Sunlight offers surprise benefit: It energizes infection fighting T cells

Sunlight, through a mechanism separate than vitamin D production, energizes T cells that play a central role in human immunity, researchers have found. The findings suggest how the skin, the body’s largest organ, stays alert to the many microbes that can nest there.

Georgetown University Medical Center researchers have found that sunlight, through a mechanism separate than vitamin D production, energizes T cells that play a central role in human immunity.
Their findings, published today in Scientific Reports, suggest how the skin, the body's largest organ, stays alert to the many microbes that can nest there.
"We all know sunlight provides vitamin D, which is suggested to have an impact on immunity, among other things. But what we found is a completely separate role of sunlight on immunity," says the study's senior investigator, Gerard Ahern, PhD, associate professor in the Georgetown's Department of Pharmacology and Physiology. "Some of the roles attributed to vitamin D on immunity may be due to this new mechanism."
They specifically found that low levels of blue light, found in sun rays, makes T cells move faster -- marking the first reported human cell responding to sunlight by speeding its pace.
"T cells, whether they are helper or killer, need to move to do their work, which is to get to the site of an infection and orchestrate a response," Ahern says. "This study shows that sunlight directly activates key immune cells by increasing their movement."
Ahern also added that while production of vitamin D required UV light, which can promote skin cancer and melanoma, blue light from the sun, as well as from special lamps, is safer.
And while the human and T cells they studied in the laboratory were not specifically skin T cells -- they were isolated from mouse cell culture and from human blood -- the skin has a large share of T cells in humans, he says, approximately twice the number circulating in the blood.
"We know that blue light can reach the dermis, the second layer of the skin, and that those T cells can move throughout the body," he says.
The researchers further decoded how blue light makes T cells move more by tracing the molecular pathway activated by the light.
What drove the motility response in T cells was synthesis of hydrogen peroxide, which then activated a signaling pathway that increases T cell movement. Hydrogen peroxide is a compound that white blood cells release when they sense an infection in order to kill bacteria and to "call" T cells and other immune cells to mount an immune response.
"We found that sunlight makes hydrogen peroxide in T cells, which makes the cells move. And we know that an immune response also uses hydrogen peroxide to make T cells move to the damage," Ahern says. "This all fits together."
Ahern says there is much work to do to understand the impact of these findings, but he suggests that if blue light T cell activation has only beneficial responses, it might make sense to offer patients blue light therapy to boost their immunity.
 

Journal Reference:

1. Thieu X. Phan, Barbara Jaruga, Sandeep C. Pingle, Bidhan C. Bandyopadhyay, Gerard P. Ahern. Intrinsic Photosensitivity Enhances Motility of T Lymphocytes. Scientific Reports, 2016; 6: 39479 DOI: 10.1038/srep39479 

Courtesy: ScienceDaily
 

Case for sexual transmission of Zika virus strengthened

Aedes aegypti mosquitoes harboring parasitic Zika virus (ZIKV) are the primary transmitters of virus to humans, potentially causing catastrophic congenital microcephaly in babies born to women bitten by infected mosquitoes. But confirmation earlier this year that ZIKV can also be sexually transmitted raised new alarm that virus could be passed between sexual partners in venues far from mosquito habitats.

Although Zika is primarily thought of as mosquito-borne illness, sexual transmission plays an important role in the spread of the virus. Weeks or even months after the virus has been cleared from the bloodstream, Zika can still be found in semen and transmitted through sexual contact. Women can pass the virus to their unborn babies during pregnancy.

