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Pooja Jain

Pooja Jain, PhD


Department: Microbiology & Immunology


  • PhD in Microbiology - Central Drug Research Institute, Dr. B.R. Ambdkar Agra University, India (2001)

Dr. Jain is a professor in the Department of Microbiology & Immunology at Drexel University College of Medicine.

Research Overview

Research interests: Dendritic cell (DC) biology and immunotherapeutic potential against human chronic viral infections (HTLV-1, HIV-1, and HIV/HCV co-infection) as well as neuroinflammatory diseases associated with retroviral infection (HAM/TSP, and NeuroAIDS) or inflammation (multiple sclerosis).

Graduate student: Rashida Ginwala, MS

Research staff: Sreesha Sreedhar, MS

Research Interests

Dendritic cells in chronic viral infections and neuroinflammatory diseases


Project #1: Restoring anti-viral immunity during HTLV-associated cancer and neuroinflammatory disease.
Worldwide, 20 million people are infected with HTLV-1. A majority of them remain asymptomatic carriers (ACs), while a few develop ATL or HAM/TSP with no effective treatment or vaccine for either disease state. The exact mechanism(s) of disease pathophysiology remain unresolved with a big question of high proviral load in HAM/TSP patients despite vigorous cellular immune response (primarily directed towards viral transactivator protein Tax).

Our initial studies implicated programmed death (PD)-1 receptor and its ligand, PD-L1 as potential underlying factors for observed immune cells’ dysfunctions leading to viral persistence and disease progression, primarily in HAM/TSP patients. PD-1:PD-L1/PD-L2 are the members of immunoglobulin superfamily (IgSF) co-signaling molecules and have been linked with CD8 T-cell exhaustion during chronic viral infections. Several members of this family (shown in Fig. 1) play a critical role in regulating antigen-specific immune responses.

Thus far, PD-1 and CTLA-4 pathways have been extensively studied; blocking antibodies against these have shown clinical benefit in the setting of both cancer and chronic viral infections. More recent data suggest that blocking multiple inhibitory receptors simultaneously may improve T-cell-based therapies, but further studies are required to clarify the role of each inhibitory receptor-ligand pair, as listed above. Moreover, the clinical applicability of checkpoint blockade remains to be tested with respect to neuroinflammatory diseases, especially those associated with chronic infection, such as HAM/TSP, neuroAIDS, etc. Interestingly, HTLV-1 provides a good model for both and thus we find it significant to investigate the role of key inhibitory receptors/ligands in HTLV-1 infection and test their combined blockade as potential immunotherapeutic strategy to restore immune cell functions in HAM/TSP patients.

Inhibitory receptor:ligand pairs to be tested along with current therapeutics,  both monoclonal Abs and Ig fusion proteins, approved or at various stages of  clinical trials

Figure 1. Inhibitory receptor:ligand pairs to be tested along with current therapeutics, both monoclonal Abs and Ig fusion proteins, approved or at various stages of clinical trials.

Given the latest identity of a functional lymphatic system within the CNS (Louveau et al., Nature, 2015), it has become crucial to elucidate the role of these immune balancing pathways in the context of neuroinflammation. Therefore, this approach is both timely and highly significant with great potential of being successful.While this approach should help in restoring functions of pre-existing antiviral immunity in patients, activating new CTLs to mimic polyclonal CD8 T-cell response found in ACs will be the key for a successful immunotherapeutic intervention of HTLV-associated diseases. Therefore, we propose to systematically identify T-cell epitopes presented by HTLV-1-infected cells that define protective immunity in silent carriers alongside blocking inhibitory pathways in order to fully restore T-cell functions in chronically infected patients. These studies will advance the current understanding of a human chronic viral infection, and bring the field closer to finding a better treatment or cure for HTLV-1-associated diseases.

Project #2:  Follicular DCs within deep cerebral lymph nodes are potential reservoir of HIV-CNS infection.
Chronic HIV-1 infection is frequently accompanied by different neuropathologies known collectively as HIV-associated neurocognitive disorders (HAND). Both HIV patients and SIV-infected macaques exhibit high levels of viral DNA and low-level inflammation within the central nervous system (CNS) during early stages of the infection. Immature DCs in the mucosal tissue, together with CD4+ T lymphocytes and macrophages, are among the first cells to encounter HIV-1. Infectious HIV-1 particles, following capture by DCs, are transported to draining lymph nodes (LNs) where the virus is efficiently transmitted to CD4+ T cells. While the role of monocytes/macrophages in neuroAIDS is well established, studies demonstrating the presence and functions of DCs in the CNS during HIV infection are lacking.

