After the completion of my PhD dissertation in 1999 on anti-viral responses in the brain 3,4,8,10-12, I switched directions slightly and began studying innate immunological responses during the development of Marek's disease (MD) in chickens at Cornell University under the guidance of Dr. Karel A. Schat. MD is caused by an alphaherpesvirus called MD herpesvirus (MDV) that induces a devastating disease of the domestic chicken and is characterized by neurological disorders, generalized immunosuppression, and neoplastic T cell transformation. The highly oncogenic nature of the virus provides the opportunity to study the transformation of lymphocytes and the metastasis of lymphoid tumors in a natural virus-host setting in living animals. The virus initially infects B lymphocytes, followed by activated T lymphocytes, where it can cause T cell transformation, and subsequently reaches the feather follicle epithelium (FFE) in the skin where it is shed into the environment and animals in contact become infected. Over the last few decades, the virulence of MDV has significantly increased, most likely as a result of widespread vaccination, which is believed to cause evolutionary pressure on the virus to “break” the vaccine protection and increase in virulence.

In my first few years at Cornell with Dr. Schat, I focused on the immune response to MDV, in particular, the innate (early, non-specific) immune response. An important finding in these studies was the increased level of nitric oxide (NO) and inflammatory cytokines produced in chickens infected with the most virulent strains of MDV called very virulent plus (vv+) MDV5,9. vv+MDV strains often cause severe immune suppression and neurological symptoms. We found that NO and inflammatory cytokine levels increased directly with the level of virulence of the strain, possibly linking the production of NO and inflammatory cytokines to the neurological symptoms seen with vv+MDV.

In 2003, my emphasis began to shift from the immunological aspects of MD to the virus itself; in particular my interests involved identifying the virulence factors that make MDV so deadly. My specific projects now include identifying specific viral factors that lead to increased virulence of MDV, as well as mechanisms involved in transformation and/or maintenance of transformation in T cells. Although still concerned with the host-pathogen relationship, I have focused more on the virological aspects of the disease, including an open reading frame (ORF), called RLORF4, which we have shown to be directly involved in attenuation of MDV6,7. In addition, other virulence factors we have been studying include glycoprotein C (gC) and a virally encoded protein kinase, UL13, which both have been shown to be important for the spread of MDV from chicken-to-chicken2. Lastly, I am currently working on a recently discovered ubiquitin-specific protease or USP encoded within the MDV genome, which could have implications for transformation of lymphocytes by herpesviruses since the protein appears to be expressed in MDV-transformed cells 1.

Reference List

1. Jarosinski, K. W., L. M. Kattenhorn, B. Kaufer, H. Ploegh, and K. Osterrieder. Proc Natl Acad Sci USA, in press.

2. Jarosinski, K. W., N. G. Margulis, J. P. Kamil, S. J. Spatz, V. K. Nair, and N. Osterrieder. 2007. Horizontal transmission of Marek's disease virus requires US2, the UL13 protein kinase, and gC. J Virol 81:10575-10587.

3. Jarosinski, K. W. and P. T. Massa. 1998. The basis for NF-kappa B and MHC class I suppression in CNS neurons. Faseb Journal 12:A600.

4. Jarosinski, K. W. and P. T. Massa. 2002. Interferon regulatory factor-1 is required for interferon-gamma-induced MHC class I genes in astrocytes. J Neuroimmunol 122:74-84.

5. Jarosinski, K. W., B. L. Njaa, P. H. O'Connell, and K. A. Schat. 2005. Pro-inflammatory responses in chicken spleen and brain tissues after infection with very virulent plus Marek's disease virus. Viral Immunol 18:149-162.

6. Jarosinski, K. W., P. H. O'Connell, and K. A. Schat. 2003. Impact of deletions within the Bam HI-L fragment of attenuated Marek's disease virus on vIL-8 expression and the newly identified transcript of open reading frame LORF4. Virus Genes 26:255-269.

7. Jarosinski, K. W., N. Osterrieder, V. K. Nair, and K. A. Schat. 2005. Attenuation of Marek's disease virus by deletion of open reading frame RLORF4 but not RLORF5a. J Virol 79:11647-11659.

8. Jarosinski, K. W., L. W. Whitney, and P. T. Massa. 2001. Specific deficiency in nuclear factor-kappa B activation in neurons of the central nervous system. Lab Invest 81:1275-1288.

9. Jarosinski, K. W., R. Yunis, P. H. O'Connell, C. J. Markowski-Grimsrud, and K. A. Schat. 2002. Influence of genetic resistance of the chicken and virulence of Marek's disease virus (MDV) on nitric oxide responses after MDV infection. Avian Dis. 46:636-649.

10. Massa, P. T. and K. W. Jarosinski. 2005. Unique control of NF-kappa B activation by canonical and translational pathways in neurons. J Neurochem 94:114.

11. Massa, P. T., S. Saha, C. Wu, and K. W. Jarosinski. 2000. Expression and function of the protein tyrosine phosphatase SHP-1 in oligodendrocytes. Glia 29:376-385.

12. Massa, P. T., L. W. Whitney, C. Wu, S. L. Ropka, and K. W. Jarosinski. 1999. A mechanism for selective induction of 2 '-5 ' oligoadenylate synthetase, anti-viral state, but not MHC Class I genes by interferon-beta in neurons. J Neurovirol 5:161-171.

Contact

email: kwj4@cornell.edu