Award Abstract # 2031906
RAPID: Collaborative Research: Bat goblet cells as immuno-hotspots for infection of coronavirus

NSF Org: IOS
Division Of Integrative Organismal Systems
Recipient: THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK
Initial Amendment Date: June 9, 2020
Latest Amendment Date: June 9, 2020
Award Number: 2031906
Award Instrument: Standard Grant
Program Manager: Joanna Shisler
jshisler@nsf.gov
 (703)292-5368
IOS
 Division Of Integrative Organismal Systems
BIO
 Direct For Biological Sciences
Start Date: July 1, 2020
End Date: June 30, 2022 (Estimated)
Total Intended Award Amount: $59,204.00
Total Awarded Amount to Date: $59,204.00
Funds Obligated to Date: FY 2020 = $59,204.00
History of Investigator:
  • Liliana Davalos (Principal Investigator)
    liliana.davalos@stonybrook.edu
Recipient Sponsored Research Office: SUNY at Stony Brook
W5510 FRANKS MELVILLE MEMORIAL L
STONY BROOK
NY  US  11794-0001
(631)632-9949
Sponsor Congressional District: 01
Primary Place of Performance: SUNY at Stony Brook
WEST 5510 FRK MEL LIB
Stony Brook
NY  US  11794-0001
Primary Place of Performance
Congressional District:
01
Unique Entity Identifier (UEI): M746VC6XMNH9
Parent UEI:
NSF Program(s): COVID-19 Research
Primary Program Source: 010N2021DB R&RA CARES Act DEFC N
Program Reference Code(s): 096Z, 7914, 9179
Program Element Code(s): 158Y00
Award Agency Code: 4900
Fund Agency Code: 4900
Assistance Listing Number(s): 47.074
Note: This Award includes Coronavirus Aid, Relief, and Economic Security (CARES) Act funding.

ABSTRACT

Why are bats so likely to carry coronaviruses, yet seem little affected by them? Many studies have focused on their immune system, but there is much to learn about the cells viruses attack upon entry. Acute respiratory symptoms, as well as the curious loss of the sense of smell in human patients with COVID-19 hint that cells in the nasal passage are afflicted first. Indeed, cells that produce mucus in the nose, known as goblet cells, have been shown to be ?ground zero? for viral entry. Since these cells are also present in bat noses, there must be a difference in how coronaviruses attack goblet cells in bats versus humans. However, virtually nothing is known about immune-related proteins in bat goblet cells. This project proposes a new approach to understand how bats are resistant to respiratory viruses such as those related to SARS-CoV-2. By generating a multi-dimensional study of the anatomy and physiology of the upper respiratory tract ?nose and pharynx? of bats, the proposed work will enable researchers to better understand how viruses enter the body and infect or fail to infect their hosts. This project will also allow health agencies around the world to better survey bat populations and prevent future pandemics similar to COVID-19. In addition, this proposal supports a graduate student and post-doctoral fellow to increase training in STEM fields.

Researchers supported by this award will test the hypothesis that bats with nasal anatomy similar to humans have a specific composition of the lining of their respiratory tract, evolved to prevent viruses such as SARS-CoV-2, from infecting them. To understand how the lining, or epithelium, is modified in bats compared to humans, this grant will compare the proteins, DNA, and histology of bats to humans and mice. The proposed work will highlight the role of goblet cells, which do not only produce mucus, but also have immune and inflammatory functions, as critical for infection from- versus resistance to viral attack. The team will also integrate layers of data, from 3D imaging to proteomics, to build a complete picture of the inner and outer workings of the upper respiratory tracts of bats. By visualizing the anatomy in high resolution and uncovering which specific proteins are produced by the lining of the bat?s nasal passage, this project will produce the most thorough study of the upper respiratory tracts of bats yet. This will be critical for humanity?s fight against zoonotic viruses, and surveillance of wildlife populations. This RAPID award is made by the Physiological and Structural Systems Cluster in the BIO Division of Integrative Organismal Systems, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH

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Yohe, Laurel R. and Fabbri and Lee, Daniela and Davies, Kalina T.J. and Yohe, Thomas P. and Sánchez, Miluska K.R. and Rengifo, Edgardo M. and Hall, Ronald and Mutumi, Gregory and Hedrick, Brandon P. and Sadier, Alexa and Simmons, Nancy B. and Sears, Karen "Ecological constraints on highly evolvable olfactory receptor genes and morphology in neotropical bats" Evolution , v.76 , 2022 https://doi.org/10.1111/evo.14591 Citation Details
Weber, Natalie and Nagy, Martina and Markotter, Wanda and Schaer, Juliane and Puechmaille, Sébastien J. and Sutton, Jack and Dávalos, Liliana M. and Dusabe, Marie-Claire and Ejotre, Imran and Fenton, M. Brock and Knörnschild, Mirjam and López-Baucells, Ad "Robust evidence for bats as reservoir hosts is lacking in most African virus studies: a review and call to optimize sampling and conserve bats" Biology Letters , v.19 , 2023 https://doi.org/10.1098/rsbl.2023.0358 Citation Details
Moreno Santillán, Diana D. and Lama, Tanya M. and Gutierrez Guerrero, Yocelyn T. and Brown, Alexis M. and Donat, Paul and Zhao, Huabin and Rossiter, Stephen J. and Yohe, Laurel R. and Potter, Joshua H. and Teeling, Emma C. and Vernes, Sonja C. and Davies, "Large?scale Genome sampling reveals unique immunity and metabolic adaptations in Bats" Molecular Ecology , 2021 https://doi.org/10.1111/mec.16027 Citation Details
Yohe, Laurel R and Leiser-Miller, Leith B and Kaliszewska, Zofia A and Donat, Paul and Santana, Sharlene E and Dávalos, Liliana M "Diversity in olfactory receptor repertoires is associated with dietary specialization in a genus of frugivorous bat" G3 Genes|Genomes|Genetics , v.11 , 2021 https://doi.org/10.1093/g3journal/jkab260 Citation Details
Castellanos, Francisco X. and Moreno-Santillán, Diana and Hughes, Graham M. and Paulat, Nicole S. and Sipperly, Nicolette and Brown, Alexis M. and Martin, Katherine R. and Poterewicz, Gregory M. and Lim, Marisa C. and Russell, Amy L. and Moore, Marianne S "The evolution of antimicrobial peptides in Chiroptera" Frontiers in Immunology , v.14 , 2023 https://doi.org/10.3389/fimmu.2023.1250229 Citation Details

