Khanna Lab - Microbiology

Kamal M. Khanna, PhD
Associate Professor, Department of Microbiology
Alexandria Center for Life Science – West Tower
430 East 29th Street, AW 3rd Floor
Lab Rm: 306A and B, Office Rm: 307
New York, NY 10016
Office: (646) 501-6762
Lab: (646) 501-6798
Email: Kamal.Khanna@nyulangone.org

 

 

KEY INTERESTS:

Immunology, Chronic Inflammation, Macrophage Activation, Host-pathogen interaction, Pathogenesis, RNA Biology, Cancer, Vaccine, Neuro-immunology, T-cell trafficking, Imaging, multi-photon microscopy
 

BIOGRAPHICAL DETAILS:

Graduate Education:

University of Pittsburgh School of Medicine, Ph.D. Immunology (May 2004)

Postdoctoral Training:

University of Connecticut Health – Department of Immunology (2004 – 2009)
Advisor: Leo Lefrancois, Ph.D.
Damon Runyon Postdoctoral Fellow

Academic Appointments:

University of Connecticut Health – Department of Immunology
Assistant Professor (2009 – 2017)
Associate Professor (2017 – 2017)
Adjunct Professor (2017 – Present)

NYU School of Medicine – Department of Microbiology
Associate Professor (2017 – Present)

Honors and Awards:

American Association of Immunologist Early Career Faculty Award (2014)
American Association of Immunologist Early Career Faculty Award (2012)
Chosen as an American Association of Immunologist Public Policy Fellow (2011)
American Association of Immunologist Junior Faculty Award (2010)
NIH Pathway to Independence Award (K99/R00) (2009)
National Institute of Allergy and Infectious Diseases Keystone Symposia scholarship award (2007)
Damon Runyon Cancer Research Foundation Fellowship award (2004 – 2008)

RESEARCH INTERESTS:

The Khanna Lab aims to dissect the complex dynamics of host-pathogen interactions during both the innate and adaptive immune response following infection. We focus on investigating the underlying cellular and molecular mechanisms responsible for the onset, maintenance, and resolution of the immune response to pathogens in vivo. The mechanisms controlling the temporal events leading to robust activation of the innate immune system and the subsequent pathogen-specific cell mediated immunity are poorly understood. Emerging data indicate that mounting a protective immune response is dependent on the orchestrated movement of cells within lymphoid and non-lymphoid organs. Organ structure is one of the underlying regulators of immune responses by promoting interactions between cells, as well as the extracellular matrix. Understanding the geography of how pathogens interface with the innate and adaptive immune cells within lymphoid and non-lymphoid organs is critical. 

In addition to investigating the cellular mechanisms utilized by the immune system to eradicate pathogens and resolve pathogen induced inflammation, we also investigate the underlying molecular mechanisms that are important for the hosts ability to respond effectively to infections.

In our lab we use several microscopy techniques (multi-color and 2-photon dynamic intravital/explant microscopy), in combination with more traditional molecular, cellular, and histological approaches to characterize host-pathogen interactions at the molecular, single cell- and whole animal level.
 

LAB PROJECTS:

One of the major lines of research that we are actively is to understand the mechanisms utilized by tissue resident macrophages for pathogen clearance and for regulating inflammation in mucosal tissues. The importance of tissue resident macrophages for pathogen clearance and homeostasis is beginning to emerge. However, our understanding of the multifaceted roles these macrophages play in mucosal tissues such as the lung remains incomplete. The lung is a very complex organ with specialized structures to allow for adequate gas exchange.  The pulmonary microenvironment is unique and has a direct and important influence on the resident immune cells, especially macrophage populations.  Currently, it is well established that lung harbors two distinct populations of macrophages known as alveolar macrophages (AMs) and interstitial macrophages (IMs). We have now discovered new subset of macrophages in the lung, One of the most important function of pulmonary macrophages is to regulate inflammatory pathways during infection and allow for the resolution inflammation after the pathogen is cleared.  The precise mechanisms that macrophage populations utilize to accomplish these critical functions in vivo are not well understood. For example, Macrophages play a critical role in regulating pathogen-induced inflammation during a respiratory infection such as with influenza.  Influenza infection causes worldwide yearly epidemics resulting in thousands of deaths and hospitalizations.  Clinical complications are caused by tissue damage due to excessive viral-induced immune responses. Thus, there is a critical need to understand the cellular and molecular mechanisms that cause infection-induced inflammation and pathology in vivo in order to develop new therapeutic strategies to alleviate damaging inflammation during infection.  Overall, our study relates structure to function at a fundamental level and provides essential insights into a novel subset of lung resident macrophages that along with alveolar macrophages are crucial in mediating protection and maintaining immune homeostasis during infection.

