Postdoctoral fellowships:

• Forschungs Institut fur Experementelle Biologie Und Medizine, Borstel, Germany
• Postdoctoral fellowship: Institute Pasteur, Paris, France

Visiting scientist:

• Uniformed Services, Bethesda, Maryland
• CNRS France
• INSA-CNRS (Indo-French) Scientist exchange program

Sabbatical deputation (CSIR) in TTHSC, TX

Senior Scientist and Deputy Director, Central Drug Research Institute (CDRI), India

Transgenic and humanized mouse models of neuroinflammatory diseases caused by retroviral (HTLV-1) infection and inflammation (EAE): The first line of investigation in the laboratory focuses on defining the mechanism of virus-induced neuro-inflammation and demyelination in the central and peripheral nervous system in order to identify potential diagnostic markers and targets for therapeutic intervention.

The model pathogen under study is human T cell leukemia virus type 1 (HTLV-1), which causes both immune and CNS disease. HTLV-1 is a human retrovirus that infects more than 20 million people worldwide, predominantly in tropical areas. HTLV-1 is the first human retrovirus discovered, and many aspects of its immunological and molecular pathogenesis remain unresolved. HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive debilitating neurological disorder. In many ways, it resembles multiple sclerosis (MS), an autoimmune disease of the brain. The HTLV-1 transcriptional transactivator protein Tax is the oncogenic protein that performs a variety of functions both intracellularly and extracellularly. The progression of HAM/TSP is suggested to be due, in part, to the ability of Tax to work as an extracellular effector molecule. Furthermore, a majority of the immune responses (humoral and cell-mediated) in HAM/TSP patients is directed against Tax, indicating that Tax is available for immune recognition. However, the mechanism of Tax cross-presentation and its direct role in neuro-degeneration remains uncharacterized.

We are addressing these issues by using a novel transgenic mouse (HHD II/DTR-Tg) model with a chimeric HTLV-1 infection and neurological disease progression. The transgenic strain will allow us to perform the HLA-A2.1 restricted Tax11-19-specific CTL studies in the absence and presence of dendritic cells (DCs). Efforts are being made to utilize this model as well as humanized (transplanted BLT) mouse model as tool to study the role of Tax and other viral factors in addition to the components of the host immune response that may play important roles in the neuropathogenesis associated with HAM/TSP. The knowledge gained will have direct links to clinical and therapeutic interventions.

Human immune cell engraftment in peripheral blood and spleen. Tissue sections of spleen from humanized Rag1 mice were stained for the presence of human leukocytes lightly counterstained with hematoxylin to enable visualization of nuclei. CD11b+ monocytes/dendritic cells (A), CD3+ T cells (B), and CD20+ B cells (C) were detected in the spleen of Rag1 mice.

Target-based high-throughput screening and preclinical evaluation of potential antiviral molecules: The second line of investigation within the laboratory is focused on discovery of novel targets in high-throughput screening and preclinical studies on novel antiviral molecules for human therapy. Currently, our research team is working on flavonoids, a group of low molecular weight phytopigments found ubiquitously in almost all dietary plants, fruits and vegetables consumed routinely in a considerable amount. Apigenin, a naturally occurring flavonoid has chemo-protective effects in leukemia, ovarian, prostate, colon and lung cancers. Apigenin is believed to regulate inflammation and has been used for centuries as an alternative therapy to treat asthma, Parkinson's disease, neuralgia, shingles, etc. Few studies attribute apigenin’s anti-inflammatory effects to the inhibition of cytokines like IL-1β and TNF-α and suppression of the activity of nitric oxide synthase (NOS) and COX-2 enzyme.

Apigenin treatment reduces DCs and other immune cell migration into the CNS. Spinal cord tissue from mice was subjected to LFB and H&E staining depicting areas of myelination (blue) and cellular infiltration (reddish brown).

There is, however, a considerable dearth of information regarding apigenin’s effects on immune cells that coordinate inflammatory response and maintain balance between protective and destructive immunity. Of these, DCs lay at the crux of innate and adaptive immunity with myeloid DCs being one of the most potent antigen presenting cells (APCs) and plasmacytoid DCs the major producers of type I interferons. Together, these cells maintain the critical balance between an immunogenic and a tolerogenic immune response. Any dysregulation in this balance leads to the generation of an autoimmune response that is especially exacerbated in immune specialized locations such as CNS.

