Chris Neufeldt, PhD
 |
(he/him) |
Assistant Professor, Department of Microbiology and Immunology, School of Medicine
Graduate Programs
- Full Member - Biochemistry, Cell and Developmental Biology
- Full Member - Microbiology and Molecular Genetics
Education
Postdoctoral Fellow, University of Heidelberg, 2021Postdoctoral Fellow, University of Alberta, 2015
PhD, University of Alberta, 2015
BSc, University of Alberta, 2007
Contact Information
Email: c.neufeldt@emory.edu
Phone: 404-727-0092
Address:
O. Wayne Rollins Research Center, Room 3105
1510 Clifton Road NE
Atlanta, GA 30322
Our research program specifically focuses on determining mechanisms by which viruses utilize ER membrane-shaping proteins and cellular vesicle trafficking pathways, to better understand virus infection and characterize fundamental cellular functions of the ER and ER-associated proteins. All studied positive-strand RNA viruses replicate in host membranes with the majority requiring the ER for formation of their replication organelles. Although the morphology of virus-induced membrane rearrangements has been characterized, the mechanisms underlying ER membrane alterations are still poorly understood. The ER is the largest cellular organelle that extends throughout the cytoplasm and is involved in connecting numerous cellular processes. Mapping connections between the ER and other cellular organelles or processes, as well as understating the functional significance of these connections, is vital for our basic understanding of the cell and many diseases. Studying virus-induced manipulation of the ER represents a unique opportunity to understand both virology and host processes that are linked to a variety of genetic diseases or disorders. Additionally, uncovering conserved host pathways utilized by different viruses has a broad therapeutic potential.
To address these questions, our research uses a diverse set of tools and methodologies ranging from fundamental biochemical analysis to advanced microscopy and gene manipulation techniques, all aimed at determining molecular processes and mechanisms functioning at the virus-host interface. We have three core areas of research encompassing a wide range of questions.
1. Functional characterization of ATLs in virus infection: a mechanistic and comparative analysis. We have recently demonstrated a central role for Atlatsin proteins in the flavivirus infection cycle. Though we have done the preliminary analysis of ATL function in flavivirus infection, there are still many questions regarding the specific role of ATLs in flavivirus replication. The first goal of this project is to investigate the role of ATLs in other positive strand RNV virus infection, such as Coronaviruses, HCV, Poliovirus, or Chikungunya virus. The second is to acquire a more mechanistic understanding of Atlastin protein in flavivirus infection. Finally, building on the mutational analysis from our recent publication, we would explore the possibility of developing inhibitors that could be used to selectively modulate Atlastin functions and manipulate different aspects of virus infections. With this work, we aim to provide mechanistic insight into ATL function, determine how these functions utilized by different viruses, and investigate the therapeutic potential of ATLs for both virus infection and for genetic diseases linked to ATLs.
2. Characterization of ER proteins associated with positive-strand RNA virus infection. Our initial analysis using proteomics and RNAi based screening identified several other proteins linked to ATLs that are also involved in DV infection. The goal of this project is to further characterize these candidates by evaluating function or location changes caused by virus infection. The resulting information would be used to understand how these factors generally coordinate ER structure and how alterations in the context of virus infection are used to reshape host cellular membranes. These studies rely on super-resolution light microscopy and specialized EM techniques for structural analysis as well as proteomics and RNAi screening for functional analysis. Through this analysis we aim to define the protein components and molecular structures required for virus-mediated membrane alterations as well as further defining how the ER network organizes cellular and viral processes.
3. Connecting the ER to vesicle trafficking and innate immune signaling. In our recent study, we describe a link between ATL3 and retrograde trafficking, specifically in internalization of molecules at the plasma membrane. This observation has a broad impact for many cellular transport pathways including immune signaling, which often relies on receptor uptake and endosomal recycling pathway. Additionally, we have recently connected cGAS-STING activation to the initiation of pro-inflammatory responses induced by SARS-CoV-2 infection. This activation leads to a selective NF-kB response that could initiate the hyper-inflammation observed in severe COVID-19 cases. Moreover, we found that STING translocation from the ER to the Golgi may be inhibited by the virus, leading to a selective pro-inflammatory response. The goal of this project is to characterize the role of the ER factors in innate immune activation and to determine how virus infection manipulates these cellular responses leading to pathogenesis.
