Over the past week, international news stories have concentrated on the devastating cyclone in Burma (Myanmar), and the almost certain consequence of disease outbreaks in the aftermath. But at the same time, there’s another microbiology story unfolding in East Asia. Beginning in March, a large outbreak of hand, foot and mouth disease (HFMD) was reported from Fuyang city in Anhui Province in China. Note that HFMD is a human disease caused by enteroviruses belonging to the picornavirus family, but is not the same as the animal disease foot and mouth (FMD) caused by a different kind of picornavirus.
HFMD usually affects infants and children, is quite common worldwide and can be caused by a number of different enteroviruses. It is highly contagious and is spread through direct contact with the mucus, saliva, or faeces of an infected person. Like other enterovirus infections (including polio), HFMD typically occurs in small epidemics, usually during the summer and autumn months with an incubation period of 3-7 days.
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Enterovirus infections are common and occur worldwide. Although many infections show no symptoms and often go unnoticed, these viruses are also associated with occasional outbreaks in which a larger than usual number of patients develop clinical disease, sometimes with fatal consequences. The current outbreak is one of these. Initial testing for a variety of respiratory diseases did not reveal any conclusive results, but on April 23, the presence of Enterovirus (EV71) was confirmed. As of May 8th, at least 30 deaths had been reported and the disease had spread to 11 cities and several provinces across China. In all the fatal cases, which represent less than 1% of the thousands of children infected, the victims died with serious complications such as neurogenic pulmonary oedema (breathing difficulties reminiscent to those seen in polio victims).
Enterovirus replication begins in the gastrointestinal or respiratory tract but once the virus is present in the bloodstream may affect various tissues and organs, causing a variety of diseases. Clinically, it is difficult to distinguish the specific cause of most enterovirus infections. Diagnostic testing for non-polio enteroviruses requires specialized laboratory facilities. Diagnosis is made by detecting virus in the throat, in faecal samples or, more convincingly, from specimens collected from the affected part of the body, for example, cerebrospinal fluid (CSF) or biopsy material. A four-fold rise in the level of neutralizing antibody in specimens collected during the acute and convalescent phases of illness provides the best evidence for a recent infection. No specific antiviral agents are currently available for treatment of enterovirus infections, although intravenous administration of immune globulin may have a use in preventing severe disease in immunocompromised individuals or those with life-threatening disease.
EV71 was first isolated in an outbreak of neurological disease in California in 1969. One of the nastier enteroviruses, EV71 has been associated with several epidemics of severe neurological disease in children, mostly in East Asia. An outbreak in Taiwan in 1998 resulted in 129,106 reported cases, 405 children hospitalized and more than 80 deaths. EV71 appears to be emerging as an important virulent neurotropic enterovirus just as poliomyelitis is nearing eradication, but little is known about the molecular mechanisms of host response to EV71 infection.
Transmission of enterovirus infections is increased by poor hygiene and overcrowded living conditions. Improved sanitation and general hygiene are important preventive measures. Measures that can be taken to avoid getting infected with enteroviruses include frequent handwashing, especially after nappy (diaper) changes or going to the toilet, disinfection of contaminated surfaces with bleach, and washing soiled articles of clothing. Enteroviruses are quite resistant to many disinfectants so it is important to use chlorinated (bleach) or iodized disinfectants. During recognised epidemics, it may be advised to close institutions such as schools or child care facilities in order to reduce transmission among young children. Chinese public health experts currently predict that the number of cases will continue to increase and peak around June-July.
Humans are hosts to nearly 300 species of parasitic worms and over 70 species of protozoa, some derived from our primate ancestors and some acquired from the animals we have domesticated or come into contact with during our history (History of human parasitology. Clin Microbiol Rev 2002 15: 595-612). The best-documented parasitic disease known from ancient times is caused by the nematode worm Dracunculus medinensis. The earliest description is from an Egyptian papyrus from 1500 BC that refers to both the nature of the infection and to techniques for removing the worm. Confirmation of the presence of this worm in ancient Egypt comes from the finding of a well-preserved worms in Egyptian mummies. Dracunculiasis, or Guinea worm disease, is one of the few diseases unambiguously described in the Bible, and most parasitologists accept that the “fiery serpents” that struck down the Israelites in the region of the Red Sea after the Exodus from Egypt somewhere between 1250 to 1200 BC were actually Guinea worms.
