SARS-CoV-2 Nsp14 mediates the effects of viral infection on the host cell transcriptome

SARS-CoV-2 is the pathogen causing the COVID-19 pandemic, that as of early February 2022 has caused 5.7 million deaths worldwide.

When a virus infects a cell, it transforms it, so it can become a “virus factory”. To do so, it needs to suspend it from doing the normal functions, but not to a point that the immune system will detect those changes and “decide” to kill the infected cell. Understanding how viruses accomplish that is very important for virology and medicine as, for example, it could be used to help the immune system identify these cells and stop the virus from spreading through the body.

Graphical abstract for Zaffagni post

To tackle this issue, researchers identify genes that get activated or repressed when a virus infects a cell. One way to monitor the genes that are “on” or “off” during the infection is to measure RNAs abundance by RNA sequencing (RNA-seq). Through this approach, recent studies showed that SARS-CoV-2 infection induces big changes on the cells that it infects. Generally, scientists believe changes induced by viral infection are the consequence of the concerned action of the virus proteins acting within the host cell. For example, the SARS-CoV-2 genome encodes 29 proteins. The effect of the virus is so strong that it changes more than 5000 genes in just 48hs, this is almost ¼ of our genes.

How do individual viral proteins contribute to these changes? To answer this question, the Kadener lab in the Department of Biology introduced singular viral SARS-CoV-2 proteins into human cells and monitored gene expression changes through RNA-seq. Between the 26 tested proteins, non-structural protein 14 (Nsp14) was the one inducing the most dramatic effect, altering the expression of ≈4000 genes. Importantly, these changes overlap well with previously published RNA-seq data from human cells infected with SARS-CoV-2. This suggests that transient expression of Nsp14 partially recapitulates the molecular events downstream to SARS-CoV-2 infection. They also showed that a cellular enzyme (IMPDH2) mediates these changes, and that treatment with IMPDH2 inhibitors partially rescues the changes induced by Nsp14.

This research contributes to understanding the function of viral proteins on the host cell and on the molecular mechanisms that control the progression of viral infection. The Kadener lab showed that Nsp14 also modulates gene expression of the host cell by activating a cellular enzyme. These events may be conserved in other coronaviruses infections and the discovery of these molecular mechanisms may be important for designing new therapeutic approaches.

Publication:

SARS-CoV-2 Nsp14 mediates the effects of viral infection on the host cell transcriptome. Michela Zaffagni, Jenna M Harris, Ines L Patop, Nagarjuna Reddy Pamudurti, Sinead Nguyen, Sebastian Kadener.  eLife 2022;11:e71945 DOI: 10.7554/eLife.71945.

Ordabayev et al. developed an open-source analysis software for colocalization single-molecule fluorescence experiments

Tapqir analysis

Yerdos Ordabayev et al. in the Department of Biochemistry use Bayesian probabilistic programming to implement computer software “Tapqir” for analysis of colocalization single-molecule spectroscopy (CoSMoS) image data. CoSMoS is a tool widely used in vitro to study the biochemical and physical mechanisms of the protein and nucleic acid macromolecular “machines” that perform essential biological functions. In this method, formation and/or dissociation of molecular complexes is observed by single-molecule fluorescence microscopy as the colocalization of binder and target macromolecules each labeled with a different color of fluorescent dye. Despite the use of the method for over twenty years, reliable analysis of CoSMoS data remains a significant challenge to the effective and more widespread use of the technique.

This work describes a holistic causal probabilistic model of CoSMoS image data formation. This model is physics-based and includes realistic shot noise in fluorescent spots, camera noise, the size and shape of spots, and the presence of both specific and nonspecific binder molecules in the images. Most importantly, instead of yielding a binary spot-/no-spot determination, the algorithm calculates the probability of a colocalization event. Unlike alternative approaches, Tapqir does not require subjective threshold settings of parameters so they can be used effectively and accurately by non-expert analysts. The program is implemented in the state-of-the-art Python-based probabilistic programming language Pyro (open-sourced by Uber AI Labs in 2017), which enables efficient use of graphics processing unit (GPU)-based hardware for rapid parallel processing of data and facilitates future modifications to the model. Tapqir is free, open-source software. We envision that Tapqir program is likely to be adopted by researchers who use single-molecule colocalization methods to study a wide range of different biological systems.

Reference:
Yerdos A Ordabayev, Larry J Friedman, Jeff Gelles, Douglas L Theobald. Bayesian machine learning analysis of single-molecule fluorescence colocalization images. eLife 2022;11:e73860.
Publication Date: March 23, 2022.

Dmitry Kleinbock is awarded a Simons Fellowship in Mathematics

Dmitry KleinbockProfessor of Mathematics Dmitry Kleinbock has been awarded a prestigious Simons Fellowship in Mathematics, which will support research activities during his sabbatical leave in the fall of 2022.