Previous data from others and us have clearly established trafficking of conventional dendritic cells (cDCs) into the CNS in response to neuroinflammation. As per their normal physiology, cDCs once exposed to HIV within CNS should enter into the cerebral or cervical lymph nodes (CxLNs) residing at the brain stem via a rostral migratory stream (RMS) in rodents or glymphatics in humans (Fig. 2). Here, they can infect CD4+ T cells, particularly those in the germinal centers of LNs contributing to viral latency or replication. These germinal centers harbor a specialized type of DCs called follicular DCs (fDCs), which can retain HIV for years even in the presence of neutralizing antibodies.

Thus we sought to determine the role of these fDCs within CxLNs of chronically SIV-infected rhesus macaques. Our data thus far suggest that fDCs in CxLNs not only retain SIV but also infect CD4+ T follicular helper (TFH) cells. Based on these observations, we infer a novel role for fDCs in viral entrapment and creation of persistent CNS reservoir. Our hypothesis is that fDCs within CxLNs could serve a potential CNS reservoir for HIV that is highly stable and protective. We are also interested in investigating novel means to inhibit HIV-fDC interactions as relate to the CNS pathogenesis. These studies will provide clues to design more effective drug therapies to ameliorate HIV CNS reservoir.

Figure 2. Model projecting steps of HIV  retrograde transport via DCs

Figure 2. Model projecting steps of HIV retrograde transport via DCs. Circulating DCs infiltrate into the choroid plexus or perivascular regions at the subventricular zone and RMS. Upon infiltration, DCs may encounter HIV virions or viral proteins that are released by productively infected or dying PVMs (see inset, top panel). DCs carrying HIV will migrate into the RMS toward the olfactory bulb and access the CxLNs (red arrow). Within CxLNs, DCs can infect and prime T cells in the T cell zone, which then migrate toward the B cell follicles (inset, bottom panel). When follicular B cells (dark zone) encounter antigen, undergo rapid proliferation to form a germinal center where fDCs will be exposed to CNS HIV particles. fDCs harboring low-level HIV infection can interact with both T and B cells which, upon getting primed, can feed back into the CNS (red arrow).

Project #3: Host genetic factors and miRNA-linked dendritic cell responses associated with the outcome of treatment response in HIV-1/HCV co-infected individuals.
HIV-1/HCV co-infection is a significant burden on global economy and public health. PEGylated interferon (PEG-IFN) and ribavirin (RBV) remain the essential components of anti-HCV treatment despite recently developed direct acting antiviral drugs. Herein, we investigated the host genetic and immunological correlates (in particular myeloid and plasmacytoid DCs) of successful treatment response in conjunction with mechanisms by which PEG-IFN is able to clear the virus in a cohort of HIV-1/HCV co-infected individuals undergoing IFN/RBV treatment.

First we demonstrate that functional state of DCs before/during therapy influences the treatment outcome. Further, upon genotyping IFNL3 polymorphisms rs12979860, rs4803217 and ss469415590, we found rs12979860 to be a better predictor of treatment outcome. Next, we compared the expression of 46 ISGs (IFN-stimulated genes) prior to and after the treatment and observed that pre-treatment levels of several ISGs were higher in SVRs compared to NRs. In continuation with molecular mechanisms, we identified miRNAs whose expression can be regulated by IFN in periphery. Specifically, we examined miRNA expression patterns in mDCs and pDCs in response to IFN-α and observed miR-221 downregulation via IFN induced STAT3 inhibition in both. Using in silico approaches followed by experimental validation, CDKN1C, CD54 and SOCS1 were identified as miR-221 targets. Moreover, miR-221 overexpression in mDCs enhanced their secretion of proinflammatory cytokines IL-6 and TNF-α but reduced the secretion of anti-inflammatory cytokine IL-10. These observations were extended and correlated with those obtained with patients’ PBMCs as well as total liver cells and kupffer cells (antigen presenting cells in liver) from HCV infected individuals as well as individuals with alcoholic cirrhosis.

In summary, these studies demonstrated the role of IFN-α/miR-221 axis in HCV pathogenesis and response to IFN-based treatments and will be extended to patients with DAA treatment in conjunction with an in depth understanding of miR-221-mediated protective effects (Fig. 3).