With these studies, we aim to elucidate details pertaining to how the ER is involved in connecting and regulating other cellular pathways, such as membrane lipid dynamics, endosomal trafficking and immune signaling, and how these functions can be utilized or manipulated by pathogens. Through a better understating of these fundamental cellular and viral process we can progress towards the development of effective antiviral therapies.
To address these questions, our research uses a diverse set of tools and methodologies ranging from fundamental biochemical analysis to advanced microscopy and gene manipulation techniques, all aimed at determining molecular processes and mechanisms functioning at the virus-host interface. We have three core areas of research encompassing a wide range of questions.
1. Functional characterization of ATLs in virus infection: a mechanistic and comparative analysis. We have recently demonstrated a central role for Atlatsin proteins in the flavivirus infection cycle. Though we have done the preliminary analysis of ATL function in flavivirus infection, there are still many questions regarding the specific role of ATLs in flavivirus replication. The first goal of this project is to investigate the role of ATLs in other positive strand RNV virus infection, such as Coronaviruses, HCV, Poliovirus, or Chikungunya virus. The second is to acquire a more mechanistic understanding of Atlastin protein in flavivirus infection. Finally, building on the mutational analysis from our recent publication, we would explore the possibility of developing inhibitors that could be used to selectively modulate Atlastin functions and manipulate different aspects of virus infections. With this work, we aim to provide mechanistic insight into ATL function, determine how these functions utilized by different viruses, and investigate the therapeutic potential of ATLs for both virus infection and for genetic diseases linked to ATLs.
2. Characterization of ER proteins associated with positive-strand RNA virus infection. Our initial analysis using proteomics and RNAi based screening identified several other proteins linked to ATLs that are also involved in DV infection. The goal of this project is to further characterize these candidates by evaluating function or location changes caused by virus infection. The resulting information would be used to understand how these factors generally coordinate ER structure and how alterations in the context of virus infection are used to reshape host cellular membranes. These studies rely on super-resolution light microscopy and specialized EM techniques for structural analysis as well as proteomics and RNAi screening for functional analysis. Through this analysis we aim to define the protein components and molecular structures required for virus-mediated membrane alterations as well as further defining how the ER network organizes cellular and viral processes.
3. Connecting the ER to vesicle trafficking and innate immune signaling. In our recent study, we describe a link between ATL3 and retrograde trafficking, specifically in internalization of molecules at the plasma membrane. This observation has a broad impact for many cellular transport pathways including immune signaling, which often relies on receptor uptake and endosomal recycling pathway. Additionally, we have recently connected cGAS-STING activation to the initiation of pro-inflammatory responses induced by SARS-CoV-2 infection. This activation leads to a selective NF-kB response that could initiate the hyper-inflammation observed in severe COVID-19 cases. Moreover, we found that STING translocation from the ER to the Golgi may be inhibited by the virus, leading to a selective pro-inflammatory response. The goal of this project is to characterize the role of the ER factors in innate immune activation and to determine how virus infection manipulates these cellular responses leading to pathogenesis.
With these studies, we aim to elucidate details pertaining to how the ER is involved in connecting and regulating other cellular pathways, such as membrane lipid dynamics, endosomal trafficking and immune signaling, and how these functions can be utilized or manipulated by pathogens. Through a better understating of these fundamental cellular and viral process we can progress towards the development of effective antiviral therapies.
Atlanta Society of Mentors (ASOM), 2022
Diversity: Inclusion in the Modern Workplace, 2022
Unconscious Bias Training, 2022
Tyshawn Ferrell
Biochemistry, Cell and Developmental Biology
Entrance Year: 2021
Topic: Characterizing the genetic landscape of Dengue virus antigenic evolution.
Jayden Harris (she/they)
Microbiology and Molecular Genetics
Entrance Year: 2024
Jonathan Owen (he/him)
Microbiology and Molecular Genetics
Entrance Year: 2021
Topic: Membrane tethering by the host GTPase Atlastin-2 is critical for flavivirus replication
