Cryptosporodium is a leading cause of diarrheal disease in young children around the world. The intestinal parasite contributes to childhood mortality and causes malnutrition and stunting. How a parasite like this one reproduces and completes its life cycle has significant impact on child health.

“It’s the product of parasite sex, that is infectious agent here, a spore, that is transmitted by contaminated water,” Striepen says. “So, if you break its ability to have sex, you would break the cycle of transmission and infection.”

In a new paper in PLOS Biology, Striepen and colleagues in his lab tread new ground in understanding how Cryptosporidium reproduces inside a host. Using an advanced imaging technique allowed the scientists to observe the entire lifecycle in the laboratory. They found the parasite completes three cycles of asexual replication and then directly switches to male and female sexual forms. Their observations refute an intermediate stage that was introduced in the 1970s and align well with the original description of physician and parasitologist Edward Tyzzer who discovered this pathogen more than a century ago.

“What we have shown contradicts what you see in most textbooks today, including the description at the Centers for Disease Control and Prevention website,” Striepen says. “It’s really a super simple lifecycle that is completed in a single host in three days and only has three characters: asexual cells, male cells, and female cells.”

Other parasites, such as the malaria parasite Plasmodium, a “cousin” of Cryptosporidium, have more complicated and lengthy paths to follow an overall similar life cycle. While Crypto completes its lifecycle in one host, most malaria parasites move between two: a mosquito, where the parasite’s sexual reproduction occurs, and a human, where its asexual replication occurs.

“Cryptosporidium is a great model to study parasite development; you can see analogous steps to what happens with the malarial parasite, but it’s much simpler because it all happens over only three days in one host, and we can observe it in simple cell cultures,” Striepen says.

In earlier work on Cryptosporidium, Striepen and colleagues had found that sexual reproduction appeared necessary for the parasite to move from one host to infect another but also to sustain itself in a host during chronic infection. Blocking developmental progression and parasite sex thus presents itself as a strategy to cure or prevent infection.

Cryptosporidium is a minuscule single-cell parasite that invades and reproduces within the cells of the intestine of its hosts. To get a closer look at what was happening, the researchers developed a live-cell microscopic imaging technique to track the progression of the parasite through multiple days in cell cultures. Using genetic engineering they added a fluorescent label to the nucleus of each parasite, allowing them to observe the replication of the parasite in real time and to distinguish its different lifecycle stages.

What they saw was the parasites “count to three,” says Striepen. Rather than responding to environmental cues, the parasites followed a rigid built-in plan. After infecting a culture, the parasite underwent three cycles of asexual reproduction. Each cycle took about 12 hours, during which the parasite established a home within the host cell and replicated itself resulting in eight new infectious parasites. Those were then released to infect surrounding host cells.

After these three waves of amplification, their fate changes abruptly, and they turn into either male or female gametes, or sex cells, in a process that also took about 12 hours. Tracking individual parasites and their offspring the researchers found no evidence for a specialized intermediate form assumed by many textbooks, demonstrating direct development.

Interestingly, the parasite appeared pre-committed to their future fate and carried that plan from one host cell into the next in a way not yet understood.

The researchers were intrigued to see that male and females arise from the infectious forms released from the same asexual parasites. “One of the really interesting aspects of sexual identity here is that it is not inherited and hard-wired in the genome but much more fluid,” Striepen says. “There’s an asexual cell that divides itself into genetically identical clones, and then those clones somehow become male or female on the fly, resulting in dramatically different cell shape and behavior.”

Future research will focus on the molecular mechanism of commitment to understand how this life cycle is programmed into the parasite’s biology. Understanding the life cycle of Cryptosporidium is critical in thinking about how to create a vaccine or therapy for the disease, Striepen says.

“How cells make decisions and execute developmental plans is one of the most fundamental questions in biology. Cryptosporidium offers a tractable system to better understand this mechanism in parasites. Hopefully we can gain insights that contribute to the understanding of cryptosporidiosis and malaria and lead the way to new urgently needed interventions for these important diseases.”

Boris Striepen is the Mark Whittier and Lila Griswold Allam Professor of Microbiology and Immunology at the University of Pennsylvania School of Veterinary Medicine.