Model figure depicting our findings regarding IFN-α-induced miR-221 downregulation and  its relevance in mDC functionalit

Figure 3. Model figure depicting our findings regarding IFN-α-induced miR-221 downregulation and its relevance in mDC functionality. STAT3 drives miR-221 expression and is therefore required for maintaining basal miR-221 levels. Binding of IFN-α to its receptor, IFNAR, results in STAT3 inhibition, which leads to miR-221 downregulation. miR-221 targets BCL2L11 (pro-apoptotic protein), CDKN1C (pro-apoptotic protein), and SOCS1 (negative regulator of JAK/STAT signaling), thus regulating apoptosis and IL-6/TNF-α production in mDCs. miR-221 indirectly controls the expression of various other pro-apoptotic proteins, CAV1, MX1, SHB and TNFSF10 as well.

Project #4: The highly enriched c-type lectins on dendritic cells provide potential therapeutic strategy to ameliorate neuroinflammatory diseases.
Thus far, our seminal contribution lies in bridging two important fields of neuroscience and immunology while strengthening DCs’ presence and functions within CNS. This is by means of our original work providing direct evidence for the ability of circulating DCs to migrate across the inflamed BBB during an active ongoing neuroinflammatory condition (EAE) by live intravital videomicroscopy. This was further substantiated by a variety of non-invasive imaging tools such as NIRF, SPECT-CT, and PET-based in vivo imaging in collaboration with scientists at Johns Hopkins University (Fig. 4).

NIRF and SPECT-CT imaging of  leukocyte presence in EAE CNS lesions

Figure 4. NIRF and SPECT-CT imaging of leukocyte presence in EAE CNS lesions. Mice were injected with either (1) anti-CD11c Ab-IRDye800, (2) anti-CD11c Ab-IRDye800+anti-CD3 Ab-IRDye680 (T cells) or (3) anti-CD11c Ab-IRDye800+anti-MBP Ab-IRDye680 on EAE day 14 and imaged 48 h post-antibody using ex vivo NIRF imaging to validate the ability to track cells to EAE lesions. A) Anti-CD11c antibody only (green) signal from DCs in a mouse with severe EAE. B) Mouse with moderate EAE score shows signal from both CD11c+ DCs (green) and CD3+ T cells (red). C) Mouse exhibiting mild EAE shows a high degree of co-localization between CD11c+ DCs and MBP signal. D) 3D rendered view of whole-body α-CD68 Ab distribution at 48h post-tracer showing mostly thyroid, stomach, spleen, and gut. E) An enhanced view of tracer uptake in thoracic spine. Red arrows denote spine uptake.

The mechanism by which DCs are recruited across the BBB during neuroinflammation has been the least explored amongst all leukocytes. For cells of myeloid origin, lectins and integrins are two major groups of receptors involved in trafficking cascade. While integrins function at the level of adhesion, the importance of lectins (highly enriched on DCs) remains unknown. Here we identified functions of one C-type lectin receptor (CLR), CLEC12A in facilitating DCs binding and transmigration across the BBB in response to CCL2 chemotaxis. At the molecular level, this process involved SHP1/2-mediated CLR signaling in coordinating actin polymerization and integrin synthesis on WIP+ podosomes.

Further, specific antibody blocking of CLEC12A significantly ameliorated the course of experimental autoimmune encephalomyelitis in mice through an inhibition of myeloid cell infiltration into the brain and spinal cord. These studies reveal the utility of a DC-specific mechanism in designing new therapeutics for MS. We now wish to proceed with pre-clinical efficacy and toxicity testing followed by phase I clinical trial for CLEC12A blockade as potential new therapy for the management of relapsing-remitting MS.

Project #5: Role of Myocyte enhancer factors (mainly MEF-2) in T-cell transformation associated with HTLV-1 infection mediated aggressive form of non-Hodgkin's lymphoma.

Lymphomas are the most common type of blood cancers. Non-Hodgkin’s lymphoma (NHL), a form of lymphoma characterized by the abnormal growth of B and T cells of the lymphatic system, is caused by a combination of factors that include genetic changes and infections by bacteria and viruses. ATLL (adult T-cell leukemia/lymphoma) is one such highly aggressive non-Hodgkin's lymphoma caused by HTLV-1 with no effective treatment, cure or vaccine. Antibodies to HTLV-1 are found in the serum of ATLL patients while the provirus is clonally integrated mainly in the CD4+CD25+ T cells. Although the exact mechanism of HTLV-1 mediated carcinogenesis is unknown, the viral transactivator protein Tax has been shown to play an important role in the initiation of ATLL. In this study we aim to describe the involvement of a novel cellular factor, MEF-2 (myocyte enhancer factor 2) in Tax-mediated viral promoter (LTR) activation in the context of HTLV-1 infection and the immortalization of T cells leading to ATLL.