The adult worms live in the subcutaneous connective tissues of their victims, from which the females emerge to release thousands of larvae into water, where they are taken up by intermediate hosts, tiny aquatic crustaceans called Cyclops. In these hosts they mature into infectious larvae that infect humans when the crustaceans are accidentally swallowed in contaminated drinking water. On maturity, the large female worm, up to nearly a metre in length, protrudes from the skin, usually of the leg, and causes intense inflammation and irritation. The effects of the disease are crippling. Its victims develop large ulcers, usually in the lower leg. The ulcers swell, sometimes to the size of a tennis ball, and burst, releasing the spaghetti-like parasitic worm. Victims experience a pain so excruciating that they say it feels as if their leg is on fire. The searing pain compels people to jump into water, often the community’s only source of drinking water, to relieve the pain. When the infected person immerses his or her leg in the water, the worm in the leg releases thousands of larvae. The larvae are then ingested by Cyclops that live in the water. Thus the cycle begins again - when people drink the water, they are in effect drinking in the disease.
The most common way to treat Guinea worm disease involves wrapping the worm around a stick. This treatment has been employed for millennia and may have inspired the Rod of Asclepius which historically has symbolized the medical profession. As the adult worm begins to emerge from the patient’s skin, it is wound around a stick, then further extracted by a few centimeters per day. This slow process can take days or even weeks, but it is required to avoid breakage and leaving behind a portion of the worm. Leaving a portion of the dead worm remain within the host’s body increases the risk of infection, and can trigger immune responses resulting in pain and swelling. In many countries, a broken worm is immediately removed surgically, or the worm can be excised surgically from the very beginning if health care facilities are available. Antihelminthic drugs such as metronidazole or thiabendazole are sometimes used in conjunction with physical extraction. However, one study found that antihelminthic therapy was associated with aberrant migration of worms, resulting in infection in areas other than the lower extremity.
Dracunculiasis is a classic example of a neglected tropical disease, a symptom of poverty and disadvantage. Those most affected are the poorest populations often living in remote, rural areas, urban slums or in conflict zones. With little political voice, neglected tropical diseases have a low profile and status in public health priorities. In 1997 the World Health Assembly pledged to completely eradicate Guinea worm disease. This is no small task, but there are several factors which make eradication a possibility. Dracunculiasis is the first parasitic disease targeted for eradication because:
Diagnosis is easy and unambiguous (presence of an emerging adult worm).
The transmission agent, Cyclops, is not a mobile vector as is a mosquito.
The incubation period in both Cyclops and humans is of limited duration.
Interventions are effective, low cost, and relatively simple to implement.
The disease has a limited geographic distribution and is seasonal in nature.
Success in eliminating the disease has been demonstrated in several countries in Asia and the Middle East.
There is no known animal reservoir.
Is Dracunculiasis eradication close? In 2007 the WHO announced that Guinea worm disease now affects around 25,000 people in nine countries, compared with an estimated 3 million people were infected in over 20 countries in the early 1980s. Twelve countries were declared Guinea worm-free in early March. If progress continues at this rate, the disease could be eradicated in less than two years. It is probable that complete eradication will take quite a few years yet, although it should be possible to eliminate the disease from seven countries in a couple of years, leaving only two endemic countries, Sudan and Ghana (Dracunculiasis eradication by 2009: will endemic countries meet the target? Tropical Medicine & International Health 2007 12: 1403-1408). One lesson to be drawn from the problems of local ownership and the experience of cash rewards is that there are dangers in throwing money at the problem. While the eradication initiative badly needs additional resources, it needs them at such a level and managed in such a way that they do not distort the priorities of the health care system, or exceed the capacity of local staff to manage them. The amounts needed are not large, but their continuity and flexibility is important. Given the highly seasonal transmission of dracunculiasis, the resources must be available at very specific times of the year, which is not always achieved. In spite of the difficulties, complete worldwide eradication of this ancient disease is drawing nearer.
Magnetic or “magnetotactic” bacteria were first discovered in the 1960s, and naturally organize themselves in the direction of Earth’s magnetic field, as shown in this video:
Inside these bacteria there is a row of iron-containing crystals aligned with the long axis of the cell, giving them the equivalent of an internal magnetic compass needle (Molecular mechanisms of magnetosome formation. Ann Rev Biochem 2007 76: 351-66). Such bacteria can sense and align themselves relative to the earth’s magnetic field. Magnetotactic bacteria are major constituents of many natural microbial communities, especially in aquatic habitats. There is a broad range of shapes and groups of magnetic bacteria. However, cultivation of these organisms in the laboratory is often difficult and only few strains of magnetotactic bacteria have been isolated in pure culture, a tiny minority of the vast diversity of naturally occurring populations from largely unexplored natural habitats such as the marine environment.
