Najla Arshad, PhD

Microbiology and Immunology Discipline

Center for Cancer Cell Biology, Immunology, and Infection

Dr. Arshad received her PhD degree from the Indian Institute of Science, Bangalore, India, under the mentorship of Dr. Sandhya S. Visweswariah. She investigated the glycan-mediated regulation of Guanylyl Cyclase-C, an intestinal surface receptor enzyme that maintains gut fluid-ion homeostasis and elucidated the mechanistic basis of its dysregulation in disease. This stoked her interest in the role of glycoproteins and chaperones in health and disease. Dr. Arshad subsequently joined the laboratory of Dr. Peter Cresswell in the Department of Immunobiology at Yale University for her postdoctoral training. Her research focused on determining the mechanisms by which antigen presentation by MHC-I is downregulated in cancers and viral infections. Dr. Arshad also closely collaborated with and then joined the laboratory of Dr. Edelson in the Department of Dermatology at Yale University, where she examined the roles of chaperones and glycoproteins in mediating immunotherapeutic responses and contributed to the development and design of novel cellular-based therapies.

The Arshad Lab will build an interdisciplinary basic and translational research program looking at the regulation of immune responses by ER chaperones. The translational arm will initially focus on myeloproliferative neoplasms, a type of chronic blood cancer, driven by mutant calreticulin. This ER chaperone is involved in both the folding of glycoproteins as well as peptide loading and antigen presentation by MHC-I, and Dr. Arshad’s work has shown that the mutations lead to the presentation of unique and tumor-associated antigens derived from glycoproteins. These epitopes be exploited as potential targets for therapy — a pressing need for this disease as it has no targeted cure. The lab will develop cutting-edge nanobody-based therapy and a cell-based therapy utilizing a novel subset of dendritic for this disease, establishing platforms of drug discovery that can be extended to other diseases. This will foster strong collaborations with clinicians and the research is partly funded by the MPN research foundation.

The goals of the basic research program will be (i) to establish the functional interaction network between ER chaperones and immune proteins and how they are dysregulated in disease, yielding future targets for therapy. (ii) The role of chaperones and the mechanisms of antigen presentation by MHC-I will also be investigated in bat cell lines as these animals have a fascinating immune system that gives them extraordinary resistance to developing tumors and getting sick from infections. Comparing immune responses across species will give us insights into how we can alter human immune responses to cope with disease. To achieve these goals, the lab will utilize the aforementioned nanobody-based technology to develop tools and establish platforms for omics-based, multi-dimensional analysis, followed by validation using molecular techniques.

