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The Prime Cellular Targets for the Novel Coronavirus

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Credit: NIH

There’s still a lot to learn about SARS-CoV-2, the novel coronavirus that causes COVID-19. But it has been remarkable and gratifying to watch researchers from around the world pull together and share their time, expertise, and hard-earned data in the urgent quest to control this devastating virus.

That collaborative spirit was on full display in a recent study that characterized the specific human cells that SARS-CoV-2 likely singles out for infection [1]. This information can now be used to study precisely how each cell type interacts with the virus. It might ultimately help to explain why some people are more susceptible to SARS-CoV-2 than others, and how exactly to target the virus with drugs, immunotherapies, and vaccines to prevent or treat infections.

This work was driven by the mostly shuttered labs of Alex K. Shalek, Massachusetts Institute of Technology, Ragon Institute of MGH, MIT, and Harvard, and Broad Institute of MIT and Harvard, Cambridge; and Jose Ordovas-Montanes at Boston Children’s Hospital. In the end, it brought together (if only remotely) dozens of their colleagues in the Human Cell Atlas Lung Biological Network and others across the U.S., Europe, and South Africa.

The project began when Shalek, Ordovas-Montanes, and others read that before infecting human cells, SARS-CoV-2 docks on a protein receptor called angiotensin-converting enzyme 2 (ACE2). This enzyme plays a role in helping the body maintain blood pressure and fluid balance.

The group was intrigued, especially when they also learned about a second enzyme that the virus uses to enter cells. This enzyme goes by the long acronym TMPRSS2, and it gets “tricked” into priming the spike proteins that cover SARS-CoV-2 to attack the cell. It’s the combination of these two proteins that provide a welcome mat for the virus.

Shalek, Ordovas-Montanes, and an international team including graduate students, post-docs, staff scientists, and principal investigators decided to dig a little deeper to find out precisely where in the body one finds cells that express this gene combination. Their curiosity took them to the wealth of data they and others had generated from model organisms and humans, the latter as part of the Human Cell Atlas. This collaborative international project is producing a comprehensive reference map of all human cells. For its first draft, the Human Cell Atlas aims to gather information on at least 10 billion cells.

To gather this information, the project relies, in part, on relatively new capabilities in sequencing the RNA of individual cells. Keep in mind that every cell in the body has essentially the same DNA genome. But different cells use different programs to decide which genes to turn on—expressing those as RNA molecules that can be translated into protein. The single-cell analysis of RNA allows them to characterize the gene expression and activities within each and every unique cell type. Based on what was known about the virus and the symptoms of COVID-19, the team focused their attention on the hundreds of cell types they identified in the lungs, nasal passages, and intestines.

As reported in Cell, by filtering through the data to identify cells that express ACE2 and TMPRSS2, the researchers narrowed the list of cell types in the nasal passages down to the mucus-producing goblet secretory cells. In the lung, evidence for activity of these two genes turned up in cells called type II pneumocytes, which line small air sacs known as alveoli and help to keep them open. In the intestine, it was the absorptive enterocytes, which play an important role in the body’s ability to take in nutrients.

The data also turned up another unexpected and potentially important connection. In these cells of interest, all of which are found in epithelial tissues that cover or line body surfaces, the ACE2 gene appeared to ramp up its activity in concert with other genes known to respond to interferon, a protein that the body makes in response to viral infections.

To dig further in the lab, the researchers treated cultured cells that line airways in the lungs with interferon. And indeed, the treatment increased ACE2 expression.

Earlier studies have suggested that ACE2 helps the lungs to tolerate damage. Completely missed was its connection to the interferon response. The researchers now suspect that’s because it hadn’t been studied in these specific human epithelial cells before.

The discovery suggests that SARS-CoV-2 and potentially other coronaviruses that rely on ACE2 may take advantage of the immune system’s natural defenses. When the body responds to the infection by producing more interferon, that in turn results in production of more ACE2, enhancing the ability of the virus to attach more readily to lung cells. While much more work is needed, the finding indicates that any potential use of interferon as a treatment to fight COVID-19 will require careful monitoring to determine if and when it might help patients.