Credit: Dr. Kenneth Kim and Dr. Gina Kirchweger, La Jolla Institute for Allergy and Immunology

Now La Jolla Institute for Allergy & Immunology (LJI) investigator Sujan Shresta, Ph.D., employs two different mouse models to confirm that live ZIKV placed directly in the vagina infects the mouse's reproductive tract, replicates, moves into the bloodstream, and causes clinical signs of disease. Intriguingly, that study published in the December 20, 2016 issue of Cell Reports, also reports that the stage of the reproductive cycle during which a female mouse is exposed to virus determines vulnerability to infection. If applicable to humans, this discovery has public health implications for virus transmission to a population of great concern, women of child-bearing age.
"Currently, almost all of our efforts in terms of Zika prevention focus on mosquito control," says Shresta, an associate professor in LJI's Center for Infectious Disease. "Our new work begs clinicians to also address whether sexual transmission of the virus constitutes a small or large proportion of cases."
Investigators knew that virus hides in semen of men who contract ZIKV from mosquitoes and that virus is transmitted vaginally in rodent models. But the biological questions -- what cells are infected, how stable the virus is in bodily fluids -- were unanswered. Shresta's group began to explore them by placing live ZIKV in the vaginas of female mice that had been genetically engineered to be immunocompromised.
But before the procedure, they treated mice with hormones to create two groups that differed with regard to where they were in their menstrual cycle. Dramatic differences emerged post-infection: mice infected in the diestrus or in between phase became progressively sick, lost weight, and died in 2-3 weeks, as one might predict in these mice. Remarkably, the same strain of immunocompromised AG129 mice infected in estrus phase showed no sign of disease.
William Weihao Tang, the study's first author, calls this one the paper's most intriguing findings. "The strain of mice we used, called AG129, were originally engineered to be extremely vulnerable to infection," he says. "But even these mice, when infected in estrus phase, appeared completely resistant to virus. That surprised us."
Shresta says that a caveat is that responses in mouse strains like AG129, which were purposely engineered to serve as a "lethal" model of infection, must be tested in mice with greater immune function. "For science to be relevant to humans, we always confirm results in the most 'immunocompetent' mouse that better reflects a normal human immune system."
To do that, her team repeated experiments in an entirely different type of engineered mouse, one only moderately susceptible to infection, which scientists call a "non-lethal" model. When infected in diestrus phase, those mice lost weight and exhibited clinical signs of disease but, unlike their AG129 counterparts, eventually recovered. However, just like the AG129 mice, when infected in estrus phase "non-lethal" mice showed no sign of Zika-like disease.
This trend was reflected in other experimental outcomes. For example, in both lethal and non-lethal strains, viral RNA, which serves as direct evidence of virus, persisted in the vaginal canal sometimes as long as 10 days post-infection in diestrus. By contrast, viral RNA disappeared three days after infection in estrus phase.
Virus persistence in vaginal fluids may account for why diestrus-infected mice become sick, regardless of mouse strain, yet the molecular or cellular basis for susceptibility remains unclear. Mice analyzed in the study were experimentally synchronized or "staged" at one of two reproductive phases by hormonal injection, which may provide a clue. "Hormones changed the mouse female reproductive tract in ways that either enhanced or protected against sexual transmission," says Tang, although he and Shresta caution it is much too early to generalize mouse findings to humans.
But if similar mechanisms prove relevant to human transmission, they are cause for concern, largely because most Zika-infected men or women show few or no symptoms. Thus they could unwittingly engage in sexual activity resulting in adult disease or even in utero transfer of virus to an unborn child.
Recent CDC "case counts" suggest that thus far that few Zika cases in the US were likely transmitted sexually. But these numbers are estimates, and sexual transmission of ZIKV is taken extremely seriously in other regions, such as South America. In fact, one mathematical modeling study of Baranquilla, Colombia, estimated that as many as 47% of Zika cases reported there emerged from sexual contact.
"In humans sexual transmission may be a bigger deal than has been thought," says Shresta, emphasizing that currently we know very little about this mode of Zika transmission. "We know that in males virus can remain in semen for possibly months, while a man shows no symptoms. During that time he could unknowingly pass it to a sexual partner."
The next step for the Shresta lab is to take advantage of these two mouse models to define immune signals that make mice susceptible to or protected from ZIKV infection. "We are ultimately interested in drugs or vaccines to prevent the disease," says Shresta, who has also used immunodeficient mice as models to study dengue virus infection. "Being able to test interventions in two animal models, one that succumbs to infection and another that recovers, is a plus. Developing vaccines requires access to models representing all scenarios."
 