Kleinbock’s research deals with dynamical systems of algebraic origin and their applications to number theory. A dynamical system is simply a set of points together with an evolution law that governs the way points move over time. It turns out that many mathematical problems concerning integer solutions of some equations or inequalities can be understood in terms of the behavior of certain dynamical systems. Furthermore, systems that arise in this context are of algebraic nature (so called flows on homogeneous spaces of Lie groups), which makes it possible to use a wide variety of sophisticated tools such as representation theory, hyperbolic geometry and geometry of lattices.

During the Spring 2022 semester Kleinbock is visiting the Institute for Mathematical Research at ETH (Zürich, Switzerland), giving a lecture course on the topic of dynamics on homogeneous spaces. The plan for the spring is to finish several projects and start new collaborations. Then in the Fall 2022 semester Kleinbock will be a member of a thematic program on Applications of Dynamics in Number Theory and Algebraic Geometry at the Institute for Advanced Studies in Princeton, NJ, led by Tamar Ziegler (Hebrew University, Jerusalem). This will be an excellent opportunity, thanks to the Simons Fellowship, to explore further connections between dynamics and number theory.

Apply to Brandeis Innovation’s 12th Annual Sprout program for access to a pool of $100,000 in funds

Applications are now open for the Sprout program. Take your translational research to the next level with a grant funded by Brandeis Innovation/Office of Technology Licensing. Research activities that Sprout funds include:

  • Proof of Concept work
  • Preclinical Study
  • Prototype development
  • Other pre-Commercialization Research

In addition to funding, you will get support in exploring the commercialization potential of your invention, including the opportunity to engage with the industry.

No overhead! A $20,000 Sprout grant is equivalent to a $32.5K federal grant.

Deadline: Apr 10, 2022 at midnight

How to Apply: Fill out the pre-application here. The application will ask you for details about your project, your team, and how you would use the funding.

Grace Han and 2 Alumni Receive 2022 Sloan Foundation Fellowships

Grace Han group photo

Grace Han (left) and her group.

The Alfred P. Sloan Foundation has announced the winners of the 2022 Sloan Research Fellowships. These fellowships are awarded to early-career scientists that represent the most promising researchers working today. Winners receive $75,000, which can be used to support their research over a two-year term. Grace Han, Assistant Professor of Chemistry and the Landsman Career Development Chair in the Sciences is one of the 2022 recipients.

The major goal of Dr. Grace Han’s research program is to develop functional organic material systems that exhibit phase transitions triggered by external stimuli, notably light. The photo-controlled phase-change materials have a game-changing potential in waste heat recycling and storage, photo-actuation, photo-lithography, and photo-regulated adhesion. In particular, the novel strategy to optically ‘fix’ a liquid phase under fluctuating temperatures allows for a long-term latent heat storage and a triggered release of energy, which is not attainable by conventional phase-change materials such as paraffins or salt hydrates. To achieve this goal, her team investigates the photo-induced structural and polarity changes of molecular switches based on azobenzene, which reversibly controls the phase of materials.
The Sloan Research Fellowship will support the new direction of Han group’s research in expanding the materials set by the rational design of photoswitches with enhanced optical and thermal properties, which will address the challenges of the current state-of-the-art switches.
Two Brandeis alumni also received 2022 fellowships: Netta Engelhardt, BS ’11 (Physics) and Dapeng Bi, PhD ’12 (Physics).

Anish Ghosh receives the 2021 Shanti Swarup Bhatnagar Prize

Anish Ghosh has received the 2021 Shanti Swarup Bhatnagar Prize in Mathematical Sciences. The Shanti Swarup Bhatnagar Prize is India’s highest science award within the country. While at Brandeis, Anish Ghosh was the student of Dmitry Kleinbock, Professor of Mathematics. He is currently a faculty member at the Tata Institute of Fundamental Research (TIFR), Mumbai where he specializes in Ergodic Theory and Number Theory.

Kleinbock wrote the following about his former student:

“It was a great pleasure to find out that Anish Ghosh, my former student here at Brandeis, has received the Shanti Swarup Bhatnagar prize. Anish is a talented mathematician working in the field of ergodic theory on homogeneous spaces. Interest in this field rose significantly during the late 1980s and early 1990s after the seminal achievements of Marina Ratner and Anish’s mathematical grandfather Gregory Margulis, whose work, in particular the proof of the Oppenheim Conjecture, has since served as a basis for numerous links between dynamics and number theory.”

“Anish has been exploring connections between the two fields throughout his mathematical career. Since his graduation in 2006 he has authored more than 40 papers, many published in top-level journals, and has become one of a few people who are shaping the subject of ergodic theory and its arithmetical applications. Among his notable achievements I can mention the work on distribution of dense lattice orbits in homogeneous spaces, on intrinsic Diophantine approximation, on applications of equidistribution to counting lattice points and – most recently – an approach to quantitative Oppenheim-type problems involving Rogers’ moment formulas.”

“Anish has also been a great mentor, who as of now has produced at least 8 PhD students and collaborated with them extensively on various problems. He has lectured extensively on the subject of connections of dynamics and number theory and edited several collections of papers. To summarize, the Bhatnagar Prize is well deserved, and I am positive that the mathematical talent of Anish Ghosh will continue to flourish.”

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