It’s clear that these new findings, from data that weren’t originally generated with COVID-19 in mind, contained several potentially important new leads. This is another demonstration of the value of basic science. We can also rest assured that, with the outpouring of effort from members of the scientific community around the globe to meet this new challenge, progress along these and many other fronts will continue at a remarkable pace.

Reference:

[1] SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Ziegler, CGK et al. Cell. April 20, 2020.

Links:

Coronaviruses (National Institute of Allergy and Infectious Diseases/NIH)

Human Cell Atlas (Broad Institute, Cambridge, MA)

Shalek Lab (Harvard Medical School and Massachusetts Institute of Technology, Cambridge)

Ordovas-Montanes Lab (Boston Children’s Hospital, MA)

NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences; National Heart, Lung, and Blood Institute


Targeting the Microbiome to Treat Malnutrition

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Caption: A Bangladeshi mother and child in the Nutritional Rehabilitation Unit.
Credit: International Centre for Diarrhoeal Disease Research, Bangladesh

A few years ago, researchers discovered that abnormalities in microbial communities, or microbiomes, in the intestine appear to contribute to childhood malnutrition. Now comes word that this discovery is being translated into action, with a new study showing that foods formulated to repair the “gut microbiome” may help malnourished kids rebuild their health [1].

In a month-long clinical trial in Bangladesh, 63 children received either regular foods to treat malnutrition or alternative formulations for needed calories and nutrition that also encouraged growth of beneficial microbes in the intestines. The kids who ate the microbiome-friendly diets showed improvements in their microbiome, which helps to extract and metabolize nutrients in our food to help the body grow. They also had significant improvements in key blood proteins associated with bone growth, brain development, immunity, and metabolism; those who ate standard therapeutic food did not experience the same benefit.

Globally, malnutrition affects an estimated 238 million children under the age 5, stunting their normal growth, compromising their health, and limiting their mental development [2]. Malnutrition can arise not only from a shortage of food but from dietary imbalances that don’t satisfy the body’s need for essential nutrients. Far too often, especially in impoverished areas, the condition can turn extremely severe and deadly. And the long term effects on intellectual development can limit the ability of a country’s citizens to lift themselves out of poverty.

Jeffrey Gordon, Washington University School of Medicine in St. Louis, and his NIH-supported research team have spent decades studying what constitutes a normal microbiome and how changes can affect health and disease. Their seminal studies have revealed that severely malnourished kids have “immature” microbiomes that don’t develop in the intestine like the microbial communities seen in well nourished, healthy children of the same age.

Gordon and team have also found that this microbial immaturity doesn’t resolve when kids consume the usual supplemental foods [3]. In another study, they turned to mice raised under sterile conditions and with no microbes of their own to demonstrate this cause and effect. The researchers colonized the intestines of the germ-free mice with microbes from malnourished children, and the rodents developed similar abnormalities in weight gain, bone growth, and metabolism [4].

All of this evidence raised a vital question: Could the right combination of foods “mature” the microbiome and help to steer malnourished children toward a healthier state?

To get the answer, Gordon and his colleagues at the International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh, led by Tahmeed Ahmed, first had to formulate the right, microbiome-friendly food supplements, and that led to some interesting science. They carefully characterized over time the immature microbiomes found in Bangladeshi children treated for severe malnutrition. This allowed them to test their new method for analyzing how individual microbial species fluctuate over time and in relationship to one another in the intestine [5]. The team then paired up these data with measurements of a set of more than 1,300 blood proteins from the children that provide “readouts” of their biological state.

Their investigation identified a network of 15 bacterial species that consistently interact in the gut microbiomes of Bangladeshi children. This network became their means to characterize sensitively and accurately the development of a child’s microbiome and/or its relative state of repair.

