Stage fright: don't get over it, get used to it

Many can feel empathy with the situation Banerjee describes: facing “a room full of scientists, who for whatever reason, did not look very happy that Read more

Beyond birthmarks and beta blockers, to cancer prevention

Ahead of this week’s Morningside Center conference on repurposing drugs, we wanted to highlight a recent paper in NPJ Precision Oncology by dermatologist Jack Arbiser. It may represent a new chapter in the story of the beta-blocker propranolol. Several years ago, doctors in France accidentally discovered that propranolol is effective against hemangiomas: bright red birthmarks made of extra blood vessels, which appear in infancy. Hemangiomas often don’t need treatment and regress naturally, but some can lead Read more

Drying up the HIV reservoir

Wnt is one of those funky developmental signaling pathways that gets re-used over and over again, whether it’s in the early embryo, the brain or the Read more

Department of Microbiology and Immunology

Immunologists identify T cell homing beacons for lungs

Scientists have identified a pair of molecules critical for T cells, part of the immune system, to travel to and populate the lungs. A potential application could be strengthening vaccines against respiratory pathogens such as influenza.

The findings were published online Thursday, September 26 in Journal of Experimental Medicine.

T cells in the lungs, courtesy of Alex Wein. Blue represents respiratory epithelium (EpCAM), while various T cells stain red, yellow or green.

Much research on immunity to influenza virus focuses on antibodies, infection- or vaccine-induced proteins in the blood that can smother viruses. But CD8 T cells, which survey other cells for signs of viral infection and kill infected cells, are an important arm of our defenses too. The epitopes – or bits of viral protein – they recognize generally do not change from year to year.

Researchers led by Jacob Kohlmeier, PhD, at Emory University School of Medicine wanted to learn more about what’s needed to get CD8 T cells into the lungs, since the lungs will often contain the first cells incoming virus will have a chance to infect. However, T cells don’t stick around in the lungs for extended amounts of time.

“The airways are a unique environment in the body,” says Alex Wein, a MD/PhD student who trained in Kohlmeier’s lab. “They’re high in oxygen but low in nutrients. Unlike other tissues, when T cells enter the airways, it’s a one-way trip and they have a half-life of a few weeks, so they must be continually repopulated.”

Wein, his fellow MD/PhD Sean McMaster, now at Boston Consulting Group, and Shiki Takamura at Kindai University are co-first authors of the paper. Kohlmeier is assistant professor of microbiology and immunology and part of the Emory-UGA Center of Excellence for Influenza Research and Surveillance.

The researchers showed that two molecules, called CXCR6 and CXCL16, are needed for CD8 T cells to reach the airways in mice. CXCR6 is found on T cells and CXCL16 is produced by the epithelial cells lining the airways of the lungs. Read more

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One more gene between us and bird flu

We’re always in favor of stopping a massive viral pandemic, or at least knowing more about what might make one happen. So we read a recent PLOS Pathogens paper with interest. The general theme is similar to this February 2019 paper from Anice Lowen’s lab in PNAS. To paraphrase Bill Murray in Ghostbusters: birds and humans living together, mass hysteria!

Here, Emory researchers looked at the M segment of influenza virus, which appears to determine host restriction, or the ability of viruses that infect bird cells to migrate to mammals. The M segment, was important for emergence of the 2009 H1N1 pandemic flu.

One of eight influenza gene segments, the M segment encodes a protein that can interfere with cellular functions (autophagic vesicles) on which the virus relies. The new data reveal that reductions in M2 protein occurred in connection with past important adaptation events, such as when a Eurasian avian-like swine virus emerged from birds in the 1970s.

“This mechanism constitutes a novel paradigm in RNA virus host adaptation, and reveals a new species barrier for IAV, which may be highly relevant for the emergence of avian IAVs into humans,” the authors conclude. Read more

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Antibody diversity mutations come from a vast genetic library

Vaccine scientists want to nudge the immune system into producing antibodies that will protect us from infection. In doing so, they are playing with fire – in a limited way. With every healthy antibody response, a process of internal evolution takes place among B cells, the immune cells that produce antibodies. It’s called “somatic hypermutation.”

In the lymph nodes, individual B cells undergo an accelerated rate of mutation. It’s as if those B cells’ DNA were being cooked with radiation or mutagenic chemicals – but only in a few genes. Then the lymph nodes select the B cells with high-affinity antibodies.

Gordon Dale, a just-defended graduate student from Joshy Jacob’s lab in Emory Vaccine Center, has a new paper in Journal of Immunology that sheds light on how somatic hypermutation takes place in both mice and humans.

In particular, Dale and Jacob found that the mutations that occur in human and mouse antibody genes are not random. They appear to borrow information from gene segments that are leftovers from the process of assembling antibody DNA in B cells.