In recent years, our collaborative team has established DCs’ trafficking into the CNS during neuro-inflammatory conditions such as experimental autoimmune encephalomyelitis (EAE), in a well-established mouse model for multiple sclerosis (MS). In fact, there is an unmet medical need for exploration of potent natural molecules that could prevent leukocyte trafficking into the CNS and maintain homeostasis in the brain while restoring protective immunity in the periphery.

Owing to the popular benefits of apigenin both in periphery and CNS, a detailed knowledge of its anti-inflammatory mechanism(s) could bring the flavonoid group of molecules to the forefront of natural product-based drug design and therapy. Therefore, these broad yet focused studies are designed to define mechanisms of apigenin action and also to identify natural molecules that facilitate key immune cells such as DCs to restore their function, maintain immune balance and prevent CNS infiltration. We hypothesize that apigenin helps regulate the production of cytokines and co-stimulatory molecules, thus preventing the neurodegenerative effects caused by the entry of peripheral components into the CNS. Additionally, owing to its suppressive effects on adhesion molecules, apigenin may also serve as a natural chemopreventive measure against neuroinflammation.

Model representing plausible mechanism of apigenin’s protective effects on MS/EAE.
1&2) DCs and other leukocytes are chemoattracted to the site of neuroinflammation due to increased expression of several chemokines, lectins and integrins.
3, 4 & 5) Apigenin may serve to inhibit the expression of pro-inflammatory cytokines, chemokines and adhesion molecules thus regulating DC function through regulation of RelB mediated NF-κB, and MAPK pathways.

Selected Publications
(Full bibliography includes over 100 publications, 6 patents, 1 edited book and 8 book chapters)

“FDC-TFH Interactions within CNS Draining Cervical Lymph Nodes of SIV-Infected Rhesus Macaques”
Dave R, Sharma R, Muir R, Haddad E, Gumber S, Villinger F, Nehra A, Khan Z K, Wigdahl B, Ansari A, Byrareddy S, and P Jain
Journal of Neuroimmune Pharmacology, 13(2): 204-218, Jun 2018
PMCID: PMC5757373

“In vivo and in vitro immunogenicity of novel MHC class I presented epitopes to confer protective immunity against chronic HTLV-1 infection”
Mulherkar R, Karabudak A, Ginwala R, Huang X, Rowan A, Philip R, Murphy E, Clements D, Ndhlovu L, Khan Z K, and P Jain
Vaccine, 36(33):5046-57. 2018.07.0022018 (Epub ahead of print) August 9, 2018

“Cell cycle regulator Cyclin D1 is essential for dendritic cell differentiation”
Scharer C, Ginwala R, Kawasawa Y, Madugula K, Chigbu D, Khan Z K, Pestell R, Boss J, and P Jain
European Journal of Immunology, in press 2018

“HTLV-1 infection and neuropathogenesis in the context of Rag1-/-γc-/- (RAG1-hu) and BLT mice”
Ginwala R, Caruso B, Khan Z K, Pattekar A, Chew G, Corley M, Loonawat R, Jacobson S, Sreedhar S, Ndhlovu L, and P Jain
Journal of Neuroimmune Pharmacology, 12:504-520, 2017
PMCID: PMC5529230

“Antibody blockade of CLEC12A delays the course of EAE and attenuates disease severity by impairing myeloid cell CNS infiltration and restoring positive immunity”
Sagar D, Singh N, Ginwala R, Huang X, Philip R, Nagarkatti M, Nagarkatti P, Neumann K, Ruland J, Andrews A, Remirez S, Khan Z K, and P Jain
Scientific Reports, 7(1): 2707-23, 2017
PMCID: PMC5457463

“Inhibition of DC-SIGN-mediated HIV-1 infection by complementary actions of dendritic cell receptor antagonists and env-targeting virus inactivators”
Pustylnikov S, Dave RS, Khan ZK, Porkolab V, Rashad AA, Hutchinson M, Fieschi F, Chaiken I, and P Jain
AIDS Research and Human Retroviruses, 31. Doi: 10.1089/aid. 0184, 2015

“IFN-α-induced downregulation of miR-221 in dendritic cells: implications for HCV pathogenesis and treatment"
Sehgal M, Zeremski M, Talal AH, Ginwala R, Elrod E, Grakoui A, Li QG, Philip R, Khan ZK and P Jain
Journal of Interferon and Cytokine Research, 2015
PMCID: PMC456085

