Abstract

IFN- produced by T cells directly induces intestinal stem cell death upon inflammation-induced intestinal injury (see the related Research Article by Takashima et al.).

Intestinal regeneration upon tissue damage is fueled by intestinal stem cells (ISCs) residing in the crypt bottom of the epithelium and marked by the gene Lgr5 (1, 2). There is growing evidence that tissue repair is at least partially mediated by a regenerative inflammatory response (3, 4). How inflammation-induced intestinal injury influences ISCs and their microenvironment (stem cell niche) remains poorly understood. In this issue of Science Immunology, Takashima et al. (5) explore the changes in the ISC niche in vivo upon T cellmediated injury as a model of graft-versus-host disease (GVHD) and in vitro using organoid T cell cocultures. Although earlier studies already implicated interferon- (IFN-) as a negative regulator of intestinal epithelial homeostasis (68), Takashima et al. now demonstrate that IFN- directly acts on ISCs by triggering apoptosis.

In an allogeneic bone marrow transplant (BMT) model, Takashima and colleagues found that ISC numbers per intestinal crypt were markedly reduced in mice receiving bone marrow alone or bone marrow and T cells when compared with normal control mice. While the ISCs in the mice receiving only bone marrow recovered 7 days later, the ISC numbers remained reduced in those mice also transplanted with donor T cells. Of note, Paneth cell numbers were also reduced after ISC depletion. The numbers of organoids established from the intestines of mice 10 days after BMT recovered back to that of control mice, whereas the organoid forming capacity from crypts of mice after combined transplantation of bone marrow and T cells remained significantly lower. Similar in vivo and in vitro results were obtained when autoreactive T cells were transplanted, pointing to a common feature of T cellmediated intestinal injury.

As seen by three-dimensional confocal microscopy, intraepithelial T cells (CD3+ IELs) preferentially localized to the villus region, whereas lamina propriaassociated T cells (CD3+ LPLs) were equally distributed along the crypt-villus axis of control mice (Fig. 1A). Conversely, mice receiving bone marrow and allogeneic T cells showed a progressive increase in the density of both CD3+ LPLs and CD3+ IELs in the crypt region.

To identify signaling molecules that cause the loss of ISCs in this model, Takashima and colleagues performed several elegant murine and human epithelial organoid coculture experiments. Murine nave allogeneic T cells did not impair murine intestinal organoid numbers, whereas alloreactive T cells effectively reduced organoid numbers. Likewise, human allogeneic cytotoxic T cells robustly inhibited human intestinal organoid forming efficiency. Even bead-activated autologous T cells suppressed human intestinal organoid growth. The authors then proceeded to screen for potential pathways mediating cytotoxicity. Organoids cocultured with T cells in the presence of antiIFN- neutralizing antibodies showed normal growth. Although IFN- receptor (IFN-R)depleted T cells were still able to affect organoid viability, IFN-Rdepleted organoids were resistant to T cellmediated killing. Organoid toxicity by IFN- was also observed in the absence of T cells. Live imaging confirmed the progressive ISC depletion upon organoid exposure to IFN-. Treatment of organoids with the immunosuppressive JAK1/2 inhibitor ruxolitinib robustly preserved numbers of both organoids and ISCs in the presence of IFN-, irrespective of whether the organoids were cultured alone or together with T cells. The authors additionally demonstrated that JAK1-depleted organoids are resistant to IFN- treatment. Further downstream, ruxolitinib prevented STAT1 phosphorylation by IFN- in intestinal crypts, and, in line, STAT1-depleted organoids were resistant to growth suppression in response to IFN- treatment.

IFN-treated organoids showed reduced expression of ISC marker genes. ISCs underwent apoptosis in vitro in a direct response to IFN-. Next, the authors confirmed in vivo that ISC numbers did not change upon transplanting allogeneic bone marrow and T cells when treating mice with IFN- neutralizing antibodies. Likewise, ruxolitinib treatment protected ISCs from T cellmediated killing in vivo. Donor T cells, particularly T helper 1 cells, were activated and IFN-+. Transplanting IFN-depleted allogeneic T cells robustly reduced the ISC loss and allowed epithelial cell proliferation to increase.