We are also investigating the role tissue resident macrophages play in regulated immune responses to tumors in mucosal tissues such as the lung and skin. The use of cancer vaccines to induce anti-tumor immunity has largely failed in clinical settings. However, we recently reported the development of a cytomegalovirus (CMV) based cancer vaccine (MCMV-gp100KGP) that elicited a robust anti-tumor CD8 T cell response and tumor rejection. We showed that certain unique properties of CMV made it an excellent vaccine candidate against melanoma and potentially other cancers. In our studies funded by the grant, we used recombinant murine CMV (MCMV) strains as prophylactic and therapeutic vaccines in an aggressive B16 lung metastatic melanoma model. Immunization with MCMV-expressing ovalbumin (OVA) induced a potent OVA-specific CD8 T-cell response and was effective in protecting mice from OVA expressing B16 melanoma in an antigen-dependent manner. We engineered MCMV to express a modified native B16 melanoma antigen gp100 (MCMV-gp100KGP). Immunization with MCMV-gp100KGP was highly effective in overcoming immune tolerance to self-antigen and induced a strong, long-lasting gp100-specific CD8 T-cell response even in the presence of preexisting anti-CMV immunity. Furthermore, both prophylactic and therapeutic vaccinations of mice with MCMV-gp100KGP effectively protected mice from highly aggressive lung B16-F10 melanoma, and gp100-specific CD8 T cells mediated the protection. Our studies showed that MCMV is a superior vaccine vector compared with a commonly used vesicular stomatitis virus vector. Collectively, our studies demonstrated that CMV is a promising vaccine vector to prevent and treat tumors. Although, therapeutic immunization with our CMV based vaccine resulted in significant tumor regression and increased life span; the animals eventually succumbed to the aggressive form of melanoma.  Interestingly, none of the check-point blockers (anti-PD-1 or anti-CTLA4) further improved vaccine efficacy.  During the course of these studies, we have made several new and interesting observations regarding melanoma. When we imaged the tumors, we observed the influx of specific macrophage populations within the B16 melanoma tumors, and we believe that these tumors associated macrophages (TAMs) may be playing an essential role in regulating anti-tumor immune responses. Thus, currently we are investigating the role of these macrophage and myeloid cell populations in the tumors following vaccination. We are currently determining the following: (i) which subset of TAMs in the lungs and skin are most anti-inflammatory and promote tumor growth, (ii) what are the mechanisms utilized by TAM subsets that suppress anti-tumoral immunity in general and following immunotherapy (CMV based vaccines or CMV + anti-checkpoint blocker combination therapy), (iii) if targeting TAMs would serve as an effective way to improve tumor regression singularly or in combination with CMV vaccine, or in combination with CMV vaccines and checkpoint blockers. 

Another project in the lab deals with the mechanisms that regulate CD8 T cell differentiation and memory cell generation.  Our understanding of the genes involved in regulating CD8 T cell differentiation into different subsets of effector T cells and memory cells following infection has improved considerably in the past two decades.  However, little is known about the role of RNA species in regulating gene expression during the CD8 T cell differentiation process.  Thus, we have begun investigating how long non-coding RNA species regulate gene expression in antigen specific CD8 T cells after infection.  With the progress in RNA sequencing technologies, we can now begin to answer the important question: what is the function of the non-coding genome, which accounts for the majority of the mammalian genome.  To this end, we have now set up a working system to perform deep RNA sequencing of the different subsets of CD8 T cell populations after infection.  We have analyzed RNA sequencing data extensively and we have also performed pathway analysis and chromosomal geographical analysis of long non-coding RNA (Lnc RNAs) and the genes that are located in the vicinity of where the RNA species are present within the chromosomes.  Now we are using CRISPR technology to generate new mouse models to study the role of specific Lnc RNA species in regulating CD8 T cell differentiation in vivo after infection.
 


Intravital multiphoton visualization of the small intestine in live mice.  CD11c+ dendritic cells (green; lamina propria), and intestinal epithelial cells (red).

