Masses of immune cells that form as a hallmark of tuberculosis (TB) have long been thought to be the body’s way of trying to protect itself by literally walling off the bacteria.  But a new study in the January 9th issue of the journal Cell, a Cell Press publication, offers evidence that the TB bacteria actually sends signals that encourage the growth of those organized granuloma structures, and for good reason: each granuloma serves as a kind of hub for the infectious bugs in the early stages of infection, allowing them to expand further and spread throughout the body.

” This fundamentally turns our understanding of granulomas all topsy turvy,” said Lalita Ramakrishnan of the University of Washington, Seattle.  “Scientists thought they were protective, but they are not—at least not in early infection.  The bacteria use them to reproduce and disseminate themselves.”

Not only do the bacteria expand themselves within the first granuloma to form, she added, but some of the immune cells in that initial mass leave to start new granulomas elsewhere.  Those new granulomas then also serve as breeding grounds for the bacteria.

The finding suggests a new avenue for TB therapy at an important time in the struggle against TB infection.  “We might think about ways to prevent granulomas that might be therapeutic,” Ramakrishnan said.  That might be done either by intercepting the bacterial signal that spurs granulomas’ formation or by manipulating the human immune system in some other way.

” Finding a new way to intervene in the infection is particularly relevant now because there is a horrible epidemic of drug-resistant TB,” she added.  “Many of the bugs are resistant to practically everything.”

At the outset of human pulmonary tuberculosis, the inhaled bacteria (Mycobacterium tuberculosis) is gobbled up by immune cells known as macrophages and transported into the lung.  There, infected macrophages recruit additional macrophages and other immune cells to form granulomas.  Under the classical view, those granulomas help protect against the bacteria, even if they don’t successfully contain the infection.  They were also thought to form only after the adaptive immune system shifts into gear.

But Ramakrishnan’s team began to find evidence calling that classical view into question by studying the disease in zebrafish embryos.  Because zebrafish embryos are transparent, they allowed the team to literally watch the infection take hold and spread in real time.

Their initial studies showed that, contrary to the classical view, granulomas form well before adaptive immunity comes into play, within days of infection.  Indeed, granulomas’ formation coincides with the bacteria’s expansion.  In addition, in embryonic fish infected with a less-virulent, mutant strain of bacteria, which lacked a secretion system known as ESX-1/RD1, granulomas didn’t form nearly as well.  Together, those findings suggested to Ramakrishnan’s team that granuloma formation actually works not as a protective maneuver on the part of the infected host, but rather as a bacterial tool for expanding infection.

To further investigate in the new study, the researchers observed and quantified the events in zebrafish embryos infected with normal TB bacteria and the mutant bacteria lacking the ESX-1/RD1 system.  They found that, once transported inside of cells by macrophages, the bacteria use the RD1 signal to call on new macrophages to come and move in to the growing granuloma.  As multiple macrophages arrive, they efficiently find and consume infected and dying macrophages to become infected themselves.  That process leads to a rapid, iterative expansion of infected macrophages and thereby bacterial numbers, they report.  The primary granuloma also seeds secondary granulomas as infected macrophages leave for other parts of the body.

” In summary,” the researchers wrote, “we propose that the pathway of granuloma formation and subsequent bacterial dissemination is based upon macrophage responses that are of themselves generally protective and that work reasonably well against less virulent (i.e., RD1-deficient) infection.  Rather than block these host responses, RD1-competent mycobacteria appear to accelerate them to turn the granuloma response into an effective tool for pathogenesis.  The initiation of the adaptive immune response then may halt bacterial expansion not by forming granulomas as suggested by the classical model but by altering the early granuloma into a form of stalemate between host and pathogen.”

Researchers at Georgetown University Medical Center (GUMC) have successfully tested a genetic strategy designed to improve treatment of human infections caused by the yeast Candida albicans, ranging from diaper rash, vaginitis, oral infections (or thrush which is common in HIV/AIDS patients), as well as invasive, blood-borne and life-threatening diseases.Their findings confirm that inhibiting a key protein could provide a new drug target against the yeast, which inhabits the mucous membranes of most humans. The research was presented today at the 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/46th Annual Meeting of the Infectious Diseases Society of America (ICAAC/IDSA) in Washington, DC.

“This is a genetically intelligent approach to target identification and drug design,” says the study’s lead author, Richard Calderone, PhD, professor and chair of the department of microbiology and immunology and co-director of the PhD program in the global infectious disease program at GUMC.

“Candida infections are often treatable, however, in patients that are immunocompromised following cancer chemotherapy, bone marrow transplantation, or surgery, diagnosis is often delayed, postponing therapy,” he says. “Also when drug-resistant yeast pathogens cause the infection, clinical management of the patient becomes a problem.”

Candida invasive, blood-borne infections are the fourth most common hospital-acquired infection in the United States, costing the healthcare system about $1.8 billion each year, Calderone says.

“More drug resistance is being seen clinically, so there is significant room for improvement in the therapies used today,” he says

This study continues research in which Calderone and his colleagues identified a protein, the product of the Ssk1 gene that Candida needs to infect its host. To date, this protein has not been found in humans or in animals, which means it could be “targeted” with a novel drug without producing toxicity because such an agent should only attack the fungus.

The researchers found that if the Ssk1 gene is deleted from Candida albicans, the “triazole” drugs that are now used to treat these diseases are much more effective in the laboratory. “This allows the triazole drugs to do their job,” Calderone says. “We propose that this finding might lead to other, possibly more effective, treatment options.”

In this study, the researchers used a gene microarray analysis to further understand what knocking out the Ssk1 gene does to the organism, and they discovered that the gene is critical to the pathogenic nature of the fungi.

