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Shyamesh Kumar

Sree Chitra Thirunal Institute for Medical Sciences and Technology

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Edward J. Dick

Texas Biomedical Research Institute

Olga González

Texas Biomedical Research Institute

Michael Owston

Charles River Laboratories (United States)

Gene B. Hubbard

Longevity Biotech (United States)

Leslie Dakin

Vertex Pharmaceuticals (United States)

Shane C. Burgess

University of Arizona

Angelo Blasio

Vertex Pharmaceuticals (United States)

Timothy J. Senter

Vertex Pharmaceuticals (United States)

Jennifer Proctor

Vertex Pharmaceuticals (United States)

Brinley F. Furey

Vertex Pharmaceuticals (United States)

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Texas Biomedical Research Institute

Vertex Pharmaceuticals (United States)

Mississippi State University

Harvard University

Emory University

The University of Texas Health Science Center at San Antonio

Charles River Laboratories (United States)

National Institutes of Health

University of Georgia

University of California, Davis

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Mechanisms of Genetic Resistance and Neoplastic Transformation in Marek's Disease

Marek's disease

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Genotype-Dependent Tumor Regression in Marek’s Disease Mediated at the Level of Tumor Immunity

Cancer Microenvironment (2009)

Shyamesh Kumar Joram Buza Shane C. Burgess

Marek's disease (MD) of chickens is a unique natural model of Hodgkin's and Non Hodgkin's lymphomas in which the neoplastically-transformed cells over-express CD30 (CD30(hi)) antigen. All chicken genotypes can be infected with MD virus and develop microscopic lymphomas. From 21 days post infection (dpi) microscopic lymphomas regress in resistant chickens but, in contrast, they progress to gross lymphomas in susceptible chickens. Here we test our hypothesis that in resistant chickens at 21 dpi the tissue microenvironment is pro T-helper (Th)-1 and compatible with cytotoxic T lymphocyte (CTL) immunity but in susceptible lines it is pro Th-2 or pro T-regulatory (T-reg) and antagonistic to CTL immunity. We used the B2, non-MHC-associated, MD resistance/susceptibility system (line [L]6(1)/line [L]7(2)) and quantified the levels of key mRNAs that can be used to define Th-1 (IL-2, IL-12, IL-18, IFNgamma), Th-2 (IL-4, IL-10) and T-reg (TGFbeta, GPR-83, CTLA-4, SMAD-7) lymphocyte phenotypes. We measured gene expression in both whole tissues (represents tissue microenvironment and tumor microenvironment) and in the lymphoma lesions (tumor microenvironment) themselves. Gene ontology-based modeling of our results shows that the dominant phenotype in whole tissue as well as in microscopic lymphoma lesions, is pro T-reg in both L6(1) and L7(2) but a minor pro Th-1 and anti Th-2 tissue microenvironment exists in L6(1) whereas there is an anti Th-1 and pro Th-2 tissue microenvironment in L7(2). The tumor microenvironment per se is pro T-reg, anti Th-1 and pro Th-2 in both L6(1) and L7(2). Together our data suggests that the neoplastic transformation is essentially the same in both L6(1) and L7(2) and that resistance/susceptibility is mediated at the level of tumor immunity in the tissues.

CTL*

Marek's disease

10.1007/s12307-008-0018-z

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Citations (21)

Inhibition of IL-6 in the LCWE Mouse Model of Kawasaki Disease Inhibits Acute Phase Reactant Serum Amyloid A but Fails to Attenuate Vasculitis

Frontiers in Immunology (2021)

Rebecca A. Porritt Carol Chase Huizar Edward J. Dick Shyamesh Kumar Renee Escalona

Objective Kawasaki disease (KD) is the most common cause of acquired pediatric heart disease in the developed world. 10% of KD patients are resistant to front-line therapy, and no interventions exist to address secondary complications such as myocardial fibrosis. We sought to identify proteins and pathways associated with disease and anti-IL-1 treatment in a mouse model of KD. Methods Vasculitis was induced via Lactobacillus casei cell wall extract (LCWE) injection in 5-week-old male mice. Groups of mice were injected with LCWE alone, LCWE and IL-1 receptor antagonist anakinra, or saline for controls. Upper heart tissue was assessed by quantitative mass spectrometry analysis. Expression and activation of STAT3 was assessed by immunohistochemistry, immunofluorescence and Western blot, and IL-6 expression by RNA-seq and ELISA. A STAT3 small molecular inhibitor and anti-IL-6R antibody were used to evaluate the role of STAT3 and IL-6 in disease development. Results STAT3 was highly expressed and phosphorylated in cardiac tissue of LCWE-injected mice, and reduced following anakinra treatment. Il6 and Stat 3 gene expression was enhanced in abdominal aorta of LCWE-injected mice and reduced with Anakinra treatment. IL-6 serum levels were enhanced in LCWE-injected mice and normalized by anakinra. However, neither inhibition of STAT3 nor blockade of IL-6 altered disease development. Conclusion Proteomic analysis of cardiac tissues demonstrates differential protein expression between KD-like, control and anakinra treated cardiac tissue. STAT3 and IL-6 were highly upregulated with LCWE and normalized by anakinra treatment. However, both STAT3 and IL-6 were dispensable for disease development indicating they may be bystanders of inflammation.