Striepen’s coauthors were lab members Elizabeth D. English, Amandine Guérin, and Jayesh Tandel.

The study was supported by grants from the National Institutes of Health to Striepen and a postdoctoral fellowship from the European Molecular Biology Organisation to Guérin.

But they don’t work in all patients. And now a new study in Nature Immunology led by researchers from Penn’s School of Veterinary Medicine suggests a possible reason why: Not only can these drugs encourage the activity of cancer killing T cells, but they can, in some cases, also activate a population of regulatory T cells that serve the opposing function — to rein in that attack.

In the study, immunologists led by Penn Vet professor Christopher Hunter and doctoral student Joseph Perry discovered that blocking the activity of the checkpoint protein PD-L1, which interacts with a T cell receptor PD-1, enhanced the activity of a subset of T cells known as effector regulatory T cells, or effector Tregs. This intervention unexpectedly reduced the ability of mice to control a parasite infection.

The findings reveal a complexity to how the body “regulates the regulators” of the immune system, says Hunter. “Once you have those Tregs to control your T cell response, you also need to control them,” he says. “It’s like with a car. You have the ignition, the accelerator, and you also need a brake. PD-1 is a brake not only on killer T cells but also on Tregs.”

T cells may be best known for their roles in fighting infections and killing cancer cells. But the immune system also has several mechanisms in place to counterbalance those responses to prevent out-of-control inflammation that could damage healthy tissue. Tregs are one aspect of this balancing act.

“You can think of Tregs as the health and safety inspectors of the immune system,” Hunter says. “They’re really important, but sometimes, when you need to mount an immune response against a pathogen, you need them to take a back seat. When an infection is present, we see Treg levels crash so that an effector response can emerge. But we never understood what causes that crash.”

The researchers began to understand more after exploring an unanticipated finding. They discovered that, when the checkpoint protein PD-L1 was blocked, mice infected with Toxoplasma gondii were less effective at fighting off the parasite than mice with an uninhibited PD-L1. “That was the opposite of what we expected,” Hunter says, as the dogma would have suggested that blocking this checkpoint inhibitor would allow for a better effector T cell response against infection.

Digging into the surprising result, Perry, Hunter, and colleagues realized that it aligned with what some cancer researchers had recently reported. In certain cancers, the other groups had found, blocking PD-L1 led to worse outcomes, seemingly because of an increase in a population of Tregs that restrained killing of cancer cells.

When the Penn-led team looked in the context of a T. gondii infection, they discovered the signaling molecule interferon gamma turned on PD-L1, which precipitated a rapid decline in Treg numbers. A PD-L1 inhibitor mitigated this effect and stopped the Treg crash. This treatment alleviated the harmful effects of inflammation on mice but also impaired the ability of T cells to fight infection. Similarly, Tregs altered to lack PD-1, the receptor which with PD-L1 interacts, also led to increases in Treg activity.

“It seems that the effector T cell versus Treg ratio is really important,” says Hunter.

As the researchers began to learn more about how Tregs were activated and operated during an infection, they were curious about whether this pathway worked when animals were in a normal, healthy state. Just as there are different types of “regular” T cells, including CD8 and CD4 T cells and many more subdivisions besides, the new work underscores that there are subpopulations of Tregs as well, which have different roles in the body. In healthy, uninfected animals, the team found differences between the proteins expressed by different Treg populations, including some that expressed PD-1, which the researchers termed “effector Tregs.”

“These results taught us that there’s a large population of activated PD-1-positive Treg cells present as a normal part of everyday life that help limit the immune system,” Perry says.

“We think these PD-1 high cells are the most active Tregs,” says Hunter. “It’s a complex landscape, and it’s possible that some checkpoint inhibitor treatments have been inadvertently targeting these Tregs and not others, leading to unexpected outcomes.”

In ongoing investigations, Hunter, Perry, and colleagues continue to examine this pathway, as well as those involved in other immune checkpoints. The findings could have implications not only in refining cancer checkpoint inhibitor therapies but also in conceiving new strategies for treating autoimmune disease. “In that case you would want to increase the number of Tregs,” Hunter says. “Maybe we could think about ways to augment that arm of the immune system to treat inflammatory diseases.”