Journal Reference:

1. William Weihao Tang, Matthew Perry Young, Anila Mamidi, Jose Angel Regla-Nava, Kenneth Kim, Sujan Shresta. A Mouse Model of Zika Virus Sexual Transmission and Vaginal Viral Replication. Cell Reports, 2016; 17 (12): 3091 DOI: 10.1016/j.celrep.2016.11.070 

Courtesy: ScienceDaily
 

Helping pays off: People who care for others live longer

Older people who help and support others live longer, a new study has concluded. The results of these findings show that this kind of caregiving can have a positive effect on the mortality of the carers. 

Older people who help and support others are also doing themselves a favor. An international research team has found that grandparents who care for their grandchildren on average live longer than grandparents who do not. The researchers conducted survival analyses of over 500 people aged between 70 and 103 years, drawing on data from the Berlin Aging Study collected between 1990 and 2009.
In contrast to most previous studies on the topic, the researchers deliberately did not include grandparents who were primary or custodial caregivers. Instead, they compared grandparents who provided occasional childcare with grandparents who did not, as well as with older adults who did not have children or grandchildren but who provided care for others in their social network.
Emotional support
The results of their analyses show that this kind of caregiving can have a positive effect on the mortality of the carers. Half of the grandparents who took care of their grandchildren were still alive about ten years after the first interview in 1990. The same applied to participants who did not have grandchildren, but who supported their children -- for example, by helping with housework. In contrast, about half of those who did not help others died within five years.
The researchers were also able to show that this positive effect of caregiving on mortality was not limited to help and caregiving within the family. The data analysis showed that childless older adults who provided others with emotional support, for example, also benefited. Half of these helpers lived for another seven years, whereas non-helpers on average lived for only another four years.
Too intense involvement causes stress
"But helping shouldn't be misunderstood as a panacea for a longer life," says Ralph Hertwig, Director of the Center for Adaptive Rationality at the Max Planck Institute for Human Development. "A moderate level of caregiving involvement does seem to have positive effects on health. But previous studies have shown that more intense involvement causes stress, which has negative effects on physical and mental health," says Hertwig. As it is not customary for grandparents in Germany and Switzerland to take custodial care of their grandchildren, primary and custodial caregivers were not included in the analyses.
The researchers think that prosocial behavior was originally rooted in the family. "It seems plausible that the development of parents' and grandparents' prosocial behavior toward their kin left its imprint on the human body in terms of a neural and hormonal system that subsequently laid the foundation for the evolution of cooperation and altruistic behavior towards non-kin," says first author Sonja Hilbrand, doctoral student in the Department of Psychology at the University of Basel.
 

ournal Reference:

1. Sonja Hilbrand, David A. Coall, Denis Gerstorf, Ralph Hertwig. Caregiving within and beyond the family is associated with lower mortality for the caregiver: A prospective study. Evolution and Human Behavior, 2016; DOI: 10.1016/j.evolhumbehav.2016.11.010 

Courtesy: ScienceDaily
 

'Shock and kill' strategy for curing HIV may endanger patients' brains

Combination drug treatments have become successful at long-term control of HIV infection, but the goal of totally wiping out the virus and curing patients has so far been stymied by HIV's ability to hide out in cells and become dormant for long periods of time. One of the proposed curative strategies for HIV, known as "shock and kill," may be harmful to patients' brains, warn researchers. 

Brain cells from an SIV-infected macaque treated with ingenol and vorinostat. Macrophages are marked in green and the virus in red; virus-infected macrophages appear orange/yellow (arrows). Blue marks the nuclei of all cells.