 

SELECT PUBLICATIONS:

Systemic TLR2 tolerance enhances central nervous system remyelination.
Wasko NJ, Kulak MH, Paul D, Nicaise AM, Yeung ST, Nichols FC, Khanna KM, Crocker S, Pachter JS, Clark RB.
J Neuroinflammation. 2019 Jul 27;16(1):158. doi: 10.1186/s12974-019-1540-2.
PMID: 31351476

Staphylococcus aureus Leukocidins Target Endothelial DARC to Cause Lethality in Mice.
Lubkin A, Lee WL, Alonzo F 3rd, Wang C, Aligo J, Keller M, Girgis NM, Reyes-Robles T, Chan R, O'Malley A, Buckley P, Vozhilla N, Vasquez MT, Su J, Sugiyama M, Yeung ST, Coffre M, Bajwa S, Chen E, Martin P, Kim SY, Loomis C, Worthen GS, Shopsin B, Khanna KM, Weinstock D, Lynch AS, Koralov SB, Loke P, Cadwell K, Torres VJ.
Cell Host Microbe. 2019 Mar 13;25(3):463-470.e9. doi: 10.1016/j.chom.2019.01.015. Epub 2019 Feb 21.
PMID: 30799265

Attrition of T Cell Zone Fibroblastic Reticular Cell Number and Function in Aged Spleens.
Masters AR, Jellison ER, Puddington L, Khanna KM, Haynes L.
Immunohorizons. 2018 May;2(5):155-163. doi: 10.4049/immunohorizons.1700062. Epub 2018 Jul 23.
PMID: 30706058

Combination Immunotherapy: Taking Cancer Vaccines to the Next Level.
Grenier JM, Yeung ST, Khanna KM
Front Immunol. 2018 Mar 22;9:610. doi: 10.3389/fimmu.2018.00610. eCollection 2018.
PMID: 29623082

Targeting the PXR-TLR4 signaling pathway to reduce intestinal inflammation in an experimental model of necrotizing enterocolitis.
Huang K, Mukherjee S, DesMarais V, Albanese JM, Rafti E, Draghi A, Maher LA, Khanna KM, Mani S, Matson AP. 
Pediatr Res. 2018 Jan 23. doi: 10.1038/pr.2018.14.
PMID: 29360809

Combining Adoptive Cell Therapy with Cytomegalovirus-Based Vaccine Is Protective against Solid Skin Tumors.
Grenier JM, Yeung ST, Qiu Z, Jellison ER, Khanna KM
Front. Immunol. 2018 Jan 16. Doi: 10.3389/fimmu.2017.01993

CD169+ Macrophages Restrain Systemic Inflammation Induced by Staphylococcus aureus Enterotoxin A Lung Response.
Svedova J, Ménoret A, Yeung ST, Tanaka M, Khanna KM, Vella AT
ImmunoHorizon. 2017 Nov 01. 1 (9) 213-222.  DOI: 10.4049/immunohorizons.1700033

CD169+ macrophages orchestrate innate immune by regulating bacterial localization in the spleen.
Perez OA, Yeung ST, Vera-Licona P, Romagnoli PA, Samji T, Ural BB, Maher L, Tanaka M, Khanna KM.
Sci Immunol. 2017 Oct 6;2(16). pii: eaah5520. doi: 10.1126/sciimmunol.aah5520.
PMID: 28986418
(Selected to be on the Cover)

Pregnane X Receptor Regulates Pathogen-Induced Inflammation and Host Defense against an Intracellular Bacterial Infection through Toll-like Receptor 4.
Qiu Z, Cervantes JL, Cicek BB, Mukherjee S, Venkatesh M, Maher LA, Salazar JC, Mani S, Khanna KM.
Sci Rep. 2016 Aug 23; 6:31936. doi: 10.1038/srep31936.
PMID: 27550658

Differentiation of distinct long-lived memory CD4 T cells in intestinal tissues after oral Listeria monocytogenes infection.
Romagnoli PA, Fu HH, Qiu Z, Khairallah C, Pham QM, Puddington L, Khanna KM, Lefrançois L, Sheridan BS.
Mucosal Immunol. 2017 Mar;10(2):520-530. doi: 10.1038/mi.2016.66. Epub 2016 Jul 27.
PMID: 27461178

IL-17A-producing resident memory γδ T cells orchestrate the innate immune response to secondary oral Listeria monocytogenes infection.
Romagnoli PA, Sheridan BS, Pham QM, Lefrançois L, Khanna KM.
Proc Natl Acad Sci U S A. 2016 Jul 26;113(30):8502-7. doi: 10.1073/pnas.1600713113. Epub 2016 Jul 11.
PMID: 27402748

TNF and CD28 Signaling Play Unique but Complementary Roles in the Systemic Recruitment of Innate Immune Cells after Staphylococcus aureus Enterotoxin A Inhalation.
Svedova J, Tsurutani N, Liu W, Khanna KM, Vella AT.
J Immunol. 2016 Jun 1;196(11):4510-21. doi: 10.4049/jimmunol.1600113. Epub 2016 Apr 20.
PMID: 27183621