In a mix and match process called VDJ recombination, B cells use one of many V, D, and J segments to form their antibody genes. What Dale and Jacob were looking at occurs after the VDJ step, when B cells get stimulated as part of an immune response.

They analyzed the patterns of mutations in human and mouse antibody genes, and found that mutations tend to come together, in a way that suggests that they are being copied from leftover V segments. They call this pattern “tem Read more

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Antibody production: an endurance sport

Antibodies defend us against infections, so they often get described as weapons. And the cells that produce them could be weapon factories?. To understand recent research from immunologist Jerry Boss’s lab, a more appropriate metaphor is the distinction between sprinting and long-distance running.

Graduate student Madeline Price in Boss’s lab has been investigating how antibody-producing cells use glucose – the simple sugar– and how the cells’ patterns of gene activity reflect that usage. Cells can use glycolysis, which is inefficient but fast, analogous to sprinting, or oxidative phosphorylation, generating much more energy overall, more like long distance running.

As Boss and Price point out:

Immunology + Molecular Pathogenesis graduate student Madeline Price

Glycolytic metabolism produces 2 molecules of ATP per molecule of glucose, while oxidative phosphorylation produces 36 molecules of ATP from the same starting glucose molecule. Where oxidative phosphorylation generates more energy from ATP, glycolysis generates metabolic intermediates that are also useful for rapid cellular proliferation.

In their recent paper in Cell Reports, they lay out what happens to B cells, which can go on to become antibody secreting cells (ASCs), after an initial encounter with bacteria. The B cells first proliferate and upregulate both glycolysis and oxidative phosphorylation. However, upon differentiating, the cells shift their preference to oxidative phosphorylation. Read more

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Access to HIV’s hideouts: T cells that take on their own

Police procedural television shows, such as Law + Order, have introduced many to the Internal Affairs Bureau: police officers that investigate other police officers. This group of unloved cops comes to mind in connection with the HIV/AIDS research published this week by Rama Amara’s lab at Yerkes National Primate Research Center and Emory Vaccine Center.

“Killer” antiviral T cells (red spots) can be found in germinal centers. The green areas are B cell follicles, which HIV researchers have identified as major reservoirs for the virus. Image courtesy of Rama Amara.

HIV infection is hard to get rid of for many reasons, but one is that the virus infects the cells in the immune system that act like police officers. The “helper” CD4 T cells that usually support immune responses become infected themselves. For the immune system to fight HIV effectively, the “killer” CD8 antiviral T cells would need to take on their own CD4 colleagues.

When someone is HIV-positive and is taking antiretroviral drugs, the virus is mostly suppressed but sticks around in a reservoir of inactive infected cells. Those cells hide out in germinal centers, specialized areas of lymph nodes, which most killer antiviral T cells don’t have access to. A 2015 Nature Medicine paper describes B cell follicles, which are part of germinal centers, as “sanctuaries” for persistent viral replication. (Imagine some elite police unit that has become corrupt, and uniformed cops can’t get into the places where the elite ones hang out. The analogy may be imperfect, but might help us visualize these cells.)

Amara’s lab has identified a group of antiviral T cells that do have the access code to germinal centers, a molecule called CXCR5. Knowing how to induce antiviral T cells displaying CXCR5 will be important for designing better therapeutic vaccines, as well as efforts to suppress HIV long-term, Amara says. The paper was published in PNAS this week. Read more

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Dengue infection makes exhausted T cells?

An ongoing collaboration between the Emory Vaccine Center and the ICGEB (International Centre for Genetic Engineering and Biotechnology) in New Delh, investigating immune responses to dengue virus, is getting some attention.

A Journal of Virology paper published by the collaboration was highlighted by Nature Asia. In that paper, the researchers show that in dengue infection, the group of antiviral immune cells known as CD8+ T cells undergoes a massive expansion. That could be dangerous if all of the CD8 T cells were making inflammatory cytokines, but they do not. Only a small fraction are making cytokines.

The authors point out that this phenomenon is “somewhat reminiscent of T-cell exhaustion seen under the conditions of prolonged antigenic stimulus in chronic viral infections [which has been studied in detail by Rafi Ahmed and colleagues] or closely resembles the ‘stunned’ phenotype reported in febrile phase of other acute infections such as HIV and viral hepatitis… The IFN-γ unresponsiveness acquired during the massive antigen-driven clonal expansion is likely to ensure that these cells do not cause excessive inflammation at the time that their numbers are high during the febrile phase of dengue disease.” Read more

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Plasma cells, antibody factories

Immune cells that serve as antibody production factories, also known as plasma cells, are the focus of a recent Nature Immunology paper from Jeremy Boss and colleagues.