Takashima and colleagues lastly investigated whether IFN- directly induces ISC apoptosis. Using tissue-specific depletion of IFN-R1, the authors found that epithelial loss of the receptor protects from the immune-mediated GVHD phenotype. IFN-R1 is expressed by both ISCs and Paneth cells, the epithelial component of the ISC niche (9). However, Paneth celldeficient organoids remained sensitive to both IFN- and allogeneic T cellmediated cytotoxicity. Likewise, T cells were able to reduce the number of organoids containing IFN-R1deficient Paneth cells, whereas organoids containing IFN-R1deficient ISC were protected from cytotoxicity. The authors demonstrated in further experiments that IFN- directly induces ISC apoptosis independent of Paneth cells (Fig. 1, B and C).

The study by Takashima et al. extends our knowledge on signaling between ISCs and immune cells, identifying ISCs as direct targets of IFN- secreted by T cells in immune-mediated intestinal damage (as caused by GVHD). In the 2015 study by Lindemans et al., this group already identified that interleukin-22 (IL-22) secreted by group 3 innate lymphoid cells (ILC3s) directly stimulates ISCs to proliferate and regenerate the intestinal epithelium upon inflammation-induced intestinal injury (4). Modulating the effects of T cellderived IFN- on ISC, for instance, by suppressing JAK/STAT signaling via ruxolitinib treatment, may provide a new therapeutic avenue to reducing GVHD-induced damage of the intestinal epithelium (10).

(A) ISCs maintain adult homeostasis of the intestinal epithelium. T lymphocytes patrol the intestine. (B) Takashima et al. show that in GVHD as modeled by BMT and aberrant activation of T lymphocytes, T cellderived IFN- directly acts on ISCs and induces apoptosis via JAK/STAT signaling. (C) Disease progression results in marked intestinal damage due to loss of ISCs and their niche.

Acknowledgments: Funding: K.K. is a long-term fellow of the Human Frontier Science Program Organization (LT771/2015). Competing interests: H.C. and K.K. are named inventors on patents or patents pending on Lgr5 stem cellbased organoid technology.

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IFN-: The T cell's license to kill stem cells in the inflamed intestine - Science

BUFFALO, N.Y. Michael W. Russell, PhD, professor emeritus in the Department of Microbiology and Immunology in the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo and the Department of Oral Biology in the UB School of Dental Medicine, has been awarded the distinction of Fellow by the American Association for the Advancement of Science.

Russell, whose specialty is mucosal immunology and vaccine development, was recognized for his novel approaches to mucosal immunization and the induction and function of secretory and serum IgA antibodies, the AAAS said.

I was very pleased to receive this honor, and especially gratified by the citation for distinguished contributions to the field of mucosal immunology, which is the major discipline governing my research career for over 50 years, Russell said.

He was nominated by Thomas Van Dyke, DDS, PhD, of the Forsyth Institute in Boston, who is a UB School of Dental Medicine alumnus.

Russell, who has been a member of the AAAS for 15 years, is one of 443 AAAS members elected as Fellows this year. These individuals have attained this rank because of their efforts on behalf of the advancement of science or its applications are scientifically and socially distinguished, the association said.

The new Fellows were announced in the AAAS News & Notes section of the Nov. 28 issue of the journal Science.

The 2019 recipients will be recognized on Feb. 15, 2020, at the Fellows Forum during the AAAS Annual Meeting at the Washington State Convention Center in Seattle. They each will receive an official certificate and a gold and blue rosette pin. The two colors represent science and engineering, respectively.

The distinction of Fellow is a lifetime honor. Fellows are expected to maintain the highest standards of professional ethics and scientific integrity.

Russell attended the University of Cambridge in England, where he studied natural sciences/biochemistry, and the University of Reading, also in England, where he studied microbiology. He was a postdoctoral research fellow at Guys Hospital Medical and Dental School in London. He held several positions at the University of Alabama at Birmingham and served as a visiting associate professor at the Royal Dental College in Aarhus, Denmark.

Russell began his career at UB in 2000. He retired in 2016. His research was funded by grants from the National Institutes of Health from 1984 to 2013.

He has published 143 peer-reviewed research papers and reviews in scientific journals, and 90 book chapters and conference reports, and was an editor for the 4th edition of Mucosal Immunology (Academic Press/Elsevier, 2015). He and his colleagues have been awarded five patents.

Russell is a resident of East Amherst.

Link:
UB researcher named a Fellow by the American Association for the Advancement of Science - UB News Center

Most people dont die from tropical diseases like hookworm, schistosomiasis, or even malaria. But these understudied diseases, often caused by parasites, rob people of health in sometimes insidious ways.

For example, schistosomiasis is a disease caused by a waterborne, snail-transmitted parasite, and its the research focus of the School of Veterinary Medicines Robert Greenberg.