We hypothesized that MEF-2 plays crucial roles in ATLL development by facilitating Tax activity and viral replication. Using a large cohort of ATLL patient samples from HTLV-1 endemic region and/or samples obtained from the Department of Veterans Affairs in Philadelphia, HTLV-infected primary CD4+ T cells and the virus-producing T cell line (MT-2), an experimental approach has been designed to test our hypothesis and to tease out the mechanisms of MEF-2 mediated viral pathogenesis in three specific aims as follows: 1) Describe the regulation and effect of MEF-2 on Tax expression and HTLV-1 replication, 2) Define the role of MEF-2 in T-cell proliferation that leads to malignant transformation of the T cells characteristic of ATLL and 3) Evaluate novel small molecule inhibitors of MEF-2 in a mouse model of ATLL.

Model explaining MEF-2 activity on  Tax-mediated transactivation of HTLV-1 LTR

Figure 5. Model explaining MEF-2 activity on Tax-mediated transactivation of HTLV-1 LTR. Type II HDACs (HDAC4/5/7/9) binds to MEF-2A and repress its transcriptional activity. Upon HTLV-1 infection, Tax activates p38 and ERK5, which phosphorylate MEF-2 leading to its dissociation from MEF-2A:HDAC repressive complex. On the other hand, Tax also binds to Smad2/3/4 to prevent their constitutive binding to transcription co-activators CBP/p300. This leads to increased availability of CBP/p300 to bind Tax/pCREB complex bound to the 5’ LTR region of the provirus. Along with Tax/pCREB/CBP/p300 complex, recruitment of MEF-2A to 5’ LTR promotes viral gene expression. Tax also activates Calcineurin (a calcium-dependent serine-threonine phosphatase), which dephosphorylates NFAT. Upon dephosphorylation, NFAT translocates to nucleus and is recruited to HTLV-1 5’ LTR along with the Tax/pCREB/CBP/p300 complex. NFAT is also recruited to MEF-2A gene promoter where it binds to MEF-2A and turns on the transcription resulting in upregulation of MEF-2A expression. HDAC, Histone deacetylase; MEF-2A, Myocyte-specific enhancer factor 2A; ERK5, Extracellular-signal-regulated kinase 5; Smad, Sma- and Mad-Related Protein; CREB, cAMP response element-binding protein; CBP, CREB-binding protein; NFAT, Nuclear factor of activated T cells.

In the Media


Initial contact of immature dendritic cells(DCs) and LPS-matured DCs by rolling or capturing with the inflamed spinal cord microvasculature in SJL mice with EAE.

Adhesion of immature DCs and LPS-matured DCs to the inflamed spinal cord white matter microvasculature in SJL mice with EAE.


Publications – Last Five Years
View all of Dr. Jain's publications in PubMed

"Inhibition of DC-SIGN interaction with HIV by the complementary actions of dendritic cell receptor antagonists and Env-targeting virus inactivators"
Pustylnikov, S., Dave, R. S., Khan, Z. K., Porkolab, V., Rashad, A. A., Hutchinson, M., Fieschi F., Chaiken I., and P. Jain
AIDS Research and Human Retroviruses, in press, 2015

"IFN-α-induced downregulation of miR-221 in dendritic cells: implications for HCV pathogenesis and treatment"
Sehgal, M., Talal, A., Comber, J., Philip, R., Khan, Z. K., and P. Jain
Journal of Interferon and Cytokine Research, Epub ahead of print, 2015

"Apigenin, a natural flavonoid, attenuates EAE severity through modulation of dendritic and other immune cell functions"
Ginwala, R., McTish, E., Raman, C., Singh, N., Nagarkatti, P., Nagarkatti, M., Sagar, D., Jain P. Jain*, and Z. K. Khan*
Journal of Neuroimmune Pharmacology, Epub ahead of print, 2015
(*Corresponding authors)

"Myocyte enhancer factor-2 plays essential roles in T-cell associated with HTLV-1 infection by stabilizing complex between Tax and CREB"
Jain, P.*, Lavorgna, A., Gao, L., Sehgal, M., Sagar, D., Ginwala, R., Harhaj, E., and Z. K. Khan*
Retrovirology, 12: 23-38, 2015
(*Corresponding authors)

"Inhibition of Endoplasmic Reticulum-Resident Glucosidases Impairs Severe Acute Respiratory Syndrome Coronavirus and Human Coronavirus NL63 Spike Protein-Mediated Entry by Altering the Glycan Processing of Angiotensin I-Converting Enzyme 2"
Zhao, X., Guo, F., Comunale, M., Mehta, A., Sehgal, M., Jain, P., Cuconati, A., Lin, H., Block, T. M., Change, J., and Ju-Tao Guo
Antimicrobial Agents and Chemotherapy, 59: 206-216, 2015