Christopher A. Hunter is the Mindy Halikman Heyer Distinguished Professor of Pathobiology at the University of Pennsylvania School of Veterinary Medicine.

Hunter’s coauthors are Penn Vet’s Joseph A. Perry, Lindsey Shallberg, Joseph T. Clark, Jodie Gullicksrud, Jonathan H. DeLong, Bonnie B. Douglas, Zachary Lanzar, Keenan O’Dea, Christoph Konradt, Jeongho Park, Daniel Grubaugh, Arielle Glatman Zaretsky, Igor E. Brodsky, and David A. Christian; Penn’s Perelman School of Medicine’s Andrew P. Hart; Merck & Co.’s Renee de Waal Malefyt; and Harvard Medical School’s Juhi R. Kuchroo and Arlene H. Sharpe.

The study was supported by the National Institute of Allergy and Infectious Diseases (grants AI125563 and AI41158).

The Vibrant Oceans Initiative presented their white paper on the future of the delicate and crucial habitats at the Our Oceans Conference held in Palau on Thursday.

Drawing on expertise from universities and wildlife conservation groups from across the world, including the University of Leicester, the group provide six key recommendations intended to promote the ‘persistence and survival’ of coral reefs.

Forecasts show that coral reef ecosystems around the globe — key to huge numbers of marine species and a source of food, livelihoods, and cultural heritage for half a billion people — are likely to become functionally degraded by 2050, if the goals of the Paris Agreement are not met.

Even with drastic emission reductions to ensure global warming is kept within 1.5°C above pre-industrial levels, up to 90% of the world’s corals could still vanish in the next three decades, leaving behind a reef structure that will lose many of its functions.

Jens Zinke is a Professor of Palaeobiology at the University of Leicester, whose research examines large coral habitats to track environmental and climate change over the last three centuries into the modern day. Speaking about the report, of which he is a co-author, Professor Zinke said:

“Coral reefs are the ‘canaries in the coal mine’ when it comes to sensing ecosystems under stress from ocean warming due to climate change. Corals can sense when ocean temperatures exceed a dangerous threshold and warn us when we need to take measures.

“Our research has shown that coral reefs have been severely impacted by ocean warming in the past three to four decades, yet some reef locations show lower rates of warming or benefit from mitigating circumstances due to local oceanography.

“Some reefs have the ability to resist or recover from thermal stress faster than others, and these reefs may serve as sanctuaries under future warming. This is a major new research direction — to find those locations and protect them before they are gone.”

In 2018 the Vibrant Oceans group identified 50 reefs that are most likely to resist and survive climate change. The habitats are located largely in the Pacific and Indian oceans, with further reefs in the Caribbean and east of Africa.

Previously the 50 reefs were mainly chosen at sites that escaped climate change. Now, the scientists call for a wider portfolio of reefs that should include resistant and fast-recovering reefs.

The group’s latest recommendations, presented in the white paper ‘Forecasting Climate Sanctuaries for Securing the Future of Coral Reefs’, include:

• Continuation of the 50 Reefs approach as ‘climate change avoidance sanctuaries’ as a priority for investment in coral reef conservation.
• Expansion of the 50 Reefs conservation portfolio for climate change to include coral resistance and recovery sanctuaries.
• Increase in support for regional evaluations of the health of the 50 Reefs portfolio, and sustainable financing initiatives to support the implementation of regional portfolios.
• Catalysing large-scale, data-driven coral reef monitoring efforts to test and develop new models and predictions of climate sanctuaries.
• Use of the latest climate coral reef science to guide investments, especially as the impacts of climate change accelerate and produce novel environmental stresses and responses among reefs.
• Embracing a far-reaching approach to the management of 50 Reefs sites, including connections to broader seascapes, fisheries and water quality management, mitigation of other pressures (for example, industrial development), so that effective and equitable management has measurable benefits for coral reefs and coastal communities.

