A tiny invader, perhaps a virus or a microbe, enters the body, and our ancient immune system responds. But how does it know what kind of invader has landed? And once it knows, how does it decide what kind of immune response it should launch?
Immunologist Bali Pulendran studies how those two systems work together to identify and respond to all kinds of intruders including pathogens, viruses and microbes.
Itâ€™s the innate immune systemâ€™s job to recognize the first signs of infectionâ€”that is, the moment a pathogen enters the body. â€œIn a sense they act as smoke detectors if you will,â€ says Pulendran. â€œLittle alarms.â€
Last year, when the H1N1 flu epidemic was a major public health concern, a relatively low proportion of individuals getting sick were elderly, compared to previous flu epidemics. To explain this, scientists hypothesized that flu strains that circulated decades ago were similar enough to the novel swine-origin H1N1 strain toÂ provide some immune protection.
A universal flu vaccine would eliminate the guesswork associated with the yearly flu shot
Now, researchers at Emory’s Influenza Pathogenesis & Immunology Research Center have directly tested that hypothesis in mice, and it holds up. Exposure of mice to flu strains that circulated in 1947 or 1934 induced “robust cross-protective immune responses” and can protect them against a lethal challenge with 2009 H1N1 virus, they report in Journal of Immunology.
Ioanna Skountzou and Dimitrios Koutsananos are co-first authors of the paper.
The Emory team, led by Joshy Jacob, also reports that antibodies produced in response to the 2009 H1N1 flu strain exhibit broad cross-reactivity — they react with other H1N1 strains as well as against H3N2 flu strains. They write:
The fact that the 2009 H1N1 virus can induce such cross-reactive Abs raises the intriguing possibility that viruses such as A/California/04/2009 can be used for vaccines to induce broadly cross-reactive humoral immune responses against influenza viruses. Identifying the mechanism behind this broad reactivity may enable us to design broadly cross-reactive universal influenza vaccines.
National Institute of Allergy and Infectious Diseases director Tony Fauci, when he was at Emory for the H1N1 flu conference in April, discussed the idea of a universal flu vaccine:
B cells are workhorses of the immune system. Their main function is to produce antibodies against bacteria or viruses when they encounter something that they recognize.Â But recently researchers have been getting hints that certain kinds of B cells can also have a calming effect on the immune system. This property could come in handy with hard-to-treat conditions such as graft-vs-host disease, multiple sclerosis, or Crohn’s disease.
Hematologist Jacques Galipeau has found that B cells treated with an artificial hybrid molecule called GIFT15 turn into “peacemakers”. These specially treated B cells can tamp down the immune system in an experimental animal model of multiple sclerosis, suggesting that they could accomplish a similar task with the human disease.
Galipeau’s paper inÂ Nature Medicine from August 2009 says succinctly: “We propose that autologous GIFT15 B regulatory cells may serve as a new treatment for autoimmune ailments.”Â Galipeau, a recent arrival to Emory from McGill University in Montreal, explains this tactic and other aspects of personalized cell therapy in the video above. Read more
One of the most important lessons from this past yearâ€™s pandemic, Fauci said, is the need to â€œconnect the dotsâ€ between seasonal and pandemic influenza and not view them as two separate phenomena.
â€œRather than trying to figure out one priority group over another,” Fauci said, “if we can get into a rhythm of getting most people vaccinated each year, we will have most of the population with some degree of immunity. We will get into a situation where we donâ€™t need to go from a seasonal approach to a crisis approach.
The scientists in the lab of Richard Compans, PhD, professor of microbiology and immunology at Emory, are hard at work, imagining the unimaginable: A time when patients can self-administer flu vaccines. A time when vaccination does not require exposure to inactive viruses. A time when a universal vaccine could protect from all varieties of influenza: swine, avian, seasonal and strains still emerging.
Richard Compans, PhD (right), with colleague Mark Prausnitz, PhD, from Georgia Tech
But it’s not just hope that motivates them as they work. Emory’s scientists are fighting the clock against another possible future: a time of pandemic and uncontrollable virus mutation. The recent emergence of H1N1 and H5N1, known colloquially as swine flu and avian flu, have added an even greater sense of urgency to their task.
“The H5N1â€”the virus derived from avian speciesâ€”has a 60 percent mortality,” says Emory microbiologist Sang-Moo Kang, PhD. Yet that strain of influenza hasn’t resulted in many human deaths, because, so far, avian flu spreads only to humans who are in contact with infected birds.
