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.”

A fungus called microsporidia that causes chronic diarrhea in AIDS patients, organ transplant recipients and travelers has been identified as a member of the family of fungi that have been discovered to reproduce sexually.  A team at Duke University Medical Center has proven that microsporidia are true fungi and that this species most likely undergoes a form of sexual reproduction during infection of humans and other host animals.

The findings could help develop effective treatments against these common global pathogens and may help explain their most virulent attacks.

“Microsporidian infections are hard to treat because until now we haven’t known a lot about this common pathogen,” says Soo Chan Lee, Ph.D., lead author and a postdoctoral researcher in the Duke Department of Molecular Genetics and Microbiology.  “Up to 50 percent of AIDS patients have microsporidial infections and develop chronic diarrhea.  These infections are also detected in patients with traveler’s diarrhea, and also in children, organ transplant recipients and the elderly.”

Of the 1200 species of microsporidia, more than a dozen infect humans.  Their identity had been obscured because these tiny fungi cannot live outside of an infected host cell and they have a small number of genes which are rapidly evolving.

The Duke scientists used two genetic studies to show that microsporidia apparently evolved from sexual fungi and are closely related to the zygomycete fungus in particular.

They found that microsporidia share 33 genes out of 2,000 with zygomycetes.  Which the microsporidia did not share with other fungi.  This genomic signature also shows that microsporidia and zygomycetes likely shared a common ancestor and are more distantly related to other known fungal lineages.

In addition, these two types of fungi have the same sex-locus genes – and in the same order – in their DNA.  Other genes involved in sexual reproduction are also present.  The findings suggest that microsporidia may have a genetically controlled sexual cycle, and may be undergoing sexual reproduction while they infect the host, Lee said.

Lee said the next step is to explore the sexual reproduction of these species, which may cause more severe (more virulent) infections because they use the host’s cellular environment and machinery as a safe haven in which to reproduce.

“These studies resolve the enigma of the evolutionary origins and proper placement of this highly successful group of pathogens, and provide better approaches to their experimental study,” said senior author Joseph Heitman, M.D., Ph.D., director of the Center for Microbial Pathogenesis and director of the Duke University Program in Genetics and Genomics.

The team will pursue further studies with Duke genetic researchers Raphael Valdivia, Ph.D., and Alejandro Aballay, Ph.D., using cultured cells and C. elegans, a worm that researchers recently found is a natural host for microsporidia.  “Using this roundworm may prove to be a useful way to study microsporidia genetics in a living creature,” Heitman said.

Scientists in the United Kingdom and Russia are reporting identification of a long-sought chink in the armor of the parasite that causes African sleeping sickness, a parasitic disease that kills at least 50,000 people each year. Their study appears in the current edition of ACS Chemical Biology, a monthly journal.

In the study, Michael Ferguson and colleagues cite an “urgent” need for new treatments for the disease, which is spread by the tsetse fly and also affects cattle — a precious possession that represents a bank account on four feet to impoverished people in sub-Sahara Africa. Current treatments for African sleeping sickness, Ferguson says, are not only difficult to administer, but also expensive and toxic.

Their research identified the first compound to impede a key step in an essential biochemical pathway in the sleeping sickness parasite. Blocking this pathway disrupts the production of a key glycolipid that anchors protective proteins to the surface of the parasite. The analysis also revealed notable differences between pathways of parasitic and human cells, which could reveal insight into possible therapeutic targets.

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.

As the first globally co-ordinated plan for the planet’s gravest health threats is hatched by government ministers from around the world this weekend, a new report sets out a 10-point plan for this new, globalised approach to infectious diseases such as avian flu.

Ministers of health and agriculture will formulate a global plan to prepare for, and respond to, the threat of avian flu and other emerging infectious diseases at the International Ministerial Conference on Avian and Pandemic Influenza in Sharm el Sheikh, Egypt (October 24-26). The plan - called the One World, One Health initiative - aims for an unprecedented integration of animal, human and ecosystem health issues to fight the threat of the avian flu virus, H5N1.