What this means is that an Ssk1 inhibitor might work in synergy with a triazole or perhaps as an effective stand-alone drug to treat Candida infections, the researchers say. If it works in Candida, it may have broader activity in other pathogens because Ssk1p is found in other fungi.

“Using the genome of the organism to find genes to target is a logical approach to drug design,” he says. The researchers are now working with other groups to find the right agent to target the Ssk1protein.

Individuals inhale measles virus particles in aerosols and it is currently thought that these particles infect the cells that line the airways (respiratory epithelial cells) before being passed to immune cells that carry the virus particles to other parts of the body and then back to the airways, which again become infected and shed virus into exhaled aerosols.  In the study, a measles virus unable to bind to and infect epithelial cells was found to cause symptoms of measles virus infection in monkeys even though it did not infect respiratory epithelial cells and was not being shed into exhaled aerosols.  These data suggest that, in fact, inhaled measles virus particles first infect lymphocytes and are only passed to respiratory epithelial cells from the lymphocytes in the tissues.  Further, they indicate that the protein that measles virus particles bind to on respiratory epithelial cells, which has yet to be identified, is likely to be found on the surface of the cells that faces the tissues rather than the surface that faces the airways, as previously assumed.  As discussed in an accompanying commentary by Makoto Takeda, at Kyushu University, Japan, the results of this study should help researchers identify this protein.

A study from researchers at Children’s Hospital Boston published in Pediatrics found that a simple infection control intervention in elementary schools – disinfecting frequently-touched surfaces and using alcohol-based hand sanitizers – helped reduce illness-related student absenteeism.Illnesses caused by bacteria and viruses account for millions of lost school days each year.(1) According to Thomas Sandora, MD, MPH, a pediatric infectious diseases specialist at Children’s Hospital Boston, “The best ways to avoid common infections are cleaning your hands and preventing exposure to the germs that cause these illnesses. Our research indicates that elementary schools should consider a few simple infection control practices to help keep students healthier.”

The study, led by Dr. Sandora, was a randomized, controlled trial involving 285 third-, fourth-, and fifth-grade students in an elementary school system in Avon, Ohio. Teachers in intervention classrooms used disinfecting wipes on student desks, and students used hand sanitizer in the classroom at key points throughout the school day. Control classrooms followed usual hand washing and cleaning procedures.

Over eight weeks, researchers tracked the frequency of absences and the reasons for missing school. Study investigators also tested several classroom surfaces for total bacterial counts and for the presence of several common viruses.

Researchers found absenteeism rates for gastrointestinal illnesses were nine percent lower in classrooms that followed the infection control regimen of disinfecting surfaces and using alcohol-based hand sanitizers. The absenteeism rate for respiratory illness was not affected by this intervention.

Gastrointestinal illnesses are extremely common for school-age children, and children can be at risk for these infections because of frequent exposure to ill peers and poor hand hygiene.(1) In fact, the bacteria and viruses that cause these gastrointestinal infections can be easily passed from one person to another on the hands.(2) The germs can also survive on surfaces in the environment, where some of them can persist for hours to days.(1)

The study suggests that schools should consider adopting simple infection control practices, including disinfecting desktops once a day and using hand sanitizer before and after lunch, to help reduce days lost to common illnesses.

New research into the toxins, virulence, spread and prevention of the superbug Clostridium difficile is reported in the June special issue of the Journal of Medical Microbiology. These findings will play a crucial role in providing us with ammunition in the fight against a sometimes deadly pathogen.

Clostridium difficile is found in the environment but is most common in hospitals. It can cause a serious hospital-acquired infection when antibiotics are used as they upset the balance of the normal gut flora, allowing C. difficile to grow and produce toxins. It is carried in the guts of 3% of healthy humans but carriage rates in hospital patients tend to be much higher and elderly people in hospitals, being treated with antibiotics are most at risk of developing infection. The bacteria produce spores when they encounter unfavourable conditions. Transmission of infection is through the ingestion of these spores which can survive on surfaces and floors for years and are resistant to many disinfectants and antiseptics, including alcohol hand gel.

Symptoms include diarrhoea, nausea, abdominal pain, loss of appetite, fever, bowel inflammation and possible perforation, which can be fatal. Only two antibiotics are regularly used to treat C. difficile infection: metronidazole and vancomycin, but relapse is a common problem following treatment. In 2004, a hypervirulent strain (C. difficile 027/NAP1/BI) was reported, which appears to make toxins more rapidly and at higher levels than other strains, as well as being resistant to many antibiotics, including fluoroquinolones.

Several studies in the Journal of Medical Microbiology look at the spread of C. difficile in different countries, including Austria and Korea. Research shows that the use of antibiotic increased the risk of outbreaks of the hypervirulent strain of C. difficile in the Netherlands. The issue also contains evidence to suggest that C. difficile could be spread between animals and humans – researchers have isolated the bacterium from food animals in Slovenia.

Scientists investigated the effects of antibiotics, antigens and other agents on the virulence and pathogenicity of C. difficile. Toxins were also studied; research reveals some important information about the synthesis, processing and effects of different toxins. A new gene sequence has been discovered in the hypervirulent C. difficile 027 strain, which could be related to its increased virulence by affecting toxin binding.

The potential for a ‘designer’ probiotic for C. difficile is discussed. Professor Ian Poxton, former Editor-in-Chief of the Journal of Medical Microbiology said “this is an important approach that is hopefully much better than previously reported studies using commercially available yoghurt-like drinks, and certainly more palatable than ‘faecal transplants’.”