Insights & Outcomes: Tick tendencies, stretchy cell membranes, and male fertility
This month, Insights & Outcomes winds its way through tick proteins, antibodies that fight the SARS-CoV-2 virus, and stretchy cell membranes. There’s also time to check in on a cholesterol regulator and the racing stripes that play a role in male fertility.
Home on the tick
B. burgdorferi, the bacterium that causes Lyme disease, has found a comfortable home in ticks which in turn transmit the dangerous pathogen by feeding on mammalian hosts.
Scientists have long wondered why, exactly, ticks offer such a safe harbor for the pernicious bacteria. Erol Fikrig, the Waldemar Von Zedtwitz Professor of Medicine (infectious diseases) and of microbial pathogenesis at the Yale School of Medicine and professor of epidemiology (microbial diseases) at the Yale School of Public Health, and his Yale colleagues have found a potential explanation for why black-legged ticks have become such a problematic reservoir for the Lyme pathogen.
The team found that ticks have proteins — called adiponectin-like receptors — that control sugar levels and aid in processing fats in mammals, just as the hormone adiponectin does. It turns out that the Lyme bacteria have essentially hijacked this receptor to obtain energy and nutrients.
When scientists blocked the activity of the receptor in an experiment, they also reduced levels of B. burgdorferi within the ticks. Targeting this molecular interaction could interfere with the life-cycle of the bacterium and suggests ways to combat Lyme disease and potentially other tick-borne infections, the authors say. The work was published in the journal eLife.
The production of antibodies such as those that fight the SARS-CoV-2 virus is something like an intricate symphony. In fact, the loss of key players in this molecular orchestra has been implicated in severe cases of COVID, leading to fears that the virus can cripple the human body’s immune response.
However, a team of Yale researchers has found that the immune system has a way to compensate when key immune system players are disabled, a surprising discovery that may lead to new ways to supplement vaccines or develop new antiviral treatments. “The immune system has multiple pathways to generating a strong antibody response,” said Yale immunologist Stephanie Eisenbarth.
Immunology textbooks teach that antibodies are made by B cells regulated by T follicular helper (Tfh) cells within the germinal center, cell structures that form temporarily in the lymph nodes during immune reactions. Newly formed B cells, in turn, create antibodies that target specific pathogens. In severe cases of COVID, the number of germinal centers is greatly diminished.
However, Eisenbarth and colleagues found that when they knocked out Tfh cells in mice, another type of T cell jumped in to trigger antibodies that were just as effective in combatting SARS-CoV-2 as antibodies created in the textbook process. “If the immune system loses its horn section, it uses violins to compensate,” she said.
Understanding how these cellular understudies combat pathogens might lead to new ways to treat multiple infections. Yale’s Craig Wilen was co-senior author and Jennifer Chen was lead author of the research published in the journal Science Immunology.
The racing stripes of male fertility
The key to male fertility lies in a series of four linear tracks of calcium channels — aligned like racing stripes on the tail of sperm — which are activated by cues in the female reproductive tract and power the sperm towards the egg. If the alignment of these channels is disrupted, studies have shown, sperm lack the ability to start their life-creating journey.
Now researchers from Yale and Osaka University have discovered a trafficking molecule that is crucial to targeting these channels and organizing them into those racing stripes, an insight that could lead to an elusive male contraceptive or, conversely, treatment for male infertility.
The calcium channel complex aligned on a sperm’s tail is called CatSper and consists of distinct subunits. The CatSper channel receives signals from the environment which in turn activate sperm motility and guide the reproductive cells to the ovum.
Yale’s Jae Yeon Hwang, from the lab of Jean-Ju Chung, associate professor of cellular and molecular physiology, wanted to know how these CatSper channel complexes are arranged uniquely along the sperm tail. In their study, the researchers found a membrane-docking protein they named CatSper-tau. The protein, they said, is necessary for targeting and trafficking the CatSper channel complex and organizing the channels into racing stripes during development of the sperm.
Blocking the formation of the linear arrangement of CatSper channel complex leads to infertility in mice and could offer targets for male contraceptives as an alternative to condoms or vasectomies, Chung said. The knowledge might also help identify roots of male infertility and provide researchers with targets for new treatments for the condition.
The study was published in the journal Cell Reports.
Going with the flow
Cell membranes serve many functions, from providing protection to transporting materials in and out of our cells — thanks largely to their 2-dimensional fluid-like behavior.
Regular cellular processes such as cell migration, infection, signaling, adhesion, and cell division lead to localized membrane “stretching,” causing a “flow” to the site where such activities occurred in order to relax increased membrane tension.
Until now it has been unclear how rapidly the cell membrane flows to relax such gradients. Recent work suggested that the flows are very slow, confining membrane tension changes to small areas on the cell surface.
A collaboration between the Erdem Karatekin and David Zenisek labs at Yale School of Medicine, and the Benjamin Machta lab in the Department of Physics, has discovered that cell membranes in fact flow at vastly different speeds, reflecting the distinct needs of different cell types. The work appears in the journal Science Advances.
The results suggest that the speed with which the cell membrane flows may be adapted to the way membranes are distributed and recycled in different cell types.
Several complex systems in the body work to keep cholesterol in check, but the way these systems maintain cholesterol balance is not fully understood. In a study published in Nature Communications, Yale researchers uncovered an unexpected regulator of cholesterol in mice as well as a previously unidentified role for vitamin B12, a vitamin involved in metabolism.
Cholesterol is important for both cell structure and function, but too much can lead to health issues like cardiovascular disease. Keeping cholesterol at the right level is essential.
The research team found that an enzyme called MMAB, which helps convert vitamin B12 into an active molecule — or one that can have an effect on the body — is part of a pathway that regulates cholesterol formation and the uptake of cholesterol into cells. “When MMAB was less active, we saw an increase in the amount of cholesterol taken into cells,” explained Carlos Fernández-Hernando, the Anthony N. Brady Professor of Comparative Medicine and senior author of the study.
MMAB also turns out to be part of a feedback loop, as the amount of cellular cholesterol influences MMAB levels in liver cells.
In humans, certain variants of the MMAB gene have been linked to altered plasma cholesterol levels and heightened risk of cardiovascular disease. “Understanding MMAB’s role in cholesterol metabolism is a key step toward understanding its connection to cardiovascular disease,” said Leigh Goedeke, an instructor at the Yale School of Medicine and lead author of the study.
ACM honors Lin Zhong
The Association for Computer Machinery (ACM), the world’s largest society of computing professionals, has named Yale’s Lin Zhong as part of its new group of fellows.
The ACM fellows program recognizes the top 1% of the association’s members for their outstanding accomplishments in computing and information technology, and for outstanding service to the larger computing community.
Zhong, who joined Yale’s Department of Computer Science in the Faculty of Arts and Science’s School of Engineering and Applied Science in 2020, was honored for his contributions to mobile and network systems. His work focuses on the design and construction of computer systems, especially mobile and wireless systems. In particular, his research seeks to make systems energy efficient, secure, and user-friendly.