Its not necessarily a death sentence, though there are fatalities says Greenberg, a research associate professor of pathobiology. But you get anemia, children get stunted in terms of growth and cognitive abilities. Its a disease that keeps people in poverty.

Such diseases, by and large, receive less financial support and, as a result, far less scientific attention than those that more often afflict residents of wealthier nations, such as diabetes and heart disease.

Penn Vet researchers, however, have committed attention to these diseases, which, taken as a whole, affect billions around the globe. Their work benefits from the niche strengths of the school, specifically in immunology and host-pathogen interactions.

At the Vet School, a third of our funding supports infectious disease research, says Phillip Scott, vice dean for research and academic resources and a professor of microbiology and immunology in the Department of Pathobiology. Thats pretty amazing, given that the School is also awarded funding for regenerative medicine, for cancer, and for a variety of other areas.

That strength is seen in the research portfolios of some of the more senior faculty, such as Christopher Hunters work on toxoplasmosis, James Sparky Loks studies of Strongyloides, Carolina Lopezs investigations of lung infections, and Bruce Freedman and Ron Hartys efforts against Ebola and other hemorrhagic viral diseases. It has attracted newer faculty members, like cryptosporidium expert Boris Striepen, to Penn Vet.

Penn VetsDeBroski Herbert, for example, an associate professor of pathobiology, had held prior positions at Cincinnati Childrens Hospital and the University of California, San Francisco. He had felt called to work on hookworm, a parasite he first learned of growing up in the South from his great-grandmother, who warned him about walking around barefoot because of the risk of contracting the parasite. But at the medical centers where he worked, he shifted gears away from studying the parasite itself, instead focusing on related research in asthma and allergy.

Here, our veterinary students are likely to encounter parasites in their patients, so working directly on the parasite is easier to justify, Herbert says.

This spring, Herbert traveled to Nigeria where, working with partners at the Nigerian Institute for Medical Research, he launched a study of hookworm in 300 school-aged children in five sites around the northern and central portions of the country.

The goal is to first establish what the prevalence of the disease really is and draw attention to that, Herbert says. And secondly, this is a place where the World Health Organization is going in and doing mass treatments, so Im also interested in learning something very novel about the association between the microbiome, tissue repair, immune suppression, and metabolism in these children in Nigeria.

Those insights could lead to treatments, but they will also likely shed new light on the basic science of how hookworms affect their host. This pairing of basic and applied work is characteristic of Penn Vet scientists. In Scotts lab, for instance, which has long pursued studies of the tropical disease leishmaniasis, advances in basic science have unfurled alongside insights that stand to reshape treatment of this parasitic infection which, in its cutaneous form, can cause serious and chronic skin ulcers.

When I was a postdoc at NIH, theres something my boss used to say that I still use in my talks, says Scott. He said, Leishmaniasis has done more for immunology than immunology has done for leishmaniasis. And you could substitute parasitology for leishmaniasis and it would be much the same quote.

What I think is exciting right now, he adds, is that thats going to change.

As part of this contribution toward advancements against parasitic disease, Scott has traveled regularly to a leishmaniasis clinic in Brazil to obtain samples for his research and, back at Penn, has paired up with dermatology and microbiome experts such as Elizabeth Grice in the Perelman School of Medicine, and Dan Beiting from Penn Vets Center for Host-Microbial Interactions to break new ground.

No vaccine exists for leishmaniasis and current therapies fail a substantial percentage of the time. But recent publications from Scotts lab have revealed new information about how the disease and existing treatments work and when to predict when they dont. At the same time, Scott and colleagues research into the immunology of the infection has identified ways that FDA-approved drugs could be leveraged to alleviate the most severe forms of leishmaniasis.

A major hurdle to matching appropriate therapies with neglected disease comes at one of the earliest stages of medical intervention: diagnostics. Researchers at Penn Vet are employing innovative techniques to fill these unmet needs. Robert Greenberg is one who has crossed disciplinary boundaries to do so.

In a partnership between Greenberg and Haim Bau of Penns School of Engineering and Applied Science, the scientists are working to craft an improved diagnostic test for schistosomes, which can lead to schistosomiasis, causing anemia, tissue fibrosis and lesions, malnutrition, learning difficulties, and, depending on the parasite species, bladder cancer and heightened HIV risk.

Greenberg has studied the ion channels that govern key biological functions in schistosomes to potentially develop drug targets that paralyze and kill the organisms. And by adapting insights from other researchers about additional parasitic-specific targets, he's helping Bau train hismicrofluidic, portable diagnostic system on schistosomes to one day help clinicians make point-of-care diagnoses and issue timely treatment for infected patients.

