Chozha V. Rathinam, Dr. rer. nat.

21. De A, Dainichi T, Rathinam CV and Ghosh S.The deubiquitinase activity of A20 is dispensable for NF-κB signaling. EMBO Reports15, 775-83 (2014).

22. Kode A, Manavalan JS, Mosialou I, Bhagat G, Rathinam CV, Luo N, Khiabanian H, Lee A, Murty VV, Friedman R, Brum A, Park D, Galili N, Mukherjee S, Teruya-Feldstein J, Raza A, Rabadan R, Berman E and Kousteni S. Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts. Nature 506, 240-4 (2014).

23. Baldzizhar R, Fedorchuk C, Jha M, Rathinam CV, Henegariu O and Czyzyk J. Anti-serpin antibody mediated regulation of proteases in autoimmune diabetes. The Journal  of Biological Chemistry 288, 1612-9 (2013).

24. Kriegel MA, Rathinam CV and Flavell RA.Pancreatic Islet expression of Chemokine CCL2 suppresses autoimmune diabetes via tolerogenic CD11C+CD11B+ Dendritic Cells. Proc Natl Acad Sci USA 109, 3457-62 (2012).

25. Ahmed N, Zeng M, Sinha I, Polin L, Wei WZ, Rathinam CV, Flavell R, Massoumi R and Venuprasad K. The E3 Ligase Itch and Deubiquitinase Cyld act together to regulate Tak1 and Inflammation. Nature Immunology, 12, 1176-83 (2011).

26. Rathinam CV, PoueymirouWT, RojasJ, MurphyAJ, ValenzuelaDM, YancopoulosGD, Rongvaux A, EynonEE, Manz  MG and FlavellRA. Efficient differentiation and functions of human macrophages in the humanized M-CSF mice. Blood 118, 3119-28 (2011).

27. Strowig T, Rongvaux A, Rathinam CV, Eynon EE, Manz MG and Flavell RA. Transgenic expression of human SIRPa improves the engraftment of human cells in Rag2-/- common gC-/- mice. Proc Natl Acad Sci USA 108, 13218-23 (2011).

28. Kamanaka M, Zenewicz LA, Huber S, Gagliani N, Rathinam CV,  O’ Connor W, Wan YY, Nakae S, Iwakura Y, Hao L and Flavell R. CD45RB^lo CD4 T cells are controlled directly by IL-10 and cause IL-22 dependent colitis. The Journal of Experimental Medicine 208,1027-40 (2011).

29. Rongvaux A, Willinger T, Takizawa H, Rathinam CV, Wojtek A, Murphy AJ, Valenzuela DM, Yancopoulos GD, Eynon EE, Stevens S, Manz MG and Flavell RA. Human thrombopoietin Knock-in mice efficiently support human hematopoietic stem and progenitor cells. Proc Natl Acad Sci USA 108, 2378-83 (2011).

30. Rathinam CV and Flavell R. c-Cbl deficiency leads to diminished lymphocyte development and functions. Proc Natl Acad Sci USA107, 8316-21 (2010).

31.RathinamCV*, KriegelM* and FlavellR. E3 Ubiquitin Ligase GRAIL Controls Primary T Cell Activation and Oral Tolerance. Proc Natl Acad Sci USA 106, 16770-5 (2009). *Equal contribution & Indicated First

32. Legrand N, Ploss A, Balling R, Becker PD, Borsotti C, Brezillon N, Debarry J, de Jong Y, Deng H, Di Santo JP, Eisenbarth S, Eynon E, Flavell RA, Guzman CA, Huntington ND, Kremsdorf D, Manns MP, Manz MG, Mention JJ, Ott M, Rathinam C, Rice CM, Rongvaux A, Stevens S, Spits H, Strick-Marchand H, Takizawa H, van Lent AU, Wang C, Weijer K, Willinger T, Ziegler P. Humanized mice for modeling human infectious disease: challenges, progress, and outlook Cell Host Microbe 6, 5-9  (2009)

33. Rathinam CV*, Schwermann J*, Schubert M*, Schumacher S, Noyan F, Koseki H,  Kotlyarov A, Klein C, Gaestel M. MAPKAP Kinase MK2 maintains self-renewal capacity of hematopoietic stem cells. The EMBO Journal 28, 1392-406 (2009). *Equal contribution & Indicated First

34. Templin C, Kotlarz D, Rathinam CV, Rudolph C, Schätzlein S, Ramireddy K,    Rudolph KL, Schlegelberger B, Klein C, Drexler H.Establishment of immortalized multipotent hematopoietic progenitor cell lines by retroviral-mediated gene transfer of beta-catenin. Experimental Hematology 36, 204-15 (2008).

35. Rathinam CV and Flavell R. The hematopoiesis paradigm: clarity or ambiguity ? Blood 112, 3534-5 (2008).

36. Ju Z, Jiang H, Jaworski M, Rathinam CV, Gompf A, Klein C, Trumpp A, and Rudolph KL. Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nature Medicine13, 742-747 (2007).