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So why would bacteria want to be magnetic? Leaving aside the possibility that they are magnetic by accident, e.g. as a consequence of some metabolic byproduct, the truth is that we really don’t know the reason. However, the most likely explanation lies not in north-south alignment, but in up and down. The magnetotactic bacteria we know about require low but very precise levels of oxygen to survive, and must live in sediments where the oxygen concentration is just right for their needs. Over much of the globe, the Earth’s magnetic field actually points down towards the centre of the planet, so by following these lines of magnetic flux, they are able to ensure that they bury themselves in the sediment, which is exactly where they want to be. Thus the majority of magnetotactic in the Northern Hemisphere are north seeking, and those in the Southern Hemisphere are south seeking.
Viroporins are virus-encoded proteins that participate in virus replication, including the promotion of release of virus particles from cells (Viroporins. FEBS Lett 2003 552: 28-34). They also affect cellular functions, including the cell vesicle system, glycoprotein trafficking and membrane permeability. Viroporins are usually not essential for the replication of viruses, but their presence enhances virus growth. Composed of 60-120 amino acids, viroporins have a hydrophobic transmembrane domain that interacts with lipid bilayers, and polymerization of viroporin monomers creates hydrophilic pores in the membranes of virus-infected cells. Viroporins are present in tiny amounts in the virus particles (virions) of many animal RNA viruses, e.g. influenza A virus M2 protein, poliovirus 2B and 3A proteins, HIV Vpu and SARS coronavirus E protein. Viroporins contribute to the pathology of virus diseases by altering membrane permeability and disrupting ion homeostasis in infected cells.
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A paper recently published in Cellular Microbiology reports that viroporins of hepatitis C virus, poliovirus and other animal RNA viruses induce apoptosis in host cells (Viroporins from RNA viruses induce caspase-dependent apoptosis. 2008 Cell Microbiol 10: 437-451). In addition to their capacity to disrupt ionic cellular homeostasis and promote cell lysis, the expressed viroporins were able to induce cell death. Degradation of DNA and generation of apoptotic bodies were observed on viroporin expression. Activation of caspase-3, altered mitochondrial morphology and detection of cytochrome c release from mitochondria suggests involvement of the mitochondrial pathway in viroporin-induced apoptosis and shows that viroporins induce caspase-dependent programmed cell death.
It is possible that viroporins have different effects depending on the level of expression and/or the host-cell type. The induction of apoptosis in host cells by viruses is common and could assist virus spread. The next step in understanding the links between viroporins and apoptosis will be to unravel the mechanisms by which viroporins trigger apoptotic pathways and to demonstrate that these findings are relevant during virus infections.
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Every year, nearly nine million people develop tuberculosis and about two million people die from the disease. Diagnostic tests for tuberculosis include chest X-rays, the tuberculin skin test, and sputum analysis. For the last of these tests, a sample of sputum (mucus and other matter brought up from the lungs by coughing) is collected and examined under the microscope for M. tuberculosis using special stains and also by trying to grow bacteria from the sample. Tuberculosis can be cured by taking several different antibiotics for several months. It is very important that this treatment is completed to ensure that all the tuberculosis bacteria in the body are killed and to prevent the emergence of drug-resistant bacteria. Very little is known about the efficiency with which M. tuberculosis spreads from one person to another.
The researchers collected sputum samples from patients with tuberculosis in the UK and in The Gambia before they had received any treatment. They looked for the presence of acid-fast bacilli containing “lipid bodies”, small structures within the cells containing a fat called triacylglycerol. M. tuberculosis accumulates triacylglycerol when it is exposed to stresses present during infection (for example, reduced oxygen, hypoxia) and it was thought that that the presence of this fat may help the bacteria survive during transmission and establish a new infection. M. tuberculosis grown in the laboratory under hypoxic conditions, which induces the bacteria to enter an antibiotic-tolerant condition called a “nonreplicating persistent” (NRP) state, accumulated lipid bodies. The researchers compared the pattern of mRNAs made by actively growing cultures of M. tuberculosis, M. tuberculosis maintained in the NRP state, and by acid-fast bacilli from sputum samples. The transcriptome of the sputum sample revealed production of many proteins made in the NRP state. Finally, they showed that the time needed to grow M. tuberculosis from sputum samples increased as the proportion of lipid body–positive acid-fast bacilli in the sputum increased.
The characteristics of this population of bacteria might help them survive the adverse conditions that M. tuberculosis encounters during transmission between people and might partly explain why complete clearance of M. tuberculosis requires extended treatment with antibiotics. To establish the clinical significance of these findings, future studies will need to examine whether antibiotic treatment affects the frequency of lipid–positive bacteria in sputum and whether there is any relationship between this measurement and infectiousness, or clinical response to treatment. Professor Mike Barer says:
These surprising findings have opened the door for us to develop new ways to stop TB from spreading and to treat it more effectively. We hope that our new ability to monitor these sleepy and resistant bacteria in sputum will enable us to treat the disease more quickly.