Credit: Stephen Wietgrefe

 

One of the proposed curative strategies for HIV, known as "shock and kill," first uses so-called latency-reversing agents to wake up dormant viruses in the body, making them vulnerable to the patient's immune system. The idea is that this, in combination with antiretroviral medicines, would wipe out the majority of infected cells.
But based on a study of macaques with SIV, a group of researchers warns in a report published in the January 2 issue of the journal AIDS that such a strategy could cause potentially harmful brain inflammation.
"The potential for the brain to harbor significant HIV reservoirs that could pose a danger if activated hasn't received much attention in the HIV eradication field," says Janice Clements, Ph.D., professor of molecular and comparative pathobiology at the Johns Hopkins University School of Medicine. "Our study sounds a major cautionary note about the potential for unintended consequences of the shock-and-kill treatment strategy."
HIV research efforts have long focused on prevention and developing antiretroviral therapies that keep the virus in check without eradicating it, essentially transforming HIV into a manageable chronic condition, says Lucio Gama, Ph.D., assistant professor of molecular and comparative pathobiology at Johns Hopkins and the lead author of the new study. Then, in 2009, a group in Berlin reported it had cured a man of HIV by giving him a bone marrow transplant from a donor whose genetics conferred natural resistance to the virus. This galvanized federal funding of new research projects aimed at finding a more broadly applicable "AIDS cure," Gama says. He and Clements are part of that pursuit as members of the Collaboratory of AIDS Researchers for Eradication.
One cure strategy being pursued is to find a medication that would "wake up" virus in the reservoirs, forcing it to reveal itself. But Gama says that could be problematic if HIV reservoirs exist in the brain, and investigators already had some evidence that they do: the many cases of AIDS dementia that developed before the current antiretroviral cocktail treatment was developed. "Research had also shown that HIV can infect monocytes in the blood, which we know cross into the brain," he says. But no studies had definitively answered whether significant reservoirs of latent HIV in patients under long-term therapy could be sustained in the brain -- in part because, in autopsies, it is unclear whether virus detected in the brain comes from brain cells themselves or surrounding blood.
For the new study, Clements, Gama and their collaborators treated three pig-tailed macaque monkeys infected with SIV with antiretrovirals for more than a year. Then the researchers gave two of the macaques ingenol-B, a latency-reversing agents thought to "wake up" the virus. "We didn't really see any significant effect," Gama says, "So we coupled ingenol-B with another latency-reversing agent, vorinostat, which is used in some cancer treatments to make cancer cells more vulnerable to the immune system." The macaques also continued their course of antiretrovirals throughout the experiment.
After a 10-day course of the combined treatment, one of the macaques remained healthy, while the other developed symptoms of encephalitis, or brain inflammation, Gama says, and blood tests revealed an active SIV infection. When the animal's illness worsened, the researchers humanely killed it and carefully removed the blood from its body so that blood sources of the virus would not muddle their examination of the brain. Testing revealed SIV was still present in the brain, but only in one of the regions analyzed: the occipital cortex, which processes visual information. The affected area was so small that "we almost missed it," he says.
Gama cautions that the results of their study on macaques with SIV may not apply to humans with HIV. It's also possible, he says, that the encephalitis was transient and could have resolved by itself. Still, he says, the results signal a need for extra caution in exploring ways to flush out HIV reservoirs and eradicate the virus from the body.
 

ournal Reference:

1. Lucio Gama, Celina M. Abreu, Erin N. Shirk, Sarah L. Price, Ming Li, Greg M. Laird, Kelly A. Metcalf Pate, Stephen W. Wietgrefe, Shelby L. O’Connor, Luiz Pianowski, Ashley T. Haase, Carine Van Lint, Robert F. Siliciano, Janice E. Clements. Reactivation of simian immunodeficiency virus reservoirs in the brain of virally suppressed macaques. AIDS, 2017; 31 (1): 5 DOI: 10.1097/QAD.0000000000001267 

Courtesy: ScienceDaily
 

Gut microbes promote motor deficits in a mouse model of Parkinson's disease

Gut microbes may play a critical role in the development of Parkinson's-like movement disorders in genetically predisposed mice, researchers report. Antibiotic treatment reduced motor deficits and molecular hallmarks of Parkinson's disease in a mouse model, whereas transplantation of gut microbes from patients with Parkinson's disease exacerbated symptoms in these mice. The findings could lead to new treatment strategies for the second most common neurodegenerative disease in the United States. 