Next, they turned to mice colonized with the same collections of microbes found in the intestines of the Bangladeshi children. Gordon’s team then tinkered with the animals’ diets in search of ingredients commonly consumed by young children in Bangladesh that also appeared to encourage a healthier, more mature microbiome. They did similar studies in young pigs, whose digestive and immune systems more closely resemble humans.

The Gordon team settled on three candidate microbiome-friendly formulations. Two included chickpea flour, soy flour, peanut flour, and banana at different concentrations; one of these two also included milk powder. The third combined chickpea flour and soy flour. All three contained similar amounts of protein, fat, and calories.

The researchers then launched a randomized, controlled clinical trial with children from a year to 18 months old with moderate acute malnutrition. These young children were enrolled into one of four treatment groups, each including 14 to 17 kids. Three groups received one of the newly formulated foods. The fourth group received standard rice-and-lentil-based meals.

The children received these supplemental meals twice a day for four weeks at the International Centre for Diarrhoeal Disease Research followed by two-weeks of observation. Mothers were encouraged throughout the study to continue breastfeeding their children.

The formulation containing chickpea, soy, peanut, and banana, but no milk powder, stood out above the rest in the study. Children taking this supplement showed a dramatic shift toward a healthier state as measured by those more than 1,300 blood proteins. Their gut microbiomes also resembled those of healthy children their age.

Their new findings published in the journal Science offer the first evidence that a therapeutic food, developed to support the growth and development of a healthy microbiome, might come with added benefits for children suffering from malnutrition. Importantly, the researchers took great care to design the supplements with foods that are readily available, affordable, culturally acceptable, and palatable for young children in Bangladesh.

A month isn’t nearly long enough to see how the new foods would help children grow and recover over time. So, the researchers are now conducting a much larger study of their leading supplement in children with histories of malnutrition, to explore its longer-term health effects for them and their microbiomes. The hope is that these new foods and others adapted for use around the world soon will help many more kids grow up to be healthy adults.

References:

[1] Effects of microbiota-directed foods in gnotobiotic animals and undernourished children. Gehrig JL, Venkatesh S, Chang HW, Hibberd MC, Kung VL, Cheng J, Chen RY, Subramanian S, Cowardin CA, Meier MF, O’Donnell D, Talcott M, Spears LD, Semenkovich CF, Henrissat B, Giannone RJ, Hettich RL, Ilkayeva O, Muehlbauer M, Newgard CB, Sawyer C, Head RD, Rodionov DA, Arzamasov AA, Leyn SA, Osterman AL, Hossain MI, Islam M, Choudhury N, Sarker SA, Huq S, Mahmud I, Mostafa I, Mahfuz M, Barratt MJ, Ahmed T, Gordon JI. Science. 2019 Jul 12;365(6449).

[2] Childhood Malnutrition. World Health Organization

[3] Persistent gut microbiota immaturity in malnourished Bangladeshi children. Subramanian S, Huq S, Yatsunenko T, Haque R, Mahfuz M, Alam MA, Benezra A, DeStefano J, Meier MF, Muegge BD, Barratt MJ, VanArendonk LG, Zhang Q, Province MA, Petri WA Jr, Ahmed T, Gordon JI. Nature. 2014 Jun 19;510(7505):417-21.

[4] Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children. Blanton LV, Charbonneau MR, Salih T, Barratt MJ, Venkatesh S, Ilkaveya O, Subramanian S, Manary MJ, Trehan I, Jorgensen JM, Fan YM, Henrissat B, Leyn SA, Rodionov DA, Osterman AL, Maleta KM, Newgard CB, Ashorn P, Dewey KG, Gordon JI. Science. 2016 Feb 19;351(6275).

[5] A sparse covarying unit that describes healthy and impaired human gut microbiota development. Raman AS, Gehrig JL, Venkatesh S, Chang HW, Hibberd MC, Subramanian S, Kang G, Bessong PO, Lima AAM, Kosek MN, Petri WA Jr, Rodionov DA, Arzamasov AA, Leyn SA, Osterman AL, Huq S, Mostafa I, Islam M, Mahfuz M, Haque R, Ahmed T, Barratt MJ, Gordon JI. Science. 2019 Jul 12;365(6449).