Publications

https://scholar.google.com/citations?user=mTM2H2oAAAAJ&hl=en

1. Sengupta D, Pereyra RG, Han P, Graham M, Liu X, Arshad N, Cresswell P, Phagosome-associated autophagosomes containing antigens and proteasomes drive TAP-independent cross-presentation J Immunol 212:7 212 (7): 1063–1068 (2024)
2. Medinas DB, Arshad N, Parakh S, Miyamoto S, Zambelli VO, Editorial: Restoring endoplasmic reticulum proteostasis to treat neurological disorders. Front Pharmacol 14:1176805 (2023)
3. Arshad N, Laurent-Rolle M, Ahmed WS, Hsu JC, Mitchell SM, Pawlak J, Sengupta D, Biswas KH, Cresswell P, SARS-CoV-2 accessory proteins ORF7a and ORF3a use distinct mechanisms to down-regulate MHC-I surface expression. Proc Natl Acad Sci U S A 120: e2208525120 (2022)
4. Arshad N^# and Cresswell P, Impact of calreticulin and its mutants on ER function in health and disease, Prog Mol Subcell Biol 59, 163-180 (2021) (^#corresponding author)
5. Han P*, Hanlon P*, Arshad N, Lee J, Tatsuno K, Robinson E, Filler R, Sobolev O, Cote C, Rivera-Molina F, Toomre D, Fahmy T, Edelson RL, Platelet P-selectin initiates cross-presentation and dendritic cell differentiation in blood monocytes, Sci Adv, 6:11 (2020) (*co-first authors)
6. Tatsuno K, Yamazaki T, Hanlon D, Han P, Robinson E, Sobolev O, Yurter A, Rivera-Molina F, Arshad N, Edelson RL and Galluzzi L Extracorporeal photochemotherapy induces bona fide immunogenic cell death, Cell Death Dis (2019)
7. Arshad N^# and Cresswell P^#, Tumor-associated calreticulin mutants functionally compromise the peptide loading complex and antigen presentation by MHC-I, J Biol Chem, 293:9555-9569 (2018) (^#co-corresponding authors)
   • F1000 Prime Recommendation, Solheim J (Dec 2018)
   • F1000 Prime Recommendation, Elliott T and van Hateren A (Jun 2018)
8. Arshad N, Ballal S and Visweswariah SS, Site-specific N-linked glycosylation of receptor guanylyl cyclase C regulates ligand binding, ligand-mediated activation and interaction with vesicular integral membrane protein 36 (VIP36), J Biol Chem, 288:3907–3917 (2013)
9. Arshad N and Visweswariah SS, Cyclic Nucleotide Signaling: Getting to the Gut of the Matter, Wiley Interdiscip Rev Syst Biol Med, 5(4):409-24, (2013)
10. Fiskerstrand T*, Arshad N*, Haukanes BI, Tronstad RR, Pham KD, Håvik B, Johansson S, Tønder S, Levy SE, Brackman D, Boman H, Biswas KH, Apold J, Hovdenak N, Visweswariah SS and Knappskog PM, Familial diarrhea syndrome caused by an activating GUCY2C mutation, N Engl J Med, 366:1586-1595 (2012) (*co-first authors)
    • Research Highlights, Vogan, K, Familial diarrhea syndrome, Nature Genetics, 44:481 (2012)
    • Research Highlight, Camilleri, M, Guanylate cyclase C signaling: an intestinal secretory pathway where bugs, genes and new drugs intersect, Genome Medicine, 4:50 (2012)
11. Arshad N and Visweswariah SS, The multiple and enigmatic roles of guanylyl cyclase C in intestinal homeostasis, FEBS Lett, 586: 2835-2840 (2012)
12. Arshad N and Visweswariah SS, Guanylyl Cyclase Receptors, Encyclopedia of Signaling Molecules, Sangdun Choi (Ed.), Springer (2012)
13. Basu N, Arshad N and Visweswariah SS, Receptor Guanylyl cyclase C (GC-C): regulation and signal transduction, Mol Cell Biochem, 334:67-80, (2010)

Manuscripts in Preparation

1. Arshad N*^#, Vigneron N*, Bozkus, CC*, Velazquez V, Stroobant V, Naulaerts S, Pereyra RG, Van den Eynde B, Bhardwaj N, Cresswell P^#, Discovery of tumor-associated, immunogenic peptides presented in a patient-derived, mutant calreticulin-driven myeloproliferative neoplasm cell line (*co-first authors, ^#co-corresponding authors)
2. Arshad N, Ayres C, Illing P, Purcell A, Baker B, Cresswell P, Peptide-induced conformational changes, not binding affinity, drives quality control of HLA-A2 by the ER chaperone UDP-glucose:glycoprotein glucosyltransferase (UGGT1)

Funding

• May 2023-April 2025: MPN Research Foundation: 2022 Thrive Initiative - Junior Investigator Award: Principal Investigator
• Feb 2015-Jan 2018: Cancer Research Institute Irvington Postdoctoral Fellowship
• Aug 2011-May 2013: Research Associate Fellowship: awarded by the Indian Institute of Science
• Aug 2006-Jul 2011: PhD Scholarship: awarded by the Indian Institute of Science