The current diagnostics are pretty terrible, Greenberg says. Were looking at some new approaches now that should give us a much earlier, more sensitive, and more specific diagnosis for individual patients that might be able to detect other coinfections simultaneously.

At Penn Vets New Bolton Center, Marie-Eve Fecteau and Ray Sweeney are also taking part in the design of a 21st-century solution to diagnostics of an insidious and challenging disease, in this case, a disease that takes a particular toll on livestock: paratuberculosis, or Johnes disease. Caused by the bacterium Mycobacterium avium paratuberculosis, the condition affects ruminants such as cows and goats and drastically decreases their weight and milk production.

Ruminants are a very important part of survival and livelihood in developing countries, says Fecteau, an associate professor of food animal medicine and surgery. Families may rely on only one or two cows to provide for their nutritional needs or income, and if that cow is affected by Johnes, thats a serious problem.

Paratuberculosis has been shown to be endemic in parts of India and elsewhere in Asia and is also a burden for U.S. farms, where 70% of dairy herds test positive for the infection. Separating infected animals from the herd is a key step to stem the spread, but the bacteria have proved difficult to grow in the lab, making diagnosis challenging.

Fecteau and Sweeney, the Mark Whittier & Lila Griswold Allam Professor at Penn Vet, are hoping to change that, working with Beiting and biotechnology firm Biomeme to develop a lab in a fanny pack, as they call it: A stall-side diagnostic test that relies on PCR to identify infected animals from stool samples within hours.

This is the kind of technology that could be extremely valuable for use in areas where sophisticated technology is harder to come by, says Sweeney.

Elsewhere at Penn Vet, researchers are approaching globally significant diseases by focusing on the vector. In the insectary that is part of Michael Poveloness lab, he and his team test methods to stop disease-transmission cycles within mosquitoes.

In the work, which relies on disrupting the way that mosquitoes interact with or respond immunologically to the pathogens they pass on, Povelones, an assistant professor of pathobiology, has explored everything from dengue to Zika to heart worm to elephantiasis, and his discoveries have implications for targeting a much longer list of diseases. In a recent study, Povelones and colleagues developed a new model system for studying the transmission of diseases caused by kinetoplastids, a group of parasites that includes the causative agents of Chagas disease and leishmaniasis.

We think this could be a model for a number of important neglected diseases, Povelones says.

In the latest of his teams work finding ways to activate mosquitoes immune system to prevent pathogen transmission, theyve identified a strategy that both blocks heartworm and the parasite that causes elephantiasis.

These two diseases have very different behavior once theyre in the mosquito, so were still figuring out why this seems to work for both, says Povelones. But were very encouraged that it does.

Using these types of creative approaches is a common thread across the Vet School, and the researchers efforts and successes seem to be multiplying. To continue accelerating progress, the School is developing a plan to harness these strengths, working with existing entities such as the Center for Host-Microbial Interactions internally and cross-school units such as the Institute for Immunology.

We are a key part of the biomedical community at Penn and bring a valuable veterinary component to the table in confronting diseases of poverty, says Scott.

Homepage image: Bruce Freedman and Ronald Harty of the School of Veterinary Medicine have used a non-infectious model to study how the Ebola virus spreads from cell to cell. Their findings have pointed to new targets for a drug to reduce the severity of Ebola infection. (Image: Gordon Ruthel/Penn Vet)

Read more here:
These overlooked global diseases take a turn under the microscope - Penn: Office of University Communications

Every year, about 300,000 people worldwide receive a new heart valve. Whenever possible, doctors use valves made of tissue from cows or pigs, because the synthetic alternatives can cause blood clots.

But there is a hitch. Although animal tissue valves can last up to 30 years in people over 60 years old, they can be destroyed in just five years in a younger person, probably because of their more aggressive immune system.

Enter the genetically engineered bull.

Scientists used CRISPR gene editing technology to create two bovine mutations that should lessen peoples immune responses to the animal tissue.

The mutations knock out two sugars which coat the bulls cells but are not found in humans: -Gal and Neu5Gc.

The objective is to have animals that express tissues that are less foreign to the human body, said Dr Emanuele Cozzi, coordinator of a project calledTRANSLINK, which has been trying to improve the long-term success of heart valve replacements.

In theory this means peoples immune systems will be less likely to attack the animal tissue, added Dr Cozzi, who is director of the Transplant Immunology Unit at Padua University Hospital in Italy.

Clone

As part the project, an Italian company,Avantea, created bovine cells with the two mutations and used them to clone a bull with a technique similar to the one that producedDolly the sheep.