T cell-intrinsic S1PR1 regulates endogenous effector T-cell egress dynamics from lymph nodes during infection.
Benechet AP, Menon M, Xu D, Samji T, Maher L, Murooka TT, Mempel TR, Sheridan BS, Lemoine FM, Khanna KM.
Proc Natl Acad Sci U S A. 2016 Feb 23;113(8):2182-7. doi: 10.1073/pnas.1516485113. Epub 2016 Feb 9.
PMID: 26862175

CD8 T Cells Enter the Splenic T Cell Zones Independently of CCR7, but the Subsequent Expansion and Trafficking Patterns of Effector T Cells after Infection Are Dysregulated in the Absence of CCR7 Migratory Cues.
Sharma N, Benechet AP, Lefrançois L, Khanna KM.
J Immunol. 2015 Dec 1;195(11):5227-36. doi: 10.4049/jimmunol.1500993. Epub 2015 Oct 23.
PMID: 26500349

Early Effector CD8 T Cells Display Plasticity in Populating the Short-Lived Effector and Memory-Precursor Pools Following Bacterial or Viral Infection.
Plumlee CR, Obar JJ, Colpitts SL, Jellison ER, Haining WN, Lefrancois L, Khanna KM.
Sci Rep. 2015 Jul 20;5:12264. doi: 10.1038/srep12264.
PMID: 26191658

Border Patrol Gone Awry: Lung NKT Cell Activation by Francisella tularensis Exacerbates Tularemia-Like Disease.
Hill TM, Gilchuk P, Cicek BB, Osina MA, Boyd KL, Durrant DM, Metzger DW, Khanna KM, Joyce S.
PLoS Pathog. 2015 Jun 11;11(6):e1004975. doi: 10.1371/journal.ppat.1004975. eCollection 2015 Jun.
PMID: 26068662

Cbl-b-deficient mice express alterations in trafficking-related molecules but retain sensitivity to the multiple sclerosis therapeutic agent, FTY720.
Fujiwara M, Anstadt EJ, Khanna KM, Clark RB.
Clin Immunol. 2015 May;158(1):103-13. doi: 10.1016/j.clim.2015.03.018. Epub 2015 Mar 28.
PMID: 25829233

Cytomegalovirus-Based Vaccine Expressing a Modified Tumor Antigen Induces Potent Tumor-Specific CD8(+) T-cell Response and Protects Mice from Melanoma.
Qiu Z, Huang H, Grenier JM, Perez OA, Smilowitz HM, Adler B, Khanna KM.
Cancer Immunol Res. 2015 May;3(5):536-46. doi: 10.1158/2326-6066.CIR-14-0044. Epub 2015 Jan 29.
PMID: 25633711

Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4.
Venkatesh M, Mukherjee S, Wang H, Li H, Sun K, Benechet AP, Qiu Z, Maher L, Redinbo MR, Phillips RS, Fleet JC, Kortagere S, Mukherjee P, Fasano A, Le Ven J, Nicholson JK, Dumas ME, Khanna KM*, Mani S.*
*Co-corresponding Authors.
Immunity. 2014 Aug 21;41(2):296-310. doi: 10.1016/j.immuni.2014.06.014. Epub 2014 Jul 24.
PMID: 25065623

Lung-resident memory CD8 T cells (TRM) are indispensable for optimal cross-protection against pulmonary virus infection.
Wu T, Hu Y, Lee YT, Bouchard KR, Benechet A, Khanna K, Cauley LS.
J Leukoc Biol. 2014 Feb;95(2):215-24. doi: 10.1189/jlb.0313180. Epub 2013 Sep 4.
PMID: 24006506

Cell-surface residence of sphingosine 1-phosphate receptor 1 on lymphocytes determines lymphocyte egress kinetics.
Thangada S, Khanna KM, Blaho VA, Oo ML, Im DS, Guo C, Lefrancois L, Hla T.
*Co-First Author.
J Exp Med. 2010 Jul 5;207(7):1475-83. doi: 10.1084/jem.20091343. Epub 2010 Jun 28.
PMID: 20584883

T cell and APC dynamics in situ control the outcome of vaccination.
Khanna KM, Blair DA, Vella AT, McSorley SJ, Datta SK, Lefrançois L.
J Immunol. 2010 Jul 1;185(1):239-52. doi: 10.4049/jimmunol.0901047. Epub 2010 Jun 7.
PMID: 20530268