Salmonella are Gram-negative bacteria which cause intestinal infections. The taxonomy of Salmonella species is complicated. Formally, there are only two species within this genus: S. bongori and S. enterica (formerly called S. choleraesuis), which are divided into six subspecies:
I - enterica
II - salamae
IIIa - arizonae
IIIb - diarizonae
IV - houtenae
V - bongori
VI - indica
However, there are numerous (over 2,500) serovars within both of these species. For the sake of simplicity, the CDC recommends that Salmonella species be referred to only by their genus and serovar, e.g. Salmonella Typhi instead of: Salmonella enterica subspecies enterica serovar Typhi. The Kauffman-White classification divides Salmonella isolates according to their somatic O antigens and flagellar H antigens. H antigens are further divided into phase 1 and phase 2, but in practice, most labs leave this level of detail to specialized reference laboratories.
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Prevention of Salmonella as a cause of food poisoning mostly involves effective sanitary precautions. Salmonellosis can also be caught from pet animals. All the disease-causing Salmonella species are now classified as a single species, Salmonella enterica, with numerous serovars. Most Salmonella isolates cause gastroenteritis which is usually self-limiting and does not require treatment with antibiotics. However, these infections can be life-threatening in the very young, very old and the seriously ill. Salmonella Typhi causes typhoid fever, a more serious systemic infection which does require medical intervention.
Investigation of the mechanisms that underlie the interactions of Salmonellae with their hosts has advanced greatly over the past decade, mainly through the study of Salmonella enterica serovar Typhimurium in tissue culture and animal models of infection. Knowledge of the bacterial processes and host responses has painted a dynamic and complex picture of the interactions between salmonellae and animal cells (Salmonellae interplay with host cells. Nature Reviews Microbiology 2008 6: 53-66).
Most Salmonella infections are acquired by ingestion of contaminated food or water. Salmonellae have an adaptive acid-tolerance response that promotes their survival in the low pH of the stomach. After entering the small intestine, they enter the intestinal mucous layer in order to gain access to the underlying epithelium and so evade being killed by digestive enzymes, bile salts, secretory IgA, antimicrobial peptides and other innate immune defences. The presence of Salmonella in the gut results also in production of pro-inflammatory cytokines such as IL-8, which stimulate inflammatory response leading to diarrhoea.
Salmonellae invade non-phagocytic enterocytes of the intestinal epithelium by bacterial-mediated endocytosis. After adherence to the apical surface of the cell, the bacteria disrupt the epithelial brush border and induce membrane ruffles that engulf the organism. Alternatively, they can translocate through the intestinal epithelia after uptake by CD18-expressing phagocytes. In vitro, Salmonellae are able to disrupt tight junctions, which seal the epithelial cell layer and restrict the passage of ions, water and immune cells. This, in addition to intestinal inflammatory responses, probably contributes to the induction of diarrhoea. The fact that there are multiple mechanisms for crossing the intestinal barrier indicates the importance of this strategy to the lifestyle of these bacteria. At least five different virulence proteins are required for efficient invasion of cultured epithelial cells, and optimal invasion of animal tissues might be even more complex and diverse.
Emerging technologies such as whole-genome sequencing will allow us to investigate the diversity of effectors that are used by the many pathogenic Salmonella isolates. The study of Salmonella pathogenesis should yield a rich treasure trove of information for those who are interested in microbial pathogenesis, innate immunity, cell biology and genomics, and will remain an important model system of host pathogen interactions for many years to come.
The structure of all retroviruses is similar, although there are some minor differences. Virus particles are far too small to see, the closest we can come to are electron micrographs. To make transmission electron micrographs, the specimen (containing virus particles) are fixed and stained with a metal-containing dye. The more dye different areas of the specimen take up, the darker they appear in the electron micrograph.
In the centre of an HIV particle, there are two molecules of RNA which together make up the genome of the virus. Associated with the RNA are two enzymes, reverse transcriptase and integrase. The genome is enclosed in a conical core consisting of the nucleocapsid proteins. Outside this is an icosahedral protein capsid, which in turn is enclosed by the matrix protein layer. The whole particle is surrounded by a lipid bilayer known as the virus envelope. The transmembrane protein penetrates through the envelope and anchors the surface glycoprotein on the outside of the particle.
To see more detail in virus particles, special imaging techniques are needed. Cryo-electron tomography makes a three dimensional reconstruction from a series of two dimensional transmission electron micrographs taken at extremely low temperatures in order to preserve the structure of the particle. The individual micrographs represent slices though the virus particle which are put together on a computer to construct a three dimensional representation with false colours added for additional clarity.