10.3389/fimmu.2021.630196

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Nuclear Factor kappa B is central to Marek’s Disease herpesvirus induced neoplastic transformation of CD30 expressing lymphocytes in-vivo

BMC Systems Biology (2012)

Shyamesh Kumar Dušan Kunec Joram Buza Hsin-I Chiang Huaijun Zhou

Marek's Disease (MD) is a hyperproliferative, lymphomatous, neoplastic disease of chickens caused by the oncogenic Gallid herpesvirus type 2 (GaHV-2; MDV). Like several human lymphomas the neoplastic MD lymphoma cells overexpress the CD30 antigen (CD30hi) and are in minority, while the non-neoplastic cells (CD30lo) form the majority of population. MD is a unique natural in-vivo model of human CD30hi lymphomas with both natural CD30hi lymphomagenesis and spontaneous regression. The exact mechanism of neoplastic transformation from CD30lo expressing phenotype to CD30hi expressing neoplastic phenotype is unknown. Here, using microarray, proteomics and Systems Biology modeling; we compare the global gene expression of CD30lo and CD30hi cells to identify key pathways of neoplastic transformation. We propose and test a specific mechanism of neoplastic transformation, and genetic resistance, involving the MDV oncogene Meq, host gene products of the Nuclear Factor Kappa B (NF-κB) family and CD30; we also identify a novel Meq protein interactome. Our results show that a) CD30lo lymphocytes are pre-neoplastic precursors and not merely reactive lymphocytes; b) multiple transformation mechanisms exist and are potentially controlled by Meq; c) Meq can drive a feed-forward cycle that induces CD30 transcription, increases CD30 signaling which activates NF-κB, and, in turn, increases Meq transcription; d) Meq transcriptional repression or activation of the CD30 promoter generally correlates with polymorphisms in the CD30 promoter distinguishing MD-lymphoma resistant and susceptible chicken genotypes e) MDV oncoprotein Meq interacts with proteins involved in physiological processes central to lymphomagenesis. In the context of the MD lymphoma microenvironment (and potentially in other CD30hi lymphomas as well), our results show that the neoplastic transformation is a continuum and the non-neoplastic cells are actually pre-neoplastic precursor cells and not merely immune bystanders. We also show that NF-κB is a central player in MDV induced neoplastic transformation of CD30-expressing lymphocytes in vivo. Our results provide insights into molecular mechanisms of neoplastic transformation in MD specifically and also herpesvirus induced lymphoma in general.

Marek's disease

Neoplastic transformation

10.1186/1752-0509-6-123

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Citations (22)

APOL1 Inhibitors Reverse Established Proteinuria in an APOL1-Mediated Kidney Disease Mouse Model

Journal of the American Society of Nephrology (2022)

Angelo Blasio Kelly Sullivan James J. Mann Guanyu Wang Shyamesh Kumar

Blasio, Angelo; Sullivan, Kelly E.; Mann, James J.; Wang, Guanyu; Kumar, Shyamesh; Bright, Franklin; Bouillez, Audrey; Daniel, Kevin; Nanthakumar, Suganthini; Rosario, Aldo A.; Aragon Mejia, Monica A.; Heighton, Thomas F.; Nanou, Evanthia; Proctor, Jennifer; Furey, Brinley; Fortier, Anne; Senter, Timothy J.; Dakin, Leslie; Zimmerman, Brandon Author Information

10.1681/asn.20223311s1169c

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Fermentation products as feed additives mitigate some ill-effects of heat stress in pigs

Journal of Animal Science (2017)

Shyamesh Kumar B. E. Bass M. Bandrick C. L. Loving Susan L. Brockmeier

10.2527/jas2016.0662

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Citations (12)

Elsevier eBooks (2023)

Roger Alison James Baily Alys Bradley Agathe Bédard Maurice Cary

10.1016/b978-0-12-813088-9.01002-8

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A case report of ovotesticular disorder of sex development (OT‐DSD) in a baboon (Papio spp.) and a brief review of the non‐human primate literature

