Scientists Develop Infection Model for Tick-Borne Flaviviruses
NIH scientists have filled a research gap by developing a laboratory model to study ticks that transmit flaviviruses, such as Powassan virus. Powassan virus was implicated in the death of a New York man earlier this year. The unusual model involves culturing organs taken from Ixodes scapularis ticks and then infecting those organ cultures with flaviviruses, according to researchers at Rocky Mountain Laboratories, part of NIAID. The researchers say the culture model, described in mBio, will greatly increase knowledge about how flaviviruses infect ticks and could become a tool to evaluate medical countermeasures against tick-borne viruses.
Flaviviruses are the cause of diseases spread by mosquitoes (e.g., dengue fever and West Nile fever) and by ticks (e.g., Powassan virus disease and tick-borne encephalitis). Powassan virus and the closely related deer tick virus are the only flaviviruses known to be spread by ticks in North America.
The NIAID scientists developed their model by dissecting three tick organs—the midgut, salivary glands and nervous tissue—and then culturing flaviviruses in those organs, evaluating their viability over several days. They found that Powassan virus and the related Langat virus could infect and spread in salivary glands and midgut. Langat virus is found typically in Southeast Asia and is an ideal model virus for study because it causes only rare, mild infections in people.Female Mouse Embryos Remove Male Reproductive Systems
A protein called COUP-TFII determines whether a mouse embryo develops a male reproductive tract, according to researchers at NIH and their colleagues at Baylor College of Medicine. The discovery, which appeared online Aug. 18 in the journal Science, changes the long-standing belief that an embryo will automatically become female unless androgens, or male hormones, in the embryo make it male.
Dr. Humphrey Hung-Chang Yao, head of the NIEHS reproductive developmental biology group, studies how male and female mouse embryos acquire their sex-specific reproductive systems. He said all early-stage mammalian embryos, regardless of their sex, contain structures for both male and female reproductive tracts. For a mouse or human to end up with the reproductive tract of one sex after birth, the other tract has to disintegrate.
“I learned in graduate school that androgens are needed to maintain the male reproductive tract, but our work finds that maintenance of the male reproductive tract can be achieved without androgen,” Yao said.
Since the 1950s, scientists have believed that androgens produced by embryonic testes, promote the survival of the male reproductive tract. The scientific consensus favored a female by default scenario, in which the absence of androgens in female embryos resulted in the breakdown of the male reproductive tract. However, Yao’s work demonstrated that female embryos actively promote the elimination of the male tract through the action of COUP-TFII, challenging the female-by-default theory.
Specialized Mouse Neurons Play a Unique Role in Pain
Researchers from NIH have identified a class of sensory neurons (nerve cells that electrically send and receive messages between the body and brain) that can be activated by stimuli as precise as the pulling of a single hair. Understanding basic mechanisms underlying these different types of responses will be an important step toward the rational design of new approaches to pain therapy. The findings were published in Neuron.
“Scientists know that distinct types of neurons detect different types of sensations, such as touch, heat, cold, pain, pressure and vibration,” said Dr. Alexander Chesler, lead author of the study and principal investigator with NCCIH. “But they know more about neurons involved with temperature and touch than those underlying mechanical pain, like anatomical pain related to specific postures or activities.”
In this study, Chesler and his colleagues used a novel strategy that combined functional imaging (which measures neuronal activity), recordings of electrical activity in the brain and genetics to see how neurons respond to various stimuli. The scientists focused on a class of sensory neurons that express a gene called Calca, as these neurons have a long history in pain research.
The scientists applied various stimuli to the hairy skin of mice cheeks, including gentle mechanical stimuli (air puff, stroking and brushing), “high-threshold” mechanical stimuli (hair pulling and skin pinching) and temperature stimulation. They found that the target neurons belong to two broad categories, both of which were insensitive to gentle stimulation. The first was a well-known type of pain fiber—a polymodal nociceptor—that responds to a host of high-intensity stimuli such as heat and pinching. The second was a unique and previously unknown type of neuron that responded robustly to hair pulling. They called this previously undescribed class of high-threshold mechanoreceptors (HTMRs) “circ-HTMRs,” due to the unusual nerve terminals these neurons made in skin. They observed that the endings of the fibers made lasso-like structures around the base of each hair follicle.
“These findings add insight into how the somatosensory system encodes pain,” said NCCIH director Dr. Josephine Briggs. “Learning more about the distinctive features of circ-HTMRs could contribute to rapid, accurate localization of brain regions activated in mechanical pain, and ultimately to the rational design of new approaches to pain therapy.”
Mice Study May Lead to Discovery of Broad-Spectrum Antiviral
After herpesviruses infect a cell, their genomes are assembled into specialized protein structures called nucleosomes. Many cellular enzyme complexes can modulate these structures to either promote or inhibit the progression of infection. Scientists studying how one of these complexes (EZH2/1) regulated herpes simplex virus (HSV) infection unexpectedly found that inhibiting EZH2/1 suppressed viral infection. The research group, from NIAID, then demonstrated that EZH2/1 inhibitors also enhanced the cellular antiviral response in cultured cells and in mice. The work was reported in mBio.
Once a person has been infected with a herpesvirus, the virus persists in a latent form, sometimes reactivating to cause recurrent disease. Two-thirds of the global population are infected with HSV-1, and at least 500 million are infected with HSV-2, according to the World Health Organization. These viruses cause a range of diseases and conditions from oral cold sores to genital lesions to serious eye infections that can lead to blindness.
People infected with HSV also have an enhanced risk of acquiring or transmitting human immunodeficiency virus (HIV). Treatment usually involves antiviral drugs that interfere with viral replication, but new approaches to combat these infections are needed.
The NIAID group demonstrated that EZH2/1 inhibitors not only suppressed HSV infection, spread and reactivation in mice, but also suppressed human cytomegalovirus, adenovirus and Zika virus infections in cell culture using human primary fibroblast cell lines. The authors suggest that EZH2/1 inhibitors have considerable potential as broad-spectrum antivirals.