Briefly, they found that increased appetite and insulin resistance can be transferred from one mouse to another via intestinal bacteria. The results were published online by Science magazine.
Previous research indicated intestinal bacteria could modify absorption of calories, but Gewirtz and his colleagues showed that they influence appetite and metabolism (in mice)
“It has been assumed that the obesity epidemic in the developed world is driven by an increasingly sedentary lifestyle and the abundance of low-cost high-calorie foods,” Gewirtz says. “However, our results suggest that excess caloric consumption is not only a result of undisciplined eating but that intestinal bacteria contribute to changes in appetite and metabolism.”
A related report in Nature illustrates how “next generation” gene sequencing is driving large advances in our understanding of all the things the bacteria in our intestines do to us.
Gewirtz’s laboratory’s discovery grew out of their study of mice with an altered immune system. The mice were engineered to lack a gene, Toll-like receptor 5 (TLR5), which helps cells sense the presence of bacteria.
Dr. Carlos del Rio possesses a keen view of how the novel H1N1 virus emerged last spring. Del Rio was in Mexico as the virus established itself south of the border. Its rapid, far-reaching spread marked the first influenza pandemic of the 21st century.
During Emoryâ€™s fifth annual predictive health symposium, “Human Health: Molecules to Mankind,” del Rio discussed his experiences in Mexico, what weâ€™ve learned, and what novel H1N1 has to do with predictive health.Â View a video of his presentation and five lessons learned.Â
Only a day after the virus was identified, on April 23, Mexican authorities closed schools, called off sporting events, and canceled religious gatherings. Known as â€œsocial distancing,â€ these actions led to a decrease in cases, an important lesson, says del Rio. The public knew what to do, they were cooperative, and whatâ€™s more, they applied a lot of peer pressure when it came to hand washing and sneezing hygiene.
Another lesson learned: preparation paid off. Anticipating a pandemic, The World Health OrganizationÂ had earlier mandated that countries draw up influenza pandemic plans. â€œThose plans were incredibly helpful in getting people to work together, communicate, and know what to do,â€ says del Rio.Â Interestingly, the plans in Mexico and the United States were aimed at a virus projected to originate from an avian source from southeastern Asia. â€œIt was not developed for a swine virus coming from inside the country,â€ explained del Rio.
Novel H1N1, even though itâ€™s thought of as a swine virus is in fact only about 47% swine–30% from North American swine and 17% from Eurasian swine. The virus also contains human and avian strains. Thatâ€™s important, says del Rio, because the characteristics of its genes determine how symptoms, susceptibility, and immunity manifest themselves.
â€œWhat weâ€™re seeing nowadays is the new strain has crowded out the seasonal influenza virus,â€ he says. Thus far, most of the deaths from novel H1N1 have been in children, young adults, and pregnant women. â€œThe people who are dying are a very different group than in previous flu seasons,â€ says del Rio.Â
Carlos del Rio, MD
Del Rio says a lot was learned early on about the novel virus thanks to frequent and transparent international communication. This flu pandemic is really the first to occur in this era of 24-hour newscasts and the Internet. So thereâ€™s a challenge for health workers: how do you continue to communicateÂ in an effective way. â€œOne thing you say one day may be contradicted the next day because you have new information. How do you make people understand that you werenâ€™t lying to them before, but you have updated information and that information is continuously changing.”
In trying to predict whatâ€™s in store for the current flu pandemic, researchers are looking back at past pandemics. Last century, there were three major flu pandemics. The largest and most important was the 1918 pandemic.
â€œA couple of things that happened back then are very important: one was there was a second wave that was actually much more severe and much more lethal than the first one.â€ says del Rio. â€œAnd over the summer, the virus actually changed. It started very much like it did this time. It started in the spring and then we had a little blip, and then we had a big blip in the second wave, and then almost a third wave. So, clearly influenza happens in waves, and weâ€™re seeing the same thing happening this time around.â€
Emory University is hosting an 800-panel display of The AIDS Memorial Quilt in recognition of World AIDS Day. â€œQuilt on the Quad,â€ on the Emory quadrangle, is the largest collegiate display and the second largest in the world today. An opening ceremony featured a talk by Sandra Thurman, president and CEO of the International AIDS Trust, based at Emoryâ€™s Rollins School of Public Health. Members of the Emory community read the names of each individual memorialized by a quilt panel on the quad.