“Apigenin, a natural flavonoid, attenuates EAE severity through the modulation of dendritic cell and other immune cell functions"
Ginwala R, McTish E, Raman C, Singh N, Nagarkatti M, Sagar D, Jain P and ZK Khan
Journal of Neuroimmune Pharmacology, 2015  
PMID: 26040501

“Myocyte enhancer factor (MEF)-2 plays essential roles in T-cell transformation associated with HTLV-1 infection by stabilizing complex between Tax and CREB”
Jain P*, Lavorgna A, Sehgal M, Gao L, Ginwala R, Sagar D, Harhaj EW and ZK Khan* (*Corresponding authors)
Retrovirology, Feb 27; 12:23.doi: 10.1186/s12977-015-0140-1, 2015
PMCID: PMC4374383

“Host genetic factors and dendritic cell responses associated with the outcome of interferon/ribavirin treatment in HIV-1/HCV co-infected individuals"
Sehgal M, Zeremski M, Talal AH, Khan ZK, Capocasale R, Philip R and P Jain
Journal of Clinical and Cellular Immunology, Oct 31; 5. pii: 1000271, 2014
PMCID: PMC4332701

“In vivo immunogenicity of tax(11-19) epitope in HLA-A2/DTR transgenic mice: implication for dendritic cell-based anti-HTLV-1 vaccine"
Sagar D, Masih S, Schell T, Jacobson S, Comber JD, Philip R, Wigdahl B, Jain P and Khan ZK
Vaccine, 32(26): 3274-84, 2014
PMCID: PMC4044917

“Effect of morphine and SIV on dendritic cell trafficking into the central nervous system of rhesus macaque"
Hollenbach R, Sagar D, Khan ZK, Callen S, Yao H, Shirazi J, Buch S and P Jain
Journal of Neurovirology, 20(2): 175-83, 2014
PMCID: PMC3925206

“Targeting the C-type lectins-mediated host-pathogen interactions with dextran"
Pustylnikov S, Sagar D, Jain P, and ZK Khan
Journal of Pharmacy and Pharmaceutical Sciences, 17(3): 371-92, 2014
PubMed [journal] PMID: 25224349

“Epigenetics, drugs of abuse, and the retroviral promoter"
Shirazi J, Shah S, Sagar D, Nonnemacher MR, Wigdahl B, Khan ZK and P Jain
Journal of Neuroimmune Pharmacology, 8(5): 1181-96, 2013
PMCID: PMC3878082

“Lack of recall response to Tax in ATL and HAM/TSP patients but not in asymptomatic carriers of humanT-cell leukemia virus type 1"
Manuel SL, Sehgal M,Connolly J, Makedonas G, Khan ZK, Gardner J, Betts MR, Jain P
Journal of Clinical Immunology, 33(7): 1223-39, 2013
PMCID: PMC3784618

“An altered maturation and adhesion phenotype of dendritic cells in diseased individuals compared to asymptomatic carriers of human T cell leukemia virus type 1"
Manuel SL, Sehgal M, Khan ZK, Goedert JJ, Betts MR and P Jain
AIDS Research and Human Retroviruses, 29(9): 1273-85, 2013
PMCID: PMC3749709

“Dendritic Cells in HIV-1 and HCV Infection: Can They Help Win the Battle?”
Sehgal M, Khan ZK, Talal AH and P Jain
Virology Research and Treatment, 4:1-25, 2013
PMC4222345

“Transgenic Animals and Their Applications”
“Masih SJ, P. Jain and ZK Khan
In: Animal Biotechnology: Models in Discovery and Translation, Edit Book: Elsevier Science Publications, USA, pp 407-423, 2013  

“Dendritic cell CNS recruitment correlates with disease severity in EAE via CCL2 chemotaxis at the blood-brain barrier through paracellular transmigration and ERK activation"
Sagar D, Lamontagne A, Foss CA, Khan ZK, Pomper M and P Jain
Journal of Neuroinflammation, 9: 245,2012  
PMCID: PMC3533869

“Mechanisms of dendritic cell trafficking across the blood-brain barrier"
Sagar D, Foss C, El Baz R, Pomper MG, Khan ZK and P Jain
Journal of Neuroimmune Pharmacology, 7(1): 74-94, 2012
PMCID: PMC3276728

