Tuesday, 25 June 2013

A feline and human pathogenic fungus joins the new species list

A new species of fungus that causes life-threatening infections in humans and cats has been discovered by a University of Sydney researcher.

"This all originated from spotting an unusual fungal infection in three cats I was seeing at the University's cat treatment centre in 2006," said Dr Vanessa Barrs, from the University's Faculty of Veterinary Science, whose findings have just been published in PLOS One.

"These cats presented with a tumour-like growth in one of their eye sockets, that had spread there from the nasal cavity. The fungal spores are inhaled and in susceptible cats they establish a life-threatening infection that is very difficult to treat."

Six years of investigation followed, including working with some of the world's leading fungal experts at the CBS-KNAW fungal biodiversity centre in The Netherlands.

"Finally I was able to confirm this as a completely new species, Aspergillus felis, which can cause virulent disease in humans and cats by infecting their respiratory tract. We were able to demonstrate that this was a new species of fungus on a molecular and reproductive level and in terms of its form.
"Similar to the closely related fungus Aspergillus fumigates, this new species of fungus can reproduce both asexually and sexually - and we discovered both phases of the fungus."

Since the first sighting of the new species, more than 20 sick domestic cats from around Australia and one cat from the United Kingdom have been diagnosed with the fungus. The fungus appears to infect otherwise healthy cats but in the two humans identified it attacked an already highly compromised immune system. The disease is not passed between humans and cats but its study in cats will not only help their treatment but provide a good model for the study of the disease in people. There is only a 15 percent survival rate of cats with the disease and it has so far proved fatal in humans. To date only one case has been identified in a dog.

"We are right at the start of recognising the diseases caused by this fungus in animals and humans. The number of cases may be increasing in frequency or it may just be we are getting better at recognising them," Dr Barrs said.

"Fungi like Aspergillus felis can be easily misidentified as the closely related fungus Aspergillus fumigatus, which is a well-studied cause of disease in humans. However, A. felis is intrinsically more resistant to antifungal drugs than A. fumigatus and this has important implications for therapy and prognosis."

The next step for Dr Barrs and her team is studying fungi in culture collections throughout Australia to determine the prevalence of A. felis infections in people with previously diagnosed aspergillosis. They will collaborate with researchers at the Westmead Millenium Institute for Medical Research.

(Left) A cat with a swollen eye due to a fungal granuloma in its eye socket. (Right) The same cat after being successfully treated. The disease has only a 15 percent survival rate.

Media enquiries: Verity Leatherdale, 02 9351 4312, 0403 067 342, verity.leatherdale@sydney.edu.au

