases are caused by staphylococcal toxins but human diseases such as food poisoning, inflammatory bowel disease, respiratory disease and infant cot death are being discussed in this dissertation. Other human diseases such as methicillin- resistant strain of S. auerus causing many hospital prone diseases are not covered as they are mainly not caused by staphylococcal enterotoxins but other type of staphylococcal toxins. Regardless of whether staphylococcal toxins are in enterotoxins itself or it act as superantigens, the general mechanism of actions are similar in all diseases. The general mechanism of actions involved the activation of T cells by the toxins which leads to clonal T cell proliferation and resulted in cytokines being released to attract more immune cells such as mast cells and macrophages to cause destruction of the tissues in the body. Moreover, one area of the body affected may involve other area too. For example, staphylococcal enterotoxins involve in chronic rhinosinusitis is believed that it can also leads to inflammatory bowel disease when the staphylococcal enterotoxins are swallowed down to the intestinal area. Staphylococcal enterotoxins can interact with the immune cells by increasing the epithelial cell barrier permeability where it may cause effects from mild to adverse such as from just a diarrhea in simple food poisoning to even death in infant cot death. Therefore, infected with staphylococcus auerus cannot be taken lightly so proper treatment or treatment strategies must be planned. Based on the Hong-Geller and Gupta (2003), there are seven strategies to combat with the action of staphylococcal superantigens. However, it required further experimental investigation to see if these strategies are really effective. Lastly, beside the treatment strategies, it is necessary to have further investigation for the real causes of the human diseases mentioned as the researchers are only able to links staphylococcal infection with these human diseases but the actual mechanism of action of how the staphylococcal superantigens function is not well known in most diseases.