PROJECT OUTCOMES REPORT

Disclaimer

This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.

 Intellectual Merit:

Despite the availability of vaccines and mitigations, COVID-19 continues to impact all aspects of our society. By reaching millions of viewers worldwide, our project has directly contributed to scientific literacy in the United States, beyond our borders. Engagement with the project has the potential to improve society, by presenting to the public with the scientific evidence for links between biodiversity and zoonotic spillovers. Our project also identified consistent differences among bats and between bats and other mammals that are likely involved in mediating viral entry and immune response. These differences encompass scales from gene expression to cell distribution, and organ location. While grounded in comparative histology, the techniques developed for this RAPID are of interest to scientists working on neurobiology, anatomy, and molecular ecology.

The project had three major objectives:

1) Compare the nasal passage of bats with and without VNOs, humans, and mice, using histology and 3D imaging.

2) Analyze the gene and protein expression of markers of goblet cell function (including SARS-CoV2 receptors) in the nasal epithelium of bats, humans, and mice.

3) Determine nasal epithelial function in bats with and without VNOs by combining transcriptomic data and immune staining.

 

Objective 1 is near completion. We were able to obtain histological specimens from samples >100 years old, as well as complement our collections with de novo noses at no cost to this grant. In addition, our data helped annotate >35 bats genomes to analyze the immune repertoires of Chiroptera and compared with outgroup mammals.

Objective 2 is partially complete. Between-species transcriptome data took some time, but we now have a full pipeline culminating in Ornstein-Uhlenbeck models of gene expression evolution and finding differential expression in key genes in the nose and other organs.

Objective 3 has been the most difficult. While immunostaining in formaldehyde preserved specimens can work, our older specimens (dating as far back as 1931) have proven difficult to immunostain. This is due, in part, to prolonged preservation in formaldehyde and ethanol, as well as unknowable elements during the specimen?s collection and preservation history. Our newly collected specimens in liquid nitrogen vapor, however, are currently being cut and should offer us with the best possible material to perform immunostaining yet.

 

Broader Impacts: The COVID-19 pandemic was a hindrance to some objectives associated with this project, but we were still able to implement broader impact activities, reaching millions. in October 2020, NOVA/ARTE filmed the work of Drs. Corthals, Davalos, and Yohe on bat nasal anatomy in connection to COVID-19 at Stony Brook University. Work for this grant is extremely well represented and the documentary has reached a wide audience of millions of both public and researchers alike. This documentary aired first in the United States in September 2021, as part of the PBS series NOVA. In Europe it releases in the arts and science cable channel ARTE, and across both regions, the documentary is still in rotation at https://www.pbs.org/wgbh/nova/video/bat-superpowers/

 

Seven undergraduate students (Francesca Yalong, Rintaro Kato, Navita Peters, Mateo Sanz, Tyler Polakovich and joining this semester (Fall 2022) are Xitlali Maceda and Rahele Gadapaka) from a minority serving institution, John Jay College of Criminal Justice at the City University of New York (CUNY), have been collaborating on this project for research credit, giving them an exposure to research opportunity, but also a purpose and special value to their work by being part of the greater worldwide scientific community, as thousands of scientists around the world are trying to uncover the origins, treatment, and prophylactics for COVID-19.

Our John Jay students have already presented their preliminary results at the PRISM and CUNY research days in May 2022 at the poster session. One of the students, Rintaro Kato, was offered a prestigious post-baccalaureate fellowship at the NIH based on a presentation of our preliminary results.

Rahele and Xitlali are continuing the work on the immunostaining and are expected to present their results at next semester's CUNY Research Day, as well as next year's NASBR meeting in Winnipeg, Manitoba.

Finally, the award was used to support three publications:

Moreno Santillan DD, Lama TM, Gutierrez Guerrero YT, Brown AM, Donat P, Zhao H, Rossiter SJ, Yohe LR, Potter JH, Teeling EC, et al. 2021. Large-scale genome sampling reveals unique immunity and metabolic adaptations in bats. Molecular Ecology 30:6449-6467.

Yohe LR, Fabbri M, Lee D, Davies KTJ, Yohe TP, Sanchez MKR, Rengifo EM, Hall R, Mutumi G, Hedrick BP, et al. 2022. Ecological constraints on highly evolvable olfactory receptor genes and morphology in neotropical bats. Evolution n/a.

Yohe LR, Leiser-Miller LB, Kaliszewska ZA, Donat P, Santana SE, Davalos LM. 2021. Diversity in olfactory receptor repertoires is associated with dietary specialization in a genus of frugivorous bat. G3 Genes|Genomes|Genetics 11:jkab260.

We also delivered 14 seminars, lectures, or posters at a variety of local and international venues.


Last Modified: 10/27/2022
Modified by: Liliana M Davalos Alvarez

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