Monday, 24 June 2013

DNA in Human Genomes

A new study finds strong evidence that bacteria can transfer genes into human genomes, especially in cancer cells. By Ed Yong | June 20, 2013 | The Scientist A team of scientists from the University of Maryland School of Medicine has found the strongest evidence yet that bacteria occasionally transfer their genes into human genomes, finding bacterial DNA sequences in about a third of healthy human genomes and in a far greater percentage of cancer cells. The results, published today (20 June) in PLOS Computational Biology, suggest that gene transfer from bacteria to humans is not only possible, but also somehow linked to over-proliferation: either cancer cells are prone to these intrusions or the incoming bacterial genes help to kick-start the transformation from healthy cells into cancerous ones. “It really does seem that human genome sequence data from somatic cells show signs of LGT events from bacteria, and so do cancer cells,” said Jonathan Eisen from University of California, Davis, who coordinated the peer review of the new study but was not involved in the work. “Wild stuff does happen.” The trillions of bacteria in our bodies regularly exchange DNA with each other, but the idea that their genes could end up in human DNA has been very controversial. In 2001, the team that sequenced the first human genome claimed to have found 113 cases of such lateral gene transfers (LGT), but their conclusion was later refuted. This high-profile error “had a chilling effect on the field,” according to Julie Dunning Hotopp who led the new study. Although her team has since found several cases of LGT between bacteria and invertebrates, “it’s still difficult to convince people that it may be happening in the human genome,” she said. Rather than looking for bacterial genes that had become permanent parts of the human genome, Dunning Hotopp’s team searched for traces of microbial DNA in somatic cells—the cells of the body that do not form gametes. Lab members David Riley and Karsten Sieber scanned publicly available data from the 1000 Genomes Project and found more than 7,000 instances of LGT from bacteria, affecting around a third of the people they studied. When they analyzed sequences from the Cancer Genome Atlas, they discovered 691,000 more instances of LGT 99.9 percent of these came from tumor samples rather than normal tissues. Acute myeloid leukaemia cells were particularly rife with bacterial sequences. A third of the microbial genes came from a genus called Acinetobacter, and had been inserted into the mitochondrial genome. Stomach cancer cells also contained lots of bacterial DNA, especially from Pseudomonas. Most of this DNA had been inserted into five genes, four of which were already known to be proto-oncogenes that can give rise to cancer, emphasizing a possible link between LGT and cancerous growth. “Finding these integrations in multiple individuals, as well as in the proto-oncogenes, really spoke to how significant this might be,” said Dunning Hotopp. “We know already that a significant proportion of cancers are due to insertion of genetic material from viruses,” said Etienne Danchin from the French National Institute for Agricultural Research, who reviewed the paper. “But this is the first time, as far as I know, that HGT from bacteria could be suspected as a cause of cancer.” However, Dunning Hotopp is very clear that her results tell us nothing about whether the inserted bacterial DNA contributed to causing the cancers, or were just along for the ride. To get at the question of causation, researchers could deliberately add bacterial DNA into the same sites within human cell lines to see if they turn cancerous, she said. But even if the bacterial LGT can initiate over-proliferation, it would be hard to prevent such transfers with antibiotics. “You don’t know when these transfers occur, and you can’t give people antibiotics their entire life,” said Dunning Hotopp. “A vaccine would be nice, but that is assuming these are causative.” “LGT is incredibly important in evolution but many claims of specific cases of LGT have been seriously flawed,” said Eisen. “I came into this as a serious skeptic. It just seemed so improbable.” But the team won him over. They ran an extensive set of checks to make sure that these bacterial sequences were not laboratory artifacts and had not come from contaminating microbes. For example, they showed that LGT was more common in cancer cells than healthy tissue, and two out of ten cancer types were particularly hard hit. If the bacterial integrations were artifacts of the methodology, it should be equally common in any tissue sample. The team also focused on sequences with high coverage—that is, those which had been read many times over. When the team found evidence of LGT, it was consistent across all of these reads. “In the end, the authors addressed every single question that I and the reviewers raised,” said Eisen. Hank Seifert from Northwestern University, who was not involved in the study, remains cautious. “This paper is very interesting and potentially important,” he said. “However, until the direct analysis of specific tumor cells can be performed to validate that these are real events, this work [is] still speculative.” But Dunning Hotopp’s team cannot do these validation studies herself. For privacy reasons, they cannot access the original tumor samples that their data came from. “People with access to the samples need to validate that the integrations are correct,” she said.  Danchin agrees that the results need to be validated but said, “I am personally convinced what they have found by screening the different databases is true. I think LGT happens much more frequently than we imagine but, most of the time, is just not detectable.” D. R. Riley et al., “Bacteria-human somatic cell lateral gene transfer is enriched in cancer samples,” PLOS Computational Biology, tbc, 2013.

Saturday, 18 May 2013

Key host–pathogen interactions for designing novel interventions against Helicobacter pylori

Helicobacter pylori is a Gram-negative bacterium which has exquisitely adapted to survive in the acidic, hostile environment of the stomach. H. pylori is extremely motile and is found in the mucus layer lining the stomach. By penetrating this thick mucus layer, the bacteria can attach to gastric epithelial cells, thus avoiding being ‘washed’ through the stomach. H. pylori infection tends to persist for the life of the host and, with more than half the population of the world being infected, it is not surprising that H. pylori strains have co-evolved with Homo sapiens. For this reason, and due to several cunning adaptations, the bacteria are able to induce low-level inflammation to gain access to the nutrients required for them to grow and survive, but simultaneously evade host immune responses. Importantly, H. pylori is presently the only bacterial species classified as a type 1 carcinogen by the World Health Organization (WHO) and remains a significant cause of morbidity and mortality worldwide. Approximately one in five infected individuals develop disease, including either peptic ulcer disease, gastric mucosal-associated lymphoid tissue lymphoma and, in the worst case (approximately 1–2% of infected individuals), gastric adenocarcinoma. Gastric cancer remains the second leading cause of death from malignancy worldwide and, with H. pylori being a major cause, it is clear that H. pylori infection still has a major impact on the global disease burden. Clearly there is a need to develop novel therapies and, ideally, a highly efficacious vaccine, based on a sound understanding of H. pylori and its interplay with the human host. This review will summarize recent findings in the context of host–pathogen interactions and modulation of inflammation as well as highlighting recent advances in vaccine development.

Every, A.L (2013) Key host–pathogen interactions for designing novel interventions against Helicobacter pylori Trends in Microbiology, 21, 253–259.