A new report by Professor Ian Scoones and Paul Forster of the ESRC STEPS Centre at the UK’s Institute of Development Studies lays out 10 key recommendations for One World, One Health, based on analysis of lessons learned from the massive $2bn international response to the avian flu over the past five years, during which time 245 people have died.

According to the report - The International Response to Highly Pathogenic Avian Influenza: Science, Policy and Politics - ministers need to rethink current ideas in order to achieve an effective, equitable and resilient international plan of response to emerging diseases.

The recommendations include rethinking disease surveillance, redefining health security, new responses to uncertainty and ignorance, emphasising access and equity as well as questions of organisational architecture and governance.

“The One World, One Health initiative is a radical departure from the conventional sectoral approaches to health. It is essential, but presents many challenges. We have identified 10 challenges for the way ahead, and urge ministers to rethink rather than repackage their measures. One World One Health needs to be more than ‘old wine in new bottles’,” said Professor Ian Scoones, IDS Fellow and co-director of the ESRC STEPS Centre.

Over the last decade, the avian flu virus, H5N1, has spread across most of Asia and Europe and parts of Africa. In some countries – including Indonesia, China, Vietnam, Bangladesh, Nigeria and Egypt – the disease has become endemic. Although 245 deaths have been reported since 2003 there has, as yet, been no human pandemic. But somewhere, some time, a new emerging infectious disease will have major impacts, given changing disease ecologies and patterns of urbanisation and climate change.

A major international response, backed by over $2bn of public money, has affected the livelihoods and businesses of millions. Markets have been restructured, surveillance and poultry vaccination campaigns implemented, and over two billion birds have died or been culled. Simultaneously substantial investment has been made in human and animal health systems and developing drugs and vaccines.

In many countries pandemic contingency and preparedness plans have been devised. Yet coordination at country level has been found wanting; rivalries between professions and organisations persist; and funding and capacities for an effective and equitable global responses to a pandemic remain weak.

The themes addressed in this report are being explored as part of a project on avian influenza policy responses in Cambodia, Indonesia, Thailand and Vietnam, in collaboration with the UN Food and Agriculture Organisation. They are central to the ESRC STEPS Centre’s research programme on ecology, politics, policy and pathways to sustainability.

Among many global health challenges, infectious diseases remain among the most problematic, accounting for about one quarter of all deaths globally, and nearly two-thirds of deaths in sub-Saharan Africa. Dr. Fauci will discuss progress–and remaining challenges–in the fight against major infectious causes of death and disability such as HIV/AIDS, malaria, tuberculosis and drug-resistant microbes. He also will discuss how conceptual and technological progress in fields such as genomics and nanotechnology has invigorated infectious disease research. These advances also are contributing to exciting studies on the ecology of human disease, including the Human Microbiome Project, which is exploring how the billions of bacteria that inhabit our bodies contribute to health and illness.

Other NIAID scientists are scheduled to present findings during the four-day meeting as well. The range of topics covered reflects the broad scope of NIAID’s research efforts aimed at better understanding, treating and preventing infectious and immune-mediated diseases.

• Noroviruses, the highly contagious viruses that cause the episodes of acute gastroenteritis also known as winter vomiting disease (Kim Green, Ph.D.)
• The role of gut-dwelling commensal bacteria in producing the symptoms of Crohn’s disease, a chronic inflammatory disease of the intestines (Warren Strober, M.D.)
• Antibiotic-resistant bacterial infections caused by Staphylococcus epidermidis (Michael Otto, Ph.D.) and Staphylococcus aureus (Frank DeLeo, Ph.D.)
• Finding ways to treat primary immunodeficiencies, inherited conditions in which immune function is impaired (Steve Holland, M.D.)
• Containing Ebola virus, for which there is currently no vaccine or specific treatment (Gary Nabel, M.D., Ph.D.)