"In vivo immunogenicity of Tax 11-19 epitope in HLA-A2/DTR transgenic mice: implication for dendritic cell-based anti-HTLV-1 vaccine"
Sagar, S., Masih, S., Schell, T., Jacobson, S., Wigdahl, B., Jain, P.*, and Z. K. Khan*
Vaccine, 32: 3274-3284, 2014
(*Corresponding authors)

"Effect of morphine and SIV on dendritic cell trafficking into the central nervous system of rhesus macaques"
Hollenbach, R., Sagar, D., Hegde R., Callen, S., Yao, H., Khan, Z. K., Buch, S., and P. Jain
Journal of NeuroVirology, 20: 175-183, 2014

"Human T-lymphotropic virus type 1 infected cells Secrete exosomes that contain Tax Protein"
Jaworski, E., Narayanan, A., Duyne, R., Iordanskiy, S., Saifuddin, M., Das, R., Afonso, P., Sampey, G., Chung, M., Popratiloff, A., Shrestha, B., Sehgal, M., Jain, P., Vertes, A., Mahieux, R., and Kashanchi, F.
Journal of Biological Chemistry, 289: 22284-22305, 2014

"Targeting the C-type lectins-mediated host-pathogen interactions with dextran"
Pustylnikov, S., Sagar, D., Jain, P., and Z. K. Khan
Journal of Pharmacy and Pharmaceutical Sciences, 17: 371-392, 2014

"Host genetic factors and dendritic cell responses associated with the outcome of Interferon/Ribavirin treatment in HIV-1/HCV co-infected individuals"
Sehgal, M., Talal, A., Comber, J., Philip, R., Capocasale, R., Khan, Z. K., and P. Jain
Journal of Clinical and Cellular Immunology, 5: 1000271-1000283, 2014

"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, S., Sehgal, M., Khan, Z. K., Betts, M., and P. Jain
AIDS Research and Human Retroviruses, 29: 1273-1285, 2013

"Drugs of abuse, epigenesis and retroviral promoter: an overview"
Shirazi, J., Shah, S., Sagar, D., Nonnemacher, M., Wigdahl, B., Khan, Z. K., and P. Jain
Journal of Neuroimmune Pharmacology, 8:1181-1196, 2013

Book chapter: "Transgenic Animals and Their Applications"
Masih, S., Jain, P., El Baz R., and Z. K. Khan
Animal Biotechnology: Models in Discovery and Translation, Chapter 22, pp. 407-423, Elsevier Science Publications, 2013

"Lack of recall response to TAX in ATL and HAM/TSP patients but not asymptomatic carriers of human T cell leukemia virus type 1"
Manuel, S., Sehgal, M., Connolly, J., Makedonas, G., Gardner, J., Khan, Z. K., Betts, M., and P. Jain
Journal of Clinical Immunology, 33:1223-39, 2013

"Effect of morphine and SIV on dendritic cell trafficking into the central nervous system of rhesus macaques"
Hollenbach, R., Sagar, D., Hegde R., Callen, S., Yao, H., Khan, Z. K., Buch, S., and P. Jain
Journal of NeuroVirology, 182: 1-9, 2013

"Dendritic cells 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 C, Khan ZK, Pomper M, and P Jain
Journal of Neuroinflammation, 9:245, Oct 26, 2012

"HTLV-1 Tax mediated downregulation 1 of miRNAs associated with chromatin remodeling factors in T cells with stably integrated viral promoter"
Rahman S, Quanna K, Khan Z.K, Pandya D, Wigdahl B. and Jain P
PLoS One, 7(4):e34490, 2012

"Unique and differential protein signatures for HIV-1 and HCV mono-infection versus co-infection"
Boukli N.V, Shetty J, Reis L, Cubano M, Ricaurte, P, Shah Z, Nickens A, Talal R, Philip and Jain P
Clinical Proteomics, 9:11, 2012

Mechanisms of dendritic cell trafficking across the blood-brain barrier"
Sagar, D., Foss, C., Baz, R., Martin, G., Khan, Z. K., and P. Jain
Journal of Neuroimmune Pharmacology, 7:74-94, 2012

"Co-transcriptional chromatin remodeling by small RNA species: A HTLV-1 perspective"
Aliya N, Rahman S,Khan Z.K, and Jain P
Leukemia Research and Treatment, 2012: 1-15, 2012

Contact Information

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