Plasma cells also appear in Ali Ellebedy and Rafi Ahmed’s recent paper on the precursors of memory B cells and Eun Lee’s work on long-lived antibody-producing cells. In addition, plasma cells appear prominently in Larry Boise’s studies of myeloma, because myeloma cancer cells are thought to come from plasma cells and have a similar biology.B cell methylation

The Boss lab’s paper focuses on patterns of methylation, modifications of DNA that usually help turn genes off. In comparison with resting B cells, plasma cells need to turn on lots of genes, so their DNA methylation level goes down when differentiation occurs (see graph). PC = plasma cells, PB = plasmablasts. DNAme indicates the extent of DNA methylation. Read more

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Two angles on cell death

One can take two very different angles when approaching Bill Kaiser’s and Ed Mocarski’s work on RIP kinases and the mechanisms of cell death. These are: the evolutionary where-does-apoptosis-come-from angle, and the anti-inflammatory drug discovery angle.

A pair of papers published this week, one in PNAS and one in Journal of Immunology, cover both of these angles. (Also, back to back papers in Cell this week, originating from Australia and Tennessee, touch on the same topic.)

First, the evolutionary angle.

Cellular suicide can be a “scorched earth” defense mechanism against viruses. Kaiser and Mocarski have been amassing evidence that some forms of cellular suicide arose as a result of an arms race of competition with viruses. The PNAS paper is part of this line of evidence. It shows that the cell-death circuits controlled by three different genes (RIP1, RIP3 and caspase 8) apparently can be lifted cleanly out of an animal. Mice lacking all three genes not only can be born, but have well-functioning immune systems.

Apoptosis is thought to be a form of cellular suicide important for the development of all multicellular organisms. That’s why, to cell and developmental biologists, it seemed rather shocking that researchers can mutate a group of genes that drive apoptosis and other forms of cellular suicide and have adult animals emerge.

Next, the drug discovery angle.

The J. Immunol paper makes that angle clear enough. Most of the authors on this paper are from GlaxoSmithKline’s “Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area.” Here, they show that a mutation in RIP1 inactivating the kinase enzyme protects mice against severe skin and multiorgan inflammation. They conclude their abstract with: “Together, these data suggest that RIP1 kinase represents an attractive therapeutic target for TNF-driven inflammatory diseases.”

Note: TNF-driven inflammatory diseases include rheumatoid arthritis, inflammatory bowel diseases and psoriasis, representing a multibillion dollar market.

 

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How CMV gets around

Human cytomegalovirus infects most people in the United States by the time they are 40 years old. HCMV is usually harmless in children and adults, but when pregnant women are infected for the first time, the infection can lead to hearing, vision or other problems in their babies once they are born. [It is also a problem for organ transplant recipients.] According to the Centers for Disease Control and Prevention, HCMV is usually transmitted by sexual contact, diapers or toys. Notably absent are references to needles. That means scientists who study how mouse CMV infection takes place by injecting the virus into the animal’s body are missing a critical step.

Postdoc Lisa Daley-Bauer, working with CMV expert Ed Mocarski, has a recent paper in the journal Cell Host & Microbe illuminating how the virus travels from sites of initial infections to the rest of the body. Defining the cells the virus uses to get around could have implications for efforts to design a HCMV vaccine.

The virus hijacks part of the immune system, the authors find. CMV emits its own attractant (or chemokine) for patrolling monocytes, a type of white blood cell that circulates in the skin and peripheral tissues. This attractant, called MCK2, is only important when mice are infected by footpad inoculation, not by systemic injection.

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Emory flu researchers support H7N9 plan

Three Emory scientists have signed a letter published last week in Nature and Science outlining proposed research on the H7N9 avian influenza virus. A strain of H7N9 transmitted from poultry to humans was responsible for 43 deaths in China earlier this year, but so far, evidence shows that the virus does not transmit easily from human to human.

The letter advocates additional research including “gain-of-function” experiments: identifying what changes to naturally occurring viral strains would make them more transmissible, deadly, or drug-resistant in mammals.

The group of 23 flu researchers, led by Ron Fouchier at http://www.agfluide.com Erasmus Medical Center in the Netherlands and Yoshihiro Kawaoka at the University of Wisconsin, say these types of experiments are needed to help public health authorities prepare for and respond to potential future outbreaks.

The letter signers from Emory are: Walter Orenstein, MD, professor of medicine and principal investigator for the Emory-University of Georgia Influenza Pathogenesis and Immunology Research Center (IPIRC), Richard Compans, PhD, professor of microbiology and immunology and scientific director of IPIRC, and John Steel, PhD, assistant professor of microbiology and immunology. Read more

Posted on by Quinn Eastman in Immunology 1 Comment