37. Klein C, Grudzien M, Appaswamy G, Germeshausen M, Sandrock I, Schäffer AA, Rathinam CV, Boztug K, Schwinzer B, Rezaei N, Bohn G, Melin M, Carlsson G, Fadeel B, Dahl N, Palmblad J, Henter JI, Zeidler C, Grimbacher B, Welte K. Hax1 deficeincy causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nature Genetics 39, 86-92 (2007).

38. Bohn G, Allroth A, Brandes G, Thiel J, Glocker E, Schaffer AA, Rathinam CV, Taub N, Teis D, Zeidler C, Dewey RA, Geffers R, Buer J, Huber LA, Welte K, Grimbacher B, Klein C. A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14. Nature Medicine 13, 38-45 (2007).

39. Jung J, Bohn G, Allroth A, Boztug K, Brandes G, Sandrock I, Schaffer AA, Rathinam CV, Kollner I, Beger C, Schilke R, Welte K, Grimbacher B, Klein C. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood 108, 362-9 (2006).

40. Rathinam CV, Sauer M, Ghosh A, Rudolph C, Hegazy A, Schlegelberger B, Welte K, Klein C. Generation and characterisation of a novel hematopoietic progenitor cell line with DC differentiation potential. Leukemia 20, 870-6 (2006).

41. Saravanamuthu SS, von Gotz F, Salunkhe P,  Rathinam CV, Geffers R, Buer J,Tummler B, Steinmetz I.Evidence for polyadenylated mRNA in Pseudomonas aeruginosa. Journal of Bacteriology 186, 7015-8 (2004).

42. Krishnamurthy KVK , Krishnaraj R, Rathinam CV, Christopher S. The Programme Of Cell Death In Plants and Animals -A Comparison. Current Science 79 (2000).

For more than a decade research at the Rathinam laboratory (@ Columbia University and University of Maryland) has contributed significantly towards an understanding on the fine-tuning of inflammatory circuits, mediated by key regulators of the NFKB pathway- A20 and IKK2,in hematopoietic defects and immune dysfunctions. While these studies have unequivocally demonstrated the pathological effects of uncontrolled infection and inflammation in animal models, the consequences of chronic viral infections on human hematopoiesis remain unclear. In particular, the physiological consequences of human immunodeficiency virus (HIV)-1 induced chronic inflammation on human hematopoietic stem cells need to be identified.  The current research of the Rathinam lab aims to unravel the cellular mechanisms through which HIV-1 affects hematopoiesis and contributes to pathophysiology in humans. 

The major lines of our current investigation include:

1. Decoding inflammatory circuits that drive immune dysfunctions in HIV- exposed, but uninfected, infants born to HIV-infected mothers: An estimated 1.3 million HIV-exposed, uninfected (HEU) children are born annually to mothers-living with HIV. A vast majority of HEU children have higher risk for opportunistic infections within the first 6 months of life, most likely due to hematopoietic & immune defects. Even though a great deal of information is available on HIV-induced hematopoietic defects in people living with HIV, hematopathologies caused by in-utero exposure of HIV in HIV-exposed uninfected (HEU) children remains largely unknown. Particularly, physiological impact of maternal exposure of HIV on hematopoietic stem cells (HSCs) of HEU infants remain completely unknown. A vast majority of HEU children have higher risk of opportunistic infections within the first 6 months of life. Indeed, HEU infants have 2- to 4- fold higher mortality rate, largely due to respiratory infections and bacterial sepsis, when compared with HIV-unexposed uninfected (HU) infants. While the clinical relevance of respiratory tract infections is well recognized, defective immune circuitry that predisposes HEU infants/children to these infections remains unidentified. In addition, the upstream circuitry responsible for hematopoietic/immune defects in HEU infants/children remains unidentified. While HIV- associated hyperinflammation is recognized as the hallmark feature in HEU children, the pathophysiological impact of inflammation on HSC maintenance and functions remains elusive. Our current research is crafted to unravel the cellular and molecular players of inflammation that cause HSC defects in HEU infants/children. In addition, our studies are aimed to identify the role of specific immune subsets of HEU infants/children in providing immunity against respiratory tract infections. Finally, we would identify the cellular source of inflammation and evaluate the therapeutic benefits of inhibiting inflammatory circuits in HEU infants/children.  We believe that our research study would be of major clinical relevance as it attempts to unravel the cellular and molecular mechanisms that may be responsible for increased morbidities and mortalities in HEU children. A deeper understanding on HIV-induced pathophysiological consequences on HSCs may define potentially new targets for treating hematologic/immune disorders and identify novel targets that prevent HIV-induced immunodeficiencies.