‘Forecasting Climate Sanctuaries for Securing the Future of Coral Reefs’ is available in full from the Wildlife Conservation Society (WCS): https://wcs.org/coral-science-whitepaper

Funding partners for the initial Vibrant Oceans study include Bloomberg Philanthropies, while ongoing conservation work partners include Oceans 5, the Paul G. Allen Family Foundation, and Tiffany & Co. Foundation.

Conservation partners include the WCS, Rare, The Nature Conservancy, Blue Ventures, and Conservation Ecosystem Partnership Fund.

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Materials provided by University of Leicester. Note: Content may be edited for style and length.

“We are beginning to recognize that a woman’s reproductive history tells a lot about her future risk of heart disease,” says first author Emily Lau, MD, MPH, cardiologist and director of the Menopause, Hormones & Cardiovascular Clinic at MGH. “Whether a woman has difficulty becoming pregnant, what happens during her pregnancies, when she transitions through menopause all influence her risk of heart disease later in life.”

Infertility affects about 1 in 5 US women and includes a spectrum of conception difficulties, but its link with heart failure has not been well-studied until recently. Partnering with the Women’s Health Initiative (WHI), which was designed in the early 1990s and queried a woman’s reproductive history, Lau and colleagues studied postmenopausal women from the WHI and examined whether infertility was associated with development of heart failure.

There are two types of heart failure: heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). Ejection fraction is a measurement related to the volume percentage of blood that is pumped from the left ventricle of the heart during each beat. An ejection fraction less than 50% is commonly viewed as abnormal or reduced.

The team found an association between infertility and overall heart failure, specifically with HFpEF, a form of heart failure that is far more common in women regardless of fertility history. Among the 38,528 postmenopausal women studied, 14% of the participants reported a history of infertility. Over a 15-year follow up period, the researchers noted that infertility was associated with 16% future risk of overall heart failure. When they examined heart failure subtypes, they found that infertility was associated with a 27% increased future risk of HFpEF.

Over the past decade, HFpEF (where the heart muscle does not relax well) as opposed to HFrEF (where the left ventricle does not pump well), has become the dominant form of heart failure in both men and women. But it remains more common in women. “It’s a challenging condition because we still do not completely understand how HFpEF develops and we do not have very good therapies to treat HFpEF,” says Lau.

“I think our findings are particularly noteworthy because heart failure with preserved ejection fraction is more prevalent in women,” says Lau. “We don’t understand why we see HFpEF more in women. Looking back in a woman’s early reproductive life may give us some clues as to why.” Of note, the team observed that the link persisted regardless of whether an individual eventually conceived or had a live birth.

The increased risk was independent of traditional cardiovascular risk factors and other infertility-related conditions. “There has been some suggestion in previous studies that women with infertility do have more cardiometabolic risk factors,” says Lau, but the team did not find that cardiometabolic risk factors explained the link between infertility with heart failure in this study. They also looked to see if other infertility-related conditions like thyroid disease, irregular menses, and early menopause explained the association between infertility and heart failure but did not evidence to support that hypothesis either.

“So it really begs the question: what are the mechanisms driving the association between infertility and heart failure,” says Lau. Is it shared risk factors, or is infertility on the causal pathway? She mentions vascular and endothelial dysfunction may be involved and plans on eventually clarifying the mechanism underlying the link between infertility and heart failure. In the future, Lau hopes to conduct a prospective study of women with an infertility history involving exercise parameters, vascular measures, and more, to solve the mystery.

“We as scientists and doctors are beginning to recognize how important a woman’s reproductive history is for their future risk of heart disease. Infertility is one of many cardiovascular risk factors, such as hypertension and high blood pressure, but reproductive history is not routinely considered as part of the cardiovascular risk assessment,” says Lau. Since people do not tend to develop heart failure until well in their 60s and beyond, and infertility is mostly experienced in the 20s, 30s, and 40s, many physicians are not thinking about the connection. “We cannot change a woman’s history of infertility, but if we know a woman has had a history of infertility, we can be more aggressive about counseling her about other modifiable risk factors including high blood pressure, high cholesterol, smoking, and beyond.”

This research was supported in part by the National Institutes of Health and American Heart Association.