Journal of Medical Primatology (2018)

Ekaterina Perminov Sara Mangosing Alexandra Confer Olga González Jason R. Crawford

Abstract Disorders of sexual development are rare in non‐human primates. We report a case of true hermaphroditism in a 19‐year‐old, nulliparous, female baboon ( Papio spp.). At necropsy, the animal was obese with adequate muscle mass and hydration. Reproductive organs appeared normal with the exception of 2 firm nodular structures in the myometrium (1‐1.5 cm diameter) and a thickened, dark endocervical mucosa. Histologically, both gonads were ovotestes and contained discrete areas of ovarian and testicular tissue. There were follicles in various stages of development surrounded by ovarian stroma. Other areas contained hypoplastic seminiferous tubules lined by Sertoli cells, but lacked germ cells and spermatozoa. The uterine lesions were consistent with adenomyosis and cystic endometrial hyperplasia. Cervical lesions were consistent with atypical glandular hyperplasia and squamous metaplasia with dysplasia. We report the first case of ovotesticular disorder of sexual development ( OT ‐ DSD ), or true hermaphroditism in a baboon.

Ovotestis

Adenomyosis

True hermaphroditism

10.1111/jmp.12339

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Citations (3)

Reovirus-Associated Meningoencephalomyelitis in Baboons

Veterinary Pathology (2013)

Shyamesh Kumar Edward J. Dick Yugendar R. Bommineni Alice Yang James N. Mubiru

Baboon orthoreovirus (BRV) is associated with meningoencephalomyelitis (MEM) among captive baboons. Sporadic cases of suspected BRV-induced MEM have been observed at Southwest National Primate Research Center (SNPRC) for the past 20 years but could not be confirmed due to lack of diagnostic assays. An immunohistochemistry (IHC)–based assay using an antibody against BRV fusion-associated small transmembrane protein p15 and a conventional polymerase chain reaction (PCR)–based assay using primers specific for BRV were developed to detect BRV in archived tissues. Sixty-eight cases of suspected BRV-induced MEM from 1989 through 2010 were tested for BRV, alphavirus, and flavivirus by IHC. Fifty-nine of 68 cases (87%) were positive for BRV by immunohistochemistry; 1 tested positive for flavivirus (but was negative for West Nile virus and St Louis encephalitis virus by real-time PCR), and 1 virus isolation (VI) positive control tested negative for BRV. Sixteen cases (9 BRV-negative and 7 BRV-positive cases, by IHC), along with VI-positive and VI-negative controls, were tested by PCR for BRV. Three (of 9) IHC-negative cases tested positive, and 3 (of 7) IHC-positive cases tested negative by PCR for BRV. Both IHC and PCR assays tested 1 VI-positive control as negative (sensitivity: 75%). This study shows that most cases of viral MEM among baboons at SNPRC are associated with BRV infection, and the BRV should be considered a differential diagnosis for nonsuppurative MEM in baboons.

Flavivirus

10.1177/0300985813497487

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Citations (15)

Fatal Canid Herpesvirus 1 Respiratory Infections in 4 Clinically Healthy Adult Dogs

Veterinary Pathology (2014)

Shyamesh Kumar Elizabeth A. Driskell A. James Cooley Kun Jia Libin Chen

Four healthy adult dogs (Golden Retrievers aged 6 years and 9 years, Dalmatian aged 13 years, and Mastiff aged 5 years) developed clinical signs of acute respiratory disease and died within 2 to 7 days of onset of clinical signs. The lungs of the 3 dogs submitted for necropsy were diffusely and severely reddened due to hyperemia and hemorrhage. Microscopic lesions in all dogs were suggestive of acute viral or toxic respiratory damage and varied from acute severe fibrinonecrotic or hemorrhagic bronchopneumonia to fibrinous or necrotizing bronchointerstitial pneumonia. Necropsied dogs also had hemorrhagic rhinitis and tracheitis with necrosis. Virus isolation, transmission electron microscopy, and polymerase chain reaction were used to confirm the presence of canid herpesvirus 1 (CaHV-1) in the lung samples of these dogs. Lung tissues were negative for influenza A virus, canine distemper virus, canine parainfluenza virus, canine respiratory coronavirus, and canine adenovirus 2. Canid herpesvirus 1 has been isolated from cases of acute infectious respiratory disease in dogs but has only rarely been associated with fatal primary viral pneumonia in adult dogs. The cases in the current report document lesions observed in association with CaHV-1 in 4 cases of fatal canine herpesvirus pneumonia in adult dogs.

Canine distemper

Tracheitis

Viral Pneumonia

10.1177/0300985814556190

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Citations (13)