Links:

Childhood Nutrition Facts (Centers for Disease Control and Prevention)

Gordon Lab (Washington University School of Medicine in St. Louis)

NIH Human Microbiome Project

International Centre for Diarrhoeal Disease Research (Dhaka, Bangladesh)

NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of General Medical Sciences; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Center for Advancing Translational Sciences; National Cancer Institute


Creative Minds: Giving Bacteria Needles to Fight Intestinal Disease

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Cammie Lesser

Cammie Lesser

For Salmonella and many other disease-causing bacteria that find their way into our bodies, infection begins with a poke. That’s because these bad bugs are equipped with a needle-like protein filament that punctures the outer membrane of human cells and then, like a syringe, injects dozens of toxic proteins that help them replicate.

Cammie Lesser at Massachusetts General Hospital and Harvard Medical School, Cambridge, and her colleagues are now on a mission to bioengineer strains of bacteria that don’t cause disease to make these same syringes, called type III secretion systems. The goal is to use such “good” bacteria to deliver therapeutic molecules, rather than toxins, to human cells. Their first target is the gastrointestinal tract, where they hope to knock out hard-to-beat bacterial infections or to relieve the chronic inflammation that comes with inflammatory bowel disease (IBD).


Protein Links Gut Microbes, Biological Clocks, and Weight Gain

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Fat calls with and without NFIL3

Caption: Lipids (red) inside mouse intestinal cells with and without NFIL3.
Credit: Lora V. Hooper, University of Texas Southwestern Medical Center, Dallas

The American epidemic of obesity is a major public health concern, and keeping off the extra pounds is a concern for many of us. Yet it can also be a real challenge for people who may eat normally but get their days and nights mixed up, including night-shift workers and those who regularly travel overseas. Why is that?

The most obvious reason is the odd hours throw a person’s 24-hour biological clock—and metabolism—out of sync. But an NIH-funded team of researchers has new evidence in mice to suggest the answer could go deeper to include the trillions of microbes that live in our guts—and, more specifically, the way they “talk” to intestinal cells. Their studies suggest that what gut microbes “say” influences the activity of a key clock-driven protein called NFIL3, which can set intestinal cells up to absorb and store more fat from the diet while operating at hours that might run counter to our fixed biological clocks.


Simplifying HIV Treatment: A Surprising New Lead

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CD4+ cells in the gut

Caption: PET/CT imaging reveals a surprisingly high concentration (yellow, light green) of key immune cells called CD4 T cells in the colon (left) of an SIV-infected animal that received antibody infusions along with antiviral treatment. Fewer immune cells were found in the small intestine (right), while the liver (lower left) shows a high level of non-specific signal (orange).
Credit: Byrareddy et al., Science (2016).

The surprising results of an animal study are raising hopes for a far simpler treatment regimen for people infected with the AIDS-causing human immunodeficiency virus (HIV). Currently, HIV-infected individuals can live a near normal life span if, every day, they take a complex combination of drugs called antiretroviral therapy (ART). The bad news is if they stop ART, the small amounts of HIV that still lurk in their bodies can bounce back and infect key immune cells, called CD4 T cells, resulting in life-threatening suppression of their immune systems.

Now, a study of rhesus macaques infected with a close relative of HIV, the simian immunodeficiency virus (SIV), suggests there might be a new therapeutic option that works by a mechanism that has researchers both excited and baffled [1]. By teaming ART with a designer antibody used to treat people with severe bowel disease, NIH-funded researchers report that they have been able to keep SIV in check in macaques for at least two years after ART is stopped. More research is needed to figure out exactly how the new strategy works, and whether it would also work for humans infected with HIV. However, the findings suggest there may be a way to achieve lasting remission from HIV without the risks, costs, and inconvenience associated with a daily regimen of drugs.


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