Most of the excess sodium comes from processed and packaged foods, so the food industry and food scientists continuously look for ways to reduce sodium. A new paper from the University of Illinois provides a comprehensive review of scientific literature on sodium reduction strategies in food production.

“Sodium overconsumption is a huge health concern, and the FDA has recommended sodium reduction in food since the 1980s, but we haven’t succeeded yet. While the unit volume of salt in the food supply has not increased, the amount of sodium consumption has gone up, because we just consume a lot of food,” says Soo-Yeun Lee, professor in the Department of Food Science and Human Nutrition (FSHN) at U of I and co-author on the paper.

We only need around 450 milligrams (mg) of sodium per day, and the recommended maximum amount is 2,300 mg, or 1,500 mg for those at risk for hypertension. But average consumption exceeds 3,000 to 3,500 mg per day — or 50% to 100% above the upper limit. More than 70% of our sodium intake comes from processed and packaged foods, primarily cured meats, bread, cheese, and soups.

The researchers conducted a scoping review including primary studies, literature reviews, book chapters, and patents covering sodium reduction in food products. They focused on studies that included sensory data with human subjects, because palatability is essential for consumer acceptance.

“In this review, we looked at different food systems. The way you would reduce salt in a solid system, like a topical application on snack foods, such as salted peanuts or salted chips, would be very different from embedded application in semi-solid foods like cheese or bread. And in a liquid system like soup, where it is completely dissolved, it would be really different in the way we could reduce salt yet provide the palatability it gives,” Lee states.

“We’re hoping this work will provide insight into the wide variety of salt-reducing technologies that exist. This can help food companies be more informed to use different strategies than what they have been doing,” she adds.

The researchers identified five main strategies: Salt reduction, salt replacers, flavor modification, physical modification, and functional modification.

“The most obvious one is to remove salt from the recipe, and that is a key component in all of the strategies when sodium reduction is the goal,” says Aubrey Dunteman, graduate student in FSHN and lead author on the paper.

But it is not possible to completely eliminate sodium, because it has both sensory and functional properties. For example, it is used for meat preservation and to make bread dough rise.

“A lot of the studies we looked at combined more than one method, such as salt removal with salt replacers and flavor modification or salt removal and physical modification,” Dunteman says.

Many studies used salt replacers such as potassium chloride, calcium chloride, or other chloride or acid salts. However, these substitutes tend to have a bitter taste, so they are often used in combination with flavor modifications, such as umami substances or bitter blockers.

“Another method is physical modification. For example, you can encapsulate the salt crystals, which changes how the salt is dissolved in the mouth. This can alter the saltiness perception allowing for a reduction in the amount of sodium necessary to create the salty taste. You can also create an uneven distribution of the salt in a product that can further help enhance the perceived saltiness of the food product through taste contrast,” Dunteman explains.

“Finally, there is functional modification. For example, you could move away from a sodium-based preservative in cured meats, perhaps using a celery-powder preservative instead of sodium nitrate.”

Functional modification is less represented in the scoping review because this type of sodium reduction research typically does not incorporate a sensory component as a main assessment method, Dunteman notes.

If consumers want to reduce their salt intake, the best strategy is to cook your own food and limit your consumption of processed and packaged foods. You can also wean yourself off salt with practice, essentially go on a “salt diet.”

“If you’re cooking at home, you can intentionally reduce salt and you’ll appreciate the reduced saltiness perception as time goes on. People can adjust to the reduced salt level, but it’s a learning and adapting process. You can also add flavor enhancers such as herbs and spices,” Lee suggests.

“If you are a consumer of canned soup, for example, you can buy a low-sodium version and add salt. Then you can gradually modify the amount of salt you add, so you can make it palatable to your taste,” she notes.

The research was supported by the Institute for the Advancement of Food and Nutrition Sciences (IAFNS) through an ILSI North America Sodium Committee grant. IAFNS is a non-profit science organization that pools funding from industry collaborators and advances science through the in-kind and financial contributions from public and private sector participants. IAFNS had no role in the design, analysis, interpretation, or presentation of the data and results.