2. Deciphering HIV-induced hematopathology: Hematological abnormalities, such as thrombocytopenia, anemia, lymphocytopenia, monocytopenia, and neutropenia, frequently occur in patients infected with Human Immunodeficiency Virus (HIV)-1. Of note, Pancytopenia has been considered as the hallmark feature of patients with advanced acquired immunodeficiency syndrome (AIDS) (Group IV). In addition, patients with HIV infection are susceptible to HIV-associated opportunistic infections and bone marrow neoplasms. More importantly, antiretroviral treatments result in incomplete rescue of hematopoiesis and are known to impair normal hematopoiesis in patients with HIV infection. Emerging evidence establish a strong link between HIV-1 and hematopoietic stem cells (HSCs) of the bone marrow. Overall, these studies provide a compelling rationale for further investigations into mechanisms through which HIV-1 dysregulates hematopoiesis. However, the cellular mechanisms responsible for pancytopenia and bone marrow failure following HIV-infection remain incompletely understood.  More importantly, it remains unclear if HIV infection is directly affecting the physiology and functions of HSCs. A deeper understanding of the cellular and molecular mechanisms that regulate HSCs in the BM of patients with HIV-1 infection would be valuable in designing novel therapies for HIV-associated hematological diseases. Therefore, our research aims to unravel the physiologic impact of HIV infection on HSCs and to identify the progenitors that are susceptible to HIV infection. We believe that the proposed research will provide detailed insights into the mechanisms through which HIV infection impairs HSC physiology and causes hematopathology. Knowledge obtained from these studies would be useful to design novel and more effective therapies for human hematologic diseases that are caused by pathogenic viruses, such HIV-1.

3. Unraveling the impact of HIV-induced chronic inflammation on innate immune system: Earlier studies have unequivocally established that dendritic cells (DCs) play pivotal roles in the control of human immunodeficiency virus (HIV)-1 infection at both acute and chronic phases. Untreated people living with HIV (PLWH) exhibit reduced frequencies of DCs in the peripheral blood. Interestingly, there exists an inverse correlation between depletion of circulating DCs and disease progression during HIV-1 infections. In agreement with these findings, DCs (particularly myeloid DCs) from elite controllers exhibit reduced spontaneous immune activation; increased functions in response to TLR activation; augmented abilities to recognize HIV-1; and increased capacities in inducing antiviral HIV-1-specific T cells, when compared to uninfected, untreated PLWH and Anti-retroviral therapy(ART)-treated PLWH. More importantly, recent studies establish that the current ART regimen does not restore DC deficiencies observed in PLWH. While thediminished numbers of DCs in the PBMCs of PLWH have been well documented, cellular, and molecular mechanisms responsible for this phenomenon remain largely unknown. To this end, our current research is designed to unravel the physiologic impact of HIV infection on DC differentiation and to identify the mechanisms responsible for reduced DC differentiation in PLWH. Understanding cellular and molecular mechanisms through which HIV-1-infection induces DC defects should help us in the fight against HIV-1 infection. Our studies will contribute to the design of novel treatment strategies preventing HIV-induced immune dysfunctions.

4. Understanding the Brain-bone marrow crosstalk during neural injuries: Traumatic brain injury (TBI) is one of the major causes of morbidity and disability worldwide.  Approximately, 1.7 million people are afflicted by TBI every year and contributes to 30 % of all injury related deaths.  The annual cost of treatment, within the United States, for patients with TBI is ~$60 billion. TBI involves a spectrum of pathoanatomical subtypes and induces complex pathophysiological pathways. In addition to causing severe trauma in the brain, TBI initiates a cascade of cellular, molecular, biochemical and immunological events that are referred to as “secondary injury”.  Indeed, clinical outcome of TBI is often determined by the nature and severity of both primary and secondary injuries. Neuroinflammation is an adverse outcome and a key manipulable aspect of secondary injury following TBI.  While the clinical significance of tightly controlled neuroinflammation has begun to unfold, the pathophysiological consequences of TBI mediated neuroinflammation remain incompletely understood. Inadequate knowledge on systemic defects caused by TBI is believed to be one of the major challenges in designing effective therapies. Recent research from our laboratory has discovered major immunodeficiencies caused by TBI-induced neuroinflammation.   We are currently identifying the cellular and molecular players that participate in and control the neuro-immune crosstalk. We believe that our studies would provide insights on novel therapeutic strategies towards treatment of patients suffering from TBI.

We currently looking for highly motivated students and postdoctoral fellows. 

2015  BD Immunology Award

2014  New Innovator Award, Leukemia Research Foundation, USA

2007  Best Ph.D thesis work award, University of Tubingen, Germany

2005  ASH Travel Award, American Society  of Hematology, USA

2000  Best Research Presentation Award, SASTRA University, India

Active Grants:

Grant 1:

Source = NIH/ NIAID

Budget = $3, 677, 656

Period = May 2024 -April, 2029

Role = Principal Investigator

Grant 2:

Source = NIH/ NIAID

Budget = $ 424, 875

Period = Feb 2023 – Jan 2025

Role = Principal Investigator

Completed Grants:

2017-2022   R01HL132194  (Role: Principal Investigator)

                          NF-kB signaling in the control of Hematopoiesis

                          National Institutes of Health/National Heart Lung Blood Institute  (NHLBI)

2014-2015  Role: Principal Investigator

                        Role of A20 in the restriction of myeloid Leukemia

                        Leukemia Research Foundation

2010-2011  Role: Lead Investigator

                       Genetic & Molecular Control of E3 Ubiquitin Ligases in Stem Differentiation

                       National Institues of Health (NCRR),  5P20RR018757-09