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Tuberculosis has had many names, including consumption, scrofula and the great white plague, but whatever you call it, this disease still claims one life every 10 seconds and global mortality rates are increasing despite the use of chemotherapy (Drugs versus bugs: in pursuit of the persistent predator Mycobacterium tuberculosis. 2008 Nature Reviews Microbiology 6: 41-52). Why have we not progressed further towards the eradication of this disease? There are many answers, including politics and poverty, and some less shameful excuses such as HIV and drug resistance. Whatever the reason, without new weapons in the armory against TB, the disease will continue to make ground.
Two factors, persistence and resistance, make the treatment of Mycobacterium tuberculosis infections particularly difficult. The term persistence describes the survival of the causative organism despite the use of antibiotics. The local concentration of antibiotics in lesions such as granulomas might not be adequate to kill the cells, or some bacteria might adopt a physiological state that renders them less susceptible to antibiotics. For these reasons, drug treatments must be extended. Currently, even the most effective regimes require a combination of at least 3 drugs and last for six months. Because patients feel better within 1 2 weeks, they have little motivation to continue with therapy, so the current World Health Organization guidelines call for treatment to be directly observed (DOTS). This can be difficult to provide in much of the world, including the areas where tuberculosis rates are highest.
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There is an excellent chance that patients who have tuberculosis can be cured using currently available drugs if they complete the required course of therapy. But what characteristics should new drugs have to improve on current treatments?
Oral bioavailability: to avoid the need for injections.
Good tolerance: to avoid unwanted side-effects might cause treatment to be abandoned.
Widespread usability: including AIDS patients, young children and pregnant women.
Compatibility with anti-retroviral drugs: because co-infection with HIV and TB is common.
Infrequent dosing: once a day drugs improve treatment compliance.
Activity against drug-resistant TB strains: possibly the most important factor with the rise of MDR and XDR-TB.
Rapid clearance of chronic infection: so that treatment times can be shortened.
Affordability: so they can be used in the areas of the world where TB is most prevalent.
Mycobacterium tuberculosis has no significant animal or environmental reservoirs and shows limited genetic diversity. In spite of this, TB continues to be a widespread and devastating disease. The need for new faster-acting drugs is clear. Recent work by my colleague Dr Mark Carr from the School of Biological Sciences at the University of Leicester might help in future drug development. The M. tuberculosis ESAT-6/CFP-10 complex consists of two proteins which, together, allow the bacteria to survive inside white blood cells. Removal of the genes for these proteins from the TB genome renders the bacteria unable to cause disease. Similarly, studies of the structure of the protein complex have shown that removal of a “long arm” from the molecule prevents the complex s ability to bind to the outer surface of human white blood cells. In the structure of the ESAT-6/CFP-10 complex above, the “long arm” is in red on the right side of CFP-10. When this is intact, it allows the complex to attach to the outside of host white blood cells. When the long arm is cleaved off, the complex shows greatly reduced attachment. This data provides an insight into the important components of this complex. Mark Carr says: “Current work is attempting to identify the exact components of the human white blood cells that this complex is targeting. Once found, this should give us a greater knowledge of the action of these molecular weapons of TB and give us the edge in the war against an ancient, reawakened foe.”
Most reviews of skin microbes concentrate on understanding the population of bacteria inhabiting the skin, or on how a subset of these microbes can become pathogens. In the past decade, interdisciplinary collaborations at the interface between microbiology and immunology have greatly advanced our understanding of the host-pathogen relationship (Skin microbiota: a source of disease or defence? British Journal of Dermatology 2008 158: 442-455).
Does the hygiene hypothesis apply to the skin? Several studies have shown that the surface microflora can influence the host innate immune system. These findings complement studies that suggest disruption in microbial exposure early in development may lead to allergies. The beneficial effect of microbes in the gut has been used to support the use of probiotics. But unlike the intestine, the role of microbes on the skin surface has not been well studied.
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The relationship between the skin flora and the host can fall into three categories: parasitism, commensalism or mutualism. Symbiotic relationships can exist in which only one organism benefits while the other is harmed (parasitism, predation and competition), one organism benefits and no harm occurs to the other (commensalism) or both organisms benefit (mutualism and co-operation). Microbes found on the surface of the skin that are only infrequently associated with disease are typically referred to as commensal. This term implies that the microbe lives in peaceful coexistence with the host while benefiting from a sheltered ecological niche. An example of such a microbe is the Gram-positive bacterium Staphylococcus epidermidis. Emerging evidence indicates that this species and other so-called skin commensals may play an active role in host defence, such that they may represent a mutualistic association.