We are the first to make cattle (with these) mutations, said Professor Cesare Galli, co-founder of Avantea.

The cloning step is required to make the founder animals. Then they can breed normally, said Prof. Galli.

Avantea had created the same mutations in pig cells using a technology called Transcription activator-like effector nucleases (TALEN) to edit the DNA, before CRISPR was available.

With CRISPR it is much easier to prepare the reagents that are needed to implement the system, said Prof. Galli.

That makes CRISPR cheaper because the reagents can be prepared in-house. However, in theory at least, it is less accurate, he added.Being less precise in recognising the sequence to cut, there is the risk of undesired cuts this is a risk that has yet to be quantified.

The animals we generated could have a potential application for food consumption, at least for people who do not tolerate red meat.

Professor Cesare Galli, co-founder, Avantea, Italy

Quality of life

About 100,000 people a year are given synthetic heart valves because they are too young to receive the animal tissue version.

But these valves can lead to dangerous blood clots forming, so patients have to live on anticoagulants that impose severe limitations on a young persons life, saysDr Cozzi.

People have to avoid competitive sports and jobs with a high risk of injury, like construction or some police work.

If an accident occurs while on duty (they) may bleed to death, said Dr Cozzi.

Although preliminary data suggests that peoples immune systems attack valve transplants in response to the animal tissue used, scientists need more solid evidence of this before they can recommend using the genetically engineered animal tissue, says Dr Cozzi.

Other factors including someones blood pressure cannot yet be ruled out as affecting the valves lifespan, he says.

To understand more, TRANSLINK is carrying out a study of 1,600 cardiac patients the largest of its kind to compare their immune responses to animal or synthetic valve transplants or other types of surgery. The results are expected next year.

If the study shows convincingly that immunology is behind the premature failure of animal-derived heart valves, it should not be too difficult to find potential investors who could bring the genetically engineered tissue valves to market, says Dr Cozzi.

My hope would be that, based on the data of our study, we may change the outlook of young patients (and offer them) a better quality of life.

The mutations in both pigs and cows may pave the way for people to receive transplants of whole animal organs, Dr Cozzi says.

Red meat allergies

The cloned animals may also benefit people allergic to red meat a reaction which sometimes develops after they have been bitten by a tick.

Scientists think the main culprit is the -Gal sugar found in all animals other than primates.

Anything from a steak to collagen used in cosmetics can trigger a reaction, which can range from a skin rash to anaphylactic shock.

The animals we generated could have a potential application for food consumption, at least for people who do not tolerate red meat, said Prof. Galli.

Some scientists in the US are also looking at possible links between the Neu5Gc sugar and cancer. The World Health Organization has classified red meat asprobably carcinogenic to humans,although there is limited evidence.

Millions of years ago, humans developed a mutation that stopped the production of Neu5Gc and produced a slightly different sugar called Neu5Ac instead. The mutation made people resistant to malaria, and quickly spread across the population.

Pigs, sheep, cows and most other mammals with the exception of deer and some dogs produce the Gc form which is highly antigenic in humans, says Prof. Galli, meaning it prompts a strong immune response.

Chicken and fish do not, which is one reason they are considered to be healthier to eat.

The cloned cows could be a useful source of milk for baby food, as it would be closer to human milk because it does not carry the antigen, says Prof. Galli.

Avantea also plans to use CRISPR to create horses with the same mutations as the cows and pigs. Horse serum is used to make antidotes to snake bites, but it can trigger adverse reactions in some people. Knocking out -Gal and Neu5Gc may prevent that, he says.

The potential for the cloned pigs, cows and horses to improve peoples health is huge. But for the time being, much of it is still theory, the scientists say.

We have the tools now, but there is work to be done to prove whether there is an advantage or not, said Prof. Galli.

The research in this article was funded by the EU. If you liked this article, please consider sharing it on social media.

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Genetically engineered animals offer fresh hope to heart valve patients - ScienceBlog.com

The upcoming market report contains data for the historical year 2015, the base year of calculation is 2016 and the forecast period is 2017 to 2024. The https://marketreports.co/global-infectious-immunology-market-size-status-and-forecast-2019-2025/171459/#Free-Sample-Report

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Types of Global Infectious Immunology Market:

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Table of Content (TOC) at a glance:Overview of the market includes Definition, Specifications, and Classification of Infectious Immunology Size, Features, Scope, and Applications.

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Infectious Immunology Market 2019, Trend, CAGR Status, Growth, Analysis and Forecast to 2025 - VaporBlash