An estimated 60 million people have acquired HIV, and 25 million people have died from AIDS. Emory scientists and physicians have been leaders in research to develop effective drugs and vaccines against HIV and AIDS. The Emory Center for AIDS Research is an official National Institutes of Health CFAR site. More than 120 faculty throughout Emory are working on some aspect of HIV/AIDS prevention or treatment.
More than 94 percent of HIV patients in the U.S. on life saving antiviral therapy take a drug developed at Emory. And many of the scientists within the Emory Vaccine Center are focused on finding an effective vaccine against HIV. A vaccine developed at the Vaccine Center and Yerkes National Primate Research Center is being tested nationally in a phase II clinical trial.
The Hope Clinic of the Emory Vaccine Center is conducting several clinical trials of HIV vaccine candidates through the HIV Vaccine Trials Network (HVTN) sponsored by the NIH. The HVTN 505 vaccine trial, which is currently enrolling at the Hope Clinic and 13 other cities around the country, is a test-of-concept efficacy trial for an NIH vaccine (DNA + Adnovirus â€“ gag/pol/nef/EnvABC).
Mark Mulligan, MD, executive director of Emoryâ€™s Hope Clinic, emphasizes that on World AIDS Day there would be no better way to honor those who have already died or are already infected than to produce a vaccine that will protect their families and friends.
â€œThe recent analysis of the RV144 Thai trial surprisingly taught us that an envelope glycoprotein vaccine regimen can protect (albeit modestly, thus far)! This is an amazing result that has re-ignited the field, and is capturing the attention of the community. We must do all we can to leverage this result for success,â€ Mulligan says. â€œAlbert Sabin said that no scientist can rest while a vaccine that might help humanity sits on the shelf. To me, this underscores the importance of successfully executing the HVTN 505 trial.â€
Jorg Goronzy, MD, PhD and Cornelia Weyand, MD, PhD
Weyand and Goronzy show that with age, T cells begin to turn on genes that are usually turned on only in â€œnatural killerâ€ cells. NK cells play a major role in rejecting tumors and killing cells infected by viruses. They are white blood cells like T cells but they have a different set of receptors on their surfaces controlling their activities.
Many of these receptors act to hold the NK cells back; so when they appear on the T cells, their activation is dampened too, thus contributing to the slowing down of the immune system in elderly people.
The authors report that NK cell genes get turned on because they lose the â€œmethylationâ€ on their DNA. Methylation is a pattern of tiny modifications on DNA, emphasizing whatâ€™s important (or forbidden) in a given cell, sort of like a highlighterâ€™s yellow pen on top of text.
Apparently, in elderly people (aged 70-85), the methylation is more â€œspottyâ€ than in younger people (aged 20-30). It seems that after the DNA is copied several times, the highlighting gets fuzzy and the T cells start to look like their cousins, natural killer cells.
An outbreak of measles in the state of Washington last year sickened 19 children. Of those who fell ill, 18 had something in commonâ€”they were not vaccinated.
Saad Omer aims to increase vaccine compliance to prevent childhood diseases.
For Emory Rollins School of Public Health researcher Saad Omer, the Washington outbreak is a perfect example of the effect on an entire community when individuals are unimmunized. His research aims to shed light on ways to encourage increased vaccine compliance for adults and their children.
Omer says vaccine-preventable diseases such as measles, influenza, and pertussis often start among persons who forego vaccinations, spread rapidly within unvaccinated populations, and also spread to other subpopulations.
In a recent New England Journal of Medicinearticle, Omer and his colleagues reviewed evidence from several states showing that vaccine refusal due to nonmedical reasons puts children in communities with high rates of refusal at higher risk for infectious diseases such as measles and whooping cough.
Even children whose parents do not refuse vaccination are put at risk because “herd immunity” normally protects children who are too young to be vaccinated, who can’t be vaccinated for medical reasons, or whose immune systems do not respond sufficiently to vaccination.
Research findings indicate that everyone who lives in a community with a high proportion of unvaccinated individuals has an elevated risk of developing a vaccine-preventable disease.
Read more about Omerâ€™s research on vaccine refusals in the fall 2009 issue of Public Health magazine.
Omer also discusses the importance of vaccinating against the H1N1 virus in an Oct. 16 article in The New York Times.