It is important to recognize that the distinction between what we consider to be harmless flora or a pathogenic agent often lies in the skin’s capacity to resist infection, and not the inherent properties of the microbe. Host cutaneous defence occurs through the combined action of a large variety of complementary systems. These include the physical barrier, a hostile surface pH, and the active synthesis of gene-encoded host defence molecules such as antimicrobial peptides, proteases, lysozymes and cytokines and chemokines that serve as activators of the cellular and adaptive immune responses. Virulence factors expressed by a microbe may enable it to avoid host defences, but it is ultimately the effectiveness of the host response that determines if a microbe is a commensal (or mutual) organism, or a dangerous pathogen for the host.
Staphylococcus epidermidis: Staphylococcus epidermidis comprises more than 90% of the resident aerobic skin flora. Despite its generally innocuous nature, S. epidermidis is a frequent cause of infections. This species primarily infects compromised patients including drug abusers, those on immunosuppressive therapy, AIDS patients, premature babies and patients with an indwelling medical device such as a catheter. After entry, virulent strains of S. epidermidis form biofilms that partially shield the dividing bacteria from the host’s immune system and from exogenous antibiotics. In addition to catheter infections, patients with necrotic tumour masses also have a high tendency towards infection by S. epidermidis. In other conditions, S. epidermidis normally resides benignly on the skin surface, with infections arising only in conjunction with specific host predispositions.
Corynebacterium diphtheriae:
Coryneforms are Gram-positive, nonmotile, facultative anaerobic actinobacteria. The common members of the skin flora are divided into two species: Corynebacterium diphtheriae and nondiphtheriae corynebacteria (called diphtheroids). Toxinogenic C. diphtheriae produce the highly lethal diphtheria toxin, which can induce fatal toxaemia. Nontoxinogenic (nontoxin-producing) C. diphtheriae are capable of producing septicaemia, septic arthritis, endocarditis and osteomyelitis. Both non-toxigenic and toxigenic C. diphtheriae can be isolated from cutaneous ulcers of alcoholics, intravenous drug users and from hosts with poor hygiene standards, such as in endemic outbreaks in areas of low socioeconomic status.
The nondiphtheriae corynebacteria (diphtheroids) are a diverse group, containing 17 different species, not all of which are present on human skin. Several species commonly colonize cattle, while others, such as Corynebacterium jeikeium are normal inhabitants of human epithelium. C. jeikeium causes infections in immunocompromised patients, in conjunction with underlying malignancies, on implanted medical devices. Once the bacterium has penetrated the skin barrier, this bacterium can cause sepsis or endocarditis.
Propionibacterium acnes: Propionibacterium acnes is an aerotolerant anaerobic, Gram-positive bacillus that produces propionic acid as a metabolic byproduct. This bacterium resides in the sebaceous glands, derives energy from the fatty acids of sebum, and is susceptible to ultraviolet radiation due to the presence of endogenous porphyrins (so step away from the computer and spend some time in the sun). The most well-known ailment associated with P. acnes is the skin condition known as acne vulgaris, affecting up to 80% of adolescents in the USA. Several factors are thought to contribute to an individual’s susceptibility. Hormones, medications (including steroids and oral contraceptives), the keratinization pattern of the hair follicle, stress and genetic factors all contribute to acne. In the sebaceous gland, P. acnes produces free fatty acids as a result of triglyceride metabolism. These byproducts can irritate the follicular wall and induce inflammation through neutrophil chemotaxis to the site of residence. Inflammation due to host tissue damage or production of immunogenic factors by P. acnes subsequently leads to cutaneous infections. Like S. epidermidis, P. acnes causes many postoperative infections. Prosthetic joints, catheters and heart valves transport the cutaneous microflora into the body. Sepsis and endocarditis result from systemic infections. Another common port of entry for P. acnes is through eye injuries or operations. Propionibacterium acnes can cause endophthalmitis (inflammation of the interior of the eye causing blindness) weeks or months after trauma or eye surgery. The infection delay probably results from low-virulence phenotypes of P. acnes.
Group A Streptococcus (Streptococcus pyogenes):
Known for causing superficial infections as well as invasive diseases, GAS (such as S. pyogenes) form chains of Gram-positive cocci. GAS strains are further subclassified by their M-protein and T-antigen serotypes, which indicate the strain’s potential to cause superficial or invasive disease. GAS infections are diverse in their symptoms, with strep throat, mucosal infections and impetigo being most common. GAS is also associated with deeper-seated skin infections such as cellulitis, infections of connective tissue and underlying adipose tissue. These types of disease occur frequently in the elderly and in people in densely populated accommodation. The invasive necrotizing fasciitis, or flesh-eating disease, carries a high degree of morbidity and mortality and is frequently complicated by streptococcal toxic shock syndrome. GAS can also cause infections in many other organs including lung, bone and joint, muscle and heart valve, essentially mimicking the disease spectrum of S. aureus.