This research depicts the findings of Sampson et al., who show that signals from gut microbes are required for the neuroinflammatory responses as well as hallmark gastrointestinal and a-synuclein-dependent motor deficits in a model of Parkinson's disease.

Credit: Sampson et al./Cell 2016

 

"We have discovered for the first time a biological link between the gut microbiome and Parkinson's disease. More generally, this research reveals that a neurodegenerative disease may have its origins in the gut, and not only in the brain as had been previously thought," says senior study author Sarkis Mazmanian of the California Institute of Technology. "The discovery that changes in the microbiome may be involved in Parkinson's disease is a paradigm shift and opens entirely new possibilities for treating patients."
Parkinson's disease affects an estimated one million people and 1% of the United States population over 60 years of age. The disease is caused by the accumulation of abnormally shaped α-synuclein proteins in neurons, leading to particularly toxic effects in dopamine-releasing cells located in brain regions that control movement. As a result, patients experience debilitating symptoms such as tremors, muscle stiffness, slowness of movement, and impaired gait. First-line therapies currently focus on increasing dopamine levels in the brain, but these treatments can cause serious side effects and often lose effectiveness over time.
To address the need for safer and more effective treatments, Mazmanian and first author Timothy Sampson of the California Institute of Technology turned to gut microbes as an intriguing possibility. Patients with Parkinson's disease have an altered gut microbiome, and gastrointestinal problems such as constipation often precede motor deficits by many years in these individuals. Moreover, gut microbes have been shown to influence neuronal development, cognitive abilities, anxiety, depression, and autism. However, experimental evidence supporting a role for gut microbes in neurodegenerative diseases has been lacking.
The researchers raised genetically modified mice with a Parkinson's-like disease either in normal, non-sterile cages or in a germ-free environment. Remarkably, mice raised in the germ-free cages displayed fewer motor deficits and reducedaccumulation of misfolded protein aggregates in brain regions involved in controlling movement. In fact, these mice showed almost normal performance on tasks such as traversing a beam, removing an adhesive from their nose, and climbing down a pole.
Antibiotic treatment had a similar effect as the germ-free environment on ameliorating motor symptoms in mice predisposed to Parkinson's-like disorders. By contrast, mice raised in the germ-free cages showed worse motor symptoms when they either were treated with microbial metabolites called short-chain fatty acids or received fecal transplants of gut microbes from patients with Parkinson's disease. Taken together, the results suggest that gut microbes exacerbate motor symptoms by creating an environment that could favor the accumulation of misfolded protein aggregates.
It is important to note that, in this study, gut microbes cooperate with a specific genetic factor to influence the risk for developing Parkinson's disease. The researchers used a specific genetic mouse model that recapitulates motor symptoms through α-synuclein accumulation, and genetically normal mice that were not predisposed to Parkinson's disease did not develop motor symptoms after receiving fecal transplants from patients. Other genetic and environmental factors, such as pesticide exposure, also play a role in the disease.
The findings suggest that probiotic or prebiotic therapies have the potential to alleviate the symptoms of Parkinson's disease. However, antibiotics or fecal microbe transplants are far from being viable therapies at this time. "Long-term, high-strength antibiotic use, like we utilized in this study, comes with significant risk to humans, such as defects in immune and metabolic function," Sampson cautions. "Gut bacteria provide immense physiological benefit, and we do not yet have the data to know which particular species are problematic or beneficial in Parkinson's disease."
It is therefore critical to identify which pathogenic microbes might contribute to a higher Parkinson's disease risk or to development of a more severe symptomatology -- a research direction the researchers are planning to take. They will also look for specific bacterial species that may protect patients against motor decline. In the end, the identification of microbial species or metabolites that are altered in Parkinson's disease may serve as disease biomarkers or even drug targets, and interventions that correct microbial imbalances may provide safe and effective treatments to slow or halt the progression of often debilitating motor symptoms.
"Much like any other drug discovery process, translating this innovative work from mice to humans will take many years," Mazmanian says. "But this is an important first step toward our long-term goal of leveraging the deep, mechanistic insights that we have uncovered for a gut-brain connection to help ease the medical, economic, and social burden of Parkinson's disease."
 