In situ imaging reveals different responses by naïve and memory CD8 T cells to late antigen presentation by lymph node DC after influenza virus infection.
Khanna KM, Aguila CC, Redman JM, Suarez-Ramirez JE, Lefrançois L, Cauley LS.
Eur J Immunol. 2008 Dec;38(12):3304-15. doi: 10.1002/eji.200838602.
PMID: 19009527

Noncytotoxic lytic granule-mediated CD8+ T cell inhibition of HSV-1 reactivation from neuronal latency.
Knickelbein JE, Khanna KM, Yee MB, Baty CJ, Kinchington PR, Hendricks RL.
Science. 2008 Oct 10;322(5899):268-71. doi: 10.1126/science.1164164.
PMID: 18845757

Endogenous naive CD8+ T cell precursor frequency regulates primary and memory responses to infection.
Obar JJ, Khanna KM, Lefrançois L.
Immunity. 2008 Jun;28(6):859-69. doi: 10.1016/j.immuni.2008.04.010. Epub 2008 May 22.
PMID: 18499487

In situ imaging of the endogenous CD8 T cell response to infection.
Khanna KM, McNamara JT, Lefrançois L.
Science. 2007 Oct 5;318(5847):116-20.
PMID: 17916739

Persistent antigen presentation after acute vesicular stomatitis virus infection.
Turner DL, Cauley LS, Khanna KM, Lefrançois L.
J Virol. 2007 Feb;81(4):2039-46. Epub 2006 Dec 6.
PMID: 17151119

Latent virus influences the generation and maintenance of CD8+ T cell memory.
Sheridan BS, Khanna KM, Frank GM, Hendricks RL.
J Immunol. 2006 Dec 15;177(12):8356-64.
PMID: 17142732

Immune control of herpes simplex virus during latency.
Khanna KM, Lepisto AJ, Decman V, Hendricks RL.
Curr Opin Immunol. 2004 Aug;16(4):463-9. Review.
PMID: 15245740

Immunity to latent viral infection: many skirmishes but few fatalities.
Khanna KM, Lepisto AJ, Hendricks RL.
Trends Immunol. 2004 May;25(5):230-4. Review. No abstract available.
PMID: 15099562

Herpes simplex virus-specific memory CD8+ T cells are selectively activated and retained in latently infected sensory ganglia.
Khanna KM, Bonneau RH, Kinchington PR, Hendricks RL.
Immunity. 2003 May;18(5):593-603.
PMID: 12753737
 

REVIEWS/METHODS/BOOK CHAPTERS

Visualizing Endogenous Effector T Cell Egress from the Lymph Nodes.
Menon M, Benechet AP, Khanna KM.
Methods Mol Biol. 2017;1591:59-71. doi: 10.1007/978-1-4939-6931-9_5.
PMID: 28349475

Understanding memory CD8+ T cells.
Samji T, Khanna KM.
Immunol Lett. 2017 May;185:32-39. doi: 10.1016/j.imlet.2017.02.012. Epub 2017 Mar 6. Review.
PMID: 28274794

Reviving virus based cancer vaccines by using cytomegalovirus vectors expressing modified tumor antigens.
Qiu Z, Grenier JM, Khanna KM.
Oncoimmunology. 2015 Jun 5;5(1):e1056974. eCollection 2016.
PMID: 26942064

Visualizing T Cell Migration in situ.
Benechet AP, Menon M, Khanna KM.Front
Immunol. 2014 Jul 29;5:363. doi: 10.3389/fimmu.2014.00363. eCollection 2014. Review.
PMID: 25120547

LAB MEMBERS:

Current:

Undergraduate Students:

  • Jessica Moise-Grodsky

  • Luis Ovando

Former:

  • Mohamed Fazdly Alias (2019) – Masters Student

  • Basak B. Ural (2017) – Ph.D. Student

  • Leigh Maher (2017) – Research Assistant

  • Mai Pham (2017) – Lab Assistant

  • Manisha Menon, Ph.D. – Postdoctoral Fellow

  • Pablo A Romagnoli, Ph.D. – Postdoctoral Fellow

  • Courtney R. Plumlee, Ph.D. – Postdoctoral Fellow

  • Jeremy M Grenier, Ph.D. (2017) – M.D./Ph.D. Student

  • Oriana A Perez, Ph.D. (2017) – Ph.D. Student

  • Zhijuan Qiu, Ph.D. (2014) – Ph.D. Student

  • Alexandre P. Benechet, Ph.D. (2014) – Ph.D. Student