Pseudomonas aeruginosa: Pseudomonas aeruginosa is commonly found in nonsterile areas on healthy individuals and, much like S. epidermidis, is considered a normal constituent of a person’s natural microflora. The bacteria normally live innocuously on human skin and in the mouth, but are able to infect practically any tissue with which they come into contact. Flexible, nonstringent metabolic requirements allow P. aeruginosa to occupy a variety of niches, making it the epitome of an opportunistic pathogen. Due to the general harmlessness of the bacteria, infections occur primarily in compromised patients and in hospital-acquired infections. Immunocompromised individuals with AIDS, cystic fibrosis and haematological and malignant diseases develop systemic or localized P. aeruginosa infections. Transmission often occurs through contamination of inanimate objects and can result in ventilator-associated pneumonia and other medical device-related infections. The main route of entry is through compromised skin, with burn victims commonly suffering from P. aeruginosa infections. On the skin, P. aeruginosa occasionally causes dermatitis or deeper soft-tissue infections. Dermatitis occurs when skin comes into contact with infected water, for example in hot tubs. The infection is very mild and is treated easily with topical antibiotics.
Much current research related to infectious diseases of the skin targets microbial virulence factors and aims to eliminate harmful organisms. Some of these same microbes potentially also play an opposite role by protecting the host. The complex host-microbe and microbe-microbe interactions that exist on the surface of human skin illustrate that the microbiota have a beneficial role, much like that of the gut microflora.
An estimated 15 percent of all human cancers worldwide may be caused by viruses (Viruses and Human Cancer. Yale J Biol Med. 2006 79: 115 122). Both DNA and RNA viruses are capable of causing cancer in humans. Although it is convenient to consider human tumor viruses as a discrete group of viruses, the six viruses which cause human cancers have very different genomes, replication cycles, and come from five different virus families. The path from virus infection to tumour formation is slow and inefficient. Only a minority of infected individuals progress to cancer, usually years or even decades after primary infection. Virus infection alone is generally not sufficient for cancer, and additional events and host factors, such as immunosuppression, somatic mutations, genetic predisposition, and exposure to carcinogens must also play a role.
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Hepatitis B and C viruses Hepatitis C virus (HCV) is an enveloped RNA virus of the Flavivirus family. It is capable of causing both acute and chronic hepatitis in humans by infecting liver cells. It is estimated that approximately 3 percent of the world s population are hepatitis C carriers. Chronic infection with hepatitis C virus results in cirrhosis, which in turn can lead to primary hepatocellular carcinoma. Between 1 and 2 percent of infected patients with cirrhosis of the liver will develop primary hepatocellular carcinoma per year of infection. Transmission of HCV occurs through the blood, by shared needles in intravenous drug abuse, sexual activity, and birth being the primary routes. The hepatitis B virus (HBV) of the family Hepadnaviridae is a DNA virus, but uses reverse transcription as part of its replication cycle. Hepatitis B virus also is a blood-borne pathogen that can result in acute and chronic hepatitis. Chronic hepatitis (infections lasting more than three months) can lead to cirrhosis and liver failure, and to the development of hepatocellular carcinoma. Hepatitis B infections is a significant global health problem with an estimated 2 billion people infected and 1.2 million deaths per year attributed to subsequent hepatitis, cirrhosis and hepatocellular carcinoma.
Epstein-Barr virus (EBV) and human herpesvirus 8 (HHV- EBV and HHV-8 (also known as Kaposi sarcoma herpesvirus) are both herpesviruses that possess large double-stranded DNA genomes. As with all herpesviruses, they encode enzymes involved in DNA replication and repair and nucleotide biosynthesis. They also both possess the ability to establish latency in B lymphocytes and reactivate into the lytic cycle. Both also are associated with naturally occurring tumors in humans.
EBV is a ubiquitous virus that is most commonly known for being the primary agent for infectious mononucleosis (glandular fever). Up to 95 percent of all adults are estimated to be seropositive for EBV, and most infections are subclinical. EBV is associated with a number of malignancies: B and T cell lymphomas, Hodgkin s disease, post-transplant lymphoproliferative disease and nasopharyngeal carcinoma. Burkitt’s lymphoma, post-transplant lymphoproliferative disease show an increased frequency in patients with immunodeficiency, suggesting a role for immunosurveillance in the suppression of malignant transformation.