“Cotranscriptional Chromatin Remodeling by Small RNA Species: An HTLV-1 Perspective”
Aliya N, Rahman S, Khan ZK and P Jain
Leukemia Research and Treatment, 2012:984754, doi: 10.1155/2012/984754, 2012
PMCID: PMC3504244

“HTLV-1 Tax mediated downregulation of miRNAs associated with chromatin remodeling factors in T cells with stably integrated viral promoter”
Rahman S, Quann K, Pandya D, Singh S, Khan ZK and P Jain
PloS One, 7(4): e 34490, doi: 10.1371/journal.pone.0034490, 2012
PMCID: PMC3319589

“A novel high-throughput screening assay to identify inhibitors of HIV-1 gp120 protein interaction with DC-SIGN"
Tran TH, El Baz R, Cuconati A, Arthos J, Jain P and ZK Khan
Journal of Antivirals and Antiretrovirals, 3: 49-54, 2011
RPMCID: PMC3217269

“The tug-of-war between dendritic cells and human chronic viruses"
Rahman S, Khan ZK and P Jain
International Reviews of Immunology, 30(5-6): 341-65, 2011
PMID: 22053973

“Murine FLT3 ligand-derived dendritic cell-mediated early immune responses are critical to controlling cell-free human T cell leukemia virus type 1 infection"
Rahman S, Khan ZK, Wigdahl B, Jennings SR, Tangy F and P Jain
Journal of Immunology, 186(1): 390-402, 2011
PMCID: PMC3224812

“Structural and functional studies of CCAAT/enhancer binding sites within the human immunodeficiency virus type 1 subtype C LTR"
Liu Y, Nonnemacher MR, Stauff DL, Li L, Banerjee A, Irish B, Kilareski E, Rajagopalan
N, Suchitra JB, Khan ZK, Ranga U and B. Wigdahl
Biomedicine and Pharmacotherapy, 64(10): 672-80, 2010
PMCID: PMC2998390

“Depletion of dendritic cells enhances susceptibility to cell-free infection of human T cell Leukemia virus type 1 in CD11c-diphtheria toxin receptor transgenic mice"
Rahman S, Manuel SL, Khan ZK, Wigdahl B, Acheampong E, Tangy F and P Jain  
Journal of Immunology, 184(10): 5553-61, 2010
PMCID: PMC2946091

“DC-SIGN mediates cell-free infection and transmission of human T-cell lymphotropic virus type 1 by dendritic cells"
Jain P, Manuel SL, Khan ZK, Ahuja J, Quann K and B Wigdahl
Journal of Virology, 83(21): 10908-21, 2009
PMCID: PMC2772783

“Presentation of human T cell leukemia virus type 1 (HTLV-1) Tax protein by dendritic cells: the underlying mechanism of HTLV-1-associated neuroinflammatory disease"
Manuel SL, Schell TD, Acheampong E, Rahman S, Khan ZK and P Jain
Journal of Leukocyte Biology, 86(5): 1205-16, 2009
PMCID: PMC2774881

“Molecular mechanisms of neurodegenerative diseases induced by human retroviruses: a review"
Irish BP, Khan ZK, Jain P, Nonnemacher MR, Pirrone V, Rahman S, Rajagopalan N, Suchitra JB, Mostoller K, Wigdahl B
American Journal of Infectious Diseases, 5(3): 231-258, 2009
PMCID: PMC2845477

“Role of resident CNS cell populations in HTLV-1-associated neuroinflammatory disease"
Lepoutre V, Jain P, Quann K, Wigdahl B, Khan ZK
Frontiers in Bioscience, 14:1152-68, 2009
PMCID: PMC2739244

“Mortality among HIV-infected patients in resource limited settings: a case controlled analysis of inpatients at a community care center”.
Rajagopalan N, Suchitra JB, Shet A, Khan ZK, Martin-Garcia J, Nonnemacher MR, Jacobson JM and B Wigdahl
American Journal of Infectious Diseases, 5(3): 219-224, 2009  
PMCID: PMC2831752

“Identification of human T cell leukemia virus type 1 tax amino acid signals and cellular factors involved in secretion of the viral oncoprotein"
Jain P, Mostoller K, Flaig KE, Ahuja J, Lepoutre V, Alefantis T, Khan ZK, and B Wigdahl
The Journal of Biological Chemistry, 282(47): 34581-93, 2007
PMID: 17897946