Journal Reference:

1. Timothy R. Sampson et al. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease. Cell, December 2016 DOI: 10.1016/j.cell.2016.11.018 

Courtesy: ScienceDaily
 

 

Platypus venom could hold key to diabetes treatment

Australian researchers have discovered remarkable evolutionary changes to insulin regulation in two of the nation's most iconic native animal species -- the platypus and the echidna -- which could pave the way for new treatments for type 2 diabetes in humans. The findings reveal that the same hormone produced in the gut of the platypus to regulate blood glucose is also surprisingly produced in their venom. 

The findings, now published in the Nature journal Scientific Reports, reveal that the same hormone produced in the gut of the platypus to regulate blood glucose is also surprisingly produced in their venom.
The research is led by Professor Frank Grutzner at the University of Adelaide and Associate Professor Briony Forbes at Flinders University.
The hormone, known as glucagon-like peptide-1 (GLP-1), is normally secreted in the gut of both humans and animals, stimulating the release of insulin to lower blood glucose.
But GLP-1 typically degrades within minutes.
In people with type 2 diabetes, the short stimulus triggered by GLP-1 isn't sufficient to maintain a proper blood sugar balance. As a result, medication that includes a longer lasting form of the hormone is needed to help provide an extended release of insulin.
"Our research team has discovered that monotremes -- our iconic platypus and echidna -- have evolved changes in the hormone GLP-1 that make it resistant to the rapid degradation normally seen in humans," says co-lead author Professor Frank Grutzner, from the University of Adelaide's School of Biological Sciences and the Robinson Research Institute.
"We've found that GLP-1 is degraded in monotremes by a completely different mechanism. Further analysis of the genetics of monotremes reveals that there seems to be a kind of molecular warfare going on between the function of GLP-1, which is produced in the gut but surprisingly also in their venom," he says.
The platypus produces a powerful venom during breeding season, which is used in competition among males for females.
"We've discovered conflicting functions of GLP-1 in the platypus: in the gut as a regulator of blood glucose, and in venom to fend off other platypus males during breeding season. This tug of war between the different functions has resulted in dramatic changes in the GLP-1 system," says co-lead author Associate Professor Briony Forbes, from Flinders University's School of Medicine.
"The function in venom has most likely triggered the evolution of a stable form of GLP-1 in monotremes. Excitingly, stable GLP-1 molecules are highly desirable as potential type 2 diabetes treatments," she says.
Professor Grutzner says: "This is an amazing example of how millions of years of evolution can shape molecules and optimise their function.
"These findings have the potential to inform diabetes treatment, one of our greatest health challenges, although exactly how we can convert this finding into a treatment will need to be the subject of future research."
GLP-1 has also been discovered in the venom of echidnas. But while the platypus has spurs on its hind limbs for delivering a large amount of venom to its opponent, there is no such spur on echidnas.
"The lack of a spur on echidnas remains an evolutionary mystery, but the fact that both platypus and echidnas have evolved the same long-lasting form of the hormone GLP-1 is in itself a very exciting finding," Professor Grutzner says.
 

 

ournal Reference:

1. Enkhjargal Tsend-Ayush, Chuan He, Mark A. Myers, Sof Andrikopoulos, Nicole Wong, Patrick M. Sexton, Denise Wootten, Briony E. Forbes, Frank Grutzner. Monotreme glucagon-like peptide-1 in venom and gut: one gene – two very different functions. Scientific Reports, 2016; 6: 37744 DOI: 10.1038/srep37744 

Courtesy: ScienceDaily