In 1994, HHV-8 DNA was identified in biopsies from tumors of a patient with Kaposi sarcoma, a relatively rare malignancy prior to the AIDS epidemic. In addition to it likely being an essential cofactor for the development of Kaposi sarcoma, HHV-8 also is believed to have a role in Castleman’s disease and primary effusion lymphoma. The HHV-8 genome is expressed in these tumors and encodes transforming proteins and anti-apoptotic factors. As with EBV, the predominant cell type infected is the B lymphocyte, although in these cells the lytic cycle occurs rather than being repressed. This may play a crucial role in the pathogenesis of Kaposi sarcoma by elaboration of virus and host cytokines promoting cell proliferation, angiogenesis, and enhancement of virus spread.
Human Papillomavirus (HPV) Human papillomaviruses are small non-enveloped DNA tumour viruses that commonly cause benign papillomas or warts in humans. Persistent infection with high-risk subtypes of HPV is associated with the development of cervical cancer. HPV infects epithelial cells, and, after integration in host DNA, the production of oncoproteins, mainly E6 and E7, disrupts natural tumor suppressor pathways and is required for proliferation of cervical carcinoma cells. HPV is also believed to play a role in other human cancers, such as head and neck tumors, skin cancers in immunosuppressed patients, and other anogenital cancers.
Cervical cancer is the second leading cause of cancer mortality in women worldwide, causing 240,000 deaths annually. Of approximately 490,000 cases reported each year, more than 80 percent occur in the developing world, where effective but costly Pap smear screening programs are not in place. Early precancerous changes and early cancers detected by Pap smears are effectively treated and cured with surgical therapy or ablation. In the absence of effective screening, the disease is detected late.
The immune system plays an important role in the prevention of persistent HPV infection and progression of precancerous lesions. Human papillomavirus is a poor natural immunogen. As a double stranded DNA virus, there is no RNA intermediate, nor does infection cause cytolysis, allowing initiation of innate immune responses. HPV mainly encodes non-secreted nucleoproteins, which are poorly cross-presented and compared to other viruses its non-structural proteins are expressed at low levels. However, genital infection with HPV is usually transient. Additionally, inadequate T cell responses may lead to failure to clear HPV-infected cells. AIDS patients, renal transplant patients receiving immunosuppressive therapy, and individuals with T cell deficiencies have increased rates of HPV persistence, anogenital lesions, and cervical cancer.
Human T lymphotropic virus type I (HTLV-1) HTLV-1 is a retrovirus and is associated with adult T-cell leukemia. This virus has a worldwide distribution, with an estimated 12 to 25 million people infected. However, disease is only observed in less than 5 percent of infected individuals. It is transmitted through blood transfusions, sexual contact, and during birth. HTLV-1 displays a special tropism for CD4 cells, which clonally proliferate in adult T cell leukemia, though how this is caused is not known.
HTLV-1 infection has a very long latency period of 20 to 30 years, but once tumor formation begins, progression is rapid. Standard chemotherapy often can bring about an initial response with a partial or complete remission; however, relapse is common, and median survival is eight months. The HTLV-1 Tax gene has been postulated to play an important role in tumour formation through the activation of virus transcription and the hijacking of cellular growth and cell division machinery, but the mechanisms leading to adult T cell leukemia are not well understood.
These six viruses illustrate the diverse biological pathways to malignancy and the challenges of treating the resulting diseases. The study of viruses and human cancer has led to optimism about the development of new strategies for the prevention of the infections that can lead to carcinogenesis. Antiviral drugs such as lamuvidine used against heptatitis B and ganciclovir for Kaposi sarcoma specifically target the virus replication machinery. The presence of virus gene products in tumour cells can provide important targets for directed therapies that specifically can distinguish tumour cells from normal cells. The inability of traditional cancer therapy, such as chemotherapy and radiation, to distinguish cancer cells from normal cells is a significant drawback and leads to toxicities for patients undergoing treatment. Targeted therapies directed against virus proteins or generate immune responses in order to either prevent infection or kill infected cells or cancer cells hold much promise for more effective and tolerable treatment strategies for virus-related tumours.
Over the past week, international news stories have concentrated on the devastating cyclone in Burma (Myanmar), and the almost certain consequence of disease outbreaks in the aftermath. But at the same time, there’s another microbiology story unfolding in East Asia. Beginning in March, a large outbreak of hand, foot and mouth disease (HFMD) was reported from Fuyang city in Anhui Province in China. Note that HFMD is a human disease caused by enteroviruses belonging to the picornavirus family, but is not the same as the animal disease foot and mouth (FMD) caused by a different kind of picornavirus.
