Anita A Koshy
Associate Professor
Associate Professor, BIO5 Institute
Associate Professor, Evelyn F Mcknight Brain Institute
Associate Professor, Immunobiology
Associate Professor, Neuroscience - GIDP
Primary Department
Department Affiliations
(520) 626-1696
Work Summary
We study how a common intracellular parasite, Toxoplasma gondii, persists in, and potentially changes, the mammalian brain. Understanding the Toxoplasma-brain interaction offers the opportunity to develop better therapies to treat toxoplasmosis as well as giving new insights into how to manipulate the brain immune response which has been implicated in many neurodegenerative diseases.
Research Interest
Anita Koshy, MD is an Assistant Professor in the Department of Neurology and the Department of Immunobiology, and an affiliate of the Clinical Translational Science Institute and the Evelyn F. McKnight Brain Institute. Clinically, Dr. Koshy is a recognized expert in the area of Infectious Diseases of the Nervous System, and has co-authored 4 chapters on this subject. Dr. Koshy’s lab focuses on understanding how a common human parasite, Toxoplasma gondii, is able to persist in the mammalian brain (including in up to 1/3 of the human population.) The goals of this work are to: 1) improve treatments for patients with symptomatic toxoplasmosis (there are no drugs to cure patients of Toxoplasma) and 2) use the co-evolution between the parasite and the mammalian CNS to better understand how immune responses in brain can be triggered and aborted. The latter research may have broad applicability to disorders of the brain in which the immune response is dysfunctional; these disorders include Multiple Sclerosis, traumatic brain injury, and neurodegenerative diseases such as Alzheimer’s disease. Keywords: Neuroscience, Infectious Disease, Parasitology

Publications

Caffaro, C. E., Koshy, A. A., Liu, L., Zeiner, G. M., Hirschberg, C. B., & Boothroyd, J. C. (2013). A nucleotide sugar transporter involved in glycosylation of the Toxoplasma tissue cyst wall is required for efficient persistence of bradyzoites. PLoS pathogens, 9(5), e1003331.

Toxoplasma gondii is an intracellular parasite that transitions from acute infection to a chronic infective state in its intermediate host via encystation, which enables the parasite to evade immune detection and clearance. It is widely accepted that the tissue cyst perimeter is highly and specifically decorated with glycan modifications; however, the role of these modifications in the establishment and persistence of chronic infection has not been investigated. Here we identify and biochemically and biologically characterize a Toxoplasma nucleotide-sugar transporter (TgNST1) that is required for cyst wall glycosylation. Toxoplasma strains deleted for the TgNST1 gene (Δnst1) form cyst-like structures in vitro but no longer interact with lectins, suggesting that Δnst1 strains are deficient in the transport and use of sugars for the biosynthesis of cyst-wall structures. In vivo infection experiments demonstrate that the lack of TgNST1 activity does not detectably impact the acute (tachyzoite) stages of an infection or tropism of the parasite for the brain but that Δnst1 parasites are severely defective in persistence during the chronic stages of the infection. These results demonstrate for the first time the critical role of parasite glycoconjugates in the persistence of Toxoplasma tissue cysts.

Dupont, C. D., Christian, D. A., Selleck, E. M., Pepper, M., Leney-Greene, M., Harms Pritchard, G., Koshy, A. A., Wagage, S., Reuter, M. A., Sibley, L. D., Betts, M. R., & Hunter, C. A. (2014). Parasite fate and involvement of infected cells in the induction of CD4+ and CD8+ T cell responses to Toxoplasma gondii. PLoS pathogens, 10(4), e1004047.

During infection with the intracellular parasite Toxoplasma gondii, the presentation of parasite-derived antigens to CD4+ and CD8+ T cells is essential for long-term resistance to this pathogen. Fundamental questions remain regarding the roles of phagocytosis and active invasion in the events that lead to the processing and presentation of parasite antigens. To understand the most proximal events in this process, an attenuated non-replicating strain of T. gondii (the cpsII strain) was combined with a cytometry-based approach to distinguish active invasion from phagocytic uptake. In vivo studies revealed that T. gondii disproportionately infected dendritic cells and macrophages, and that infected dendritic cells and macrophages displayed an activated phenotype characterized by enhanced levels of CD86 compared to cells that had phagocytosed the parasite, thus suggesting a role for these cells in priming naïve T cells. Indeed, dendritic cells were required for optimal CD4+ and CD8+ T cell responses, and the phagocytosis of heat-killed or invasion-blocked parasites was not sufficient to induce T cell responses. Rather, the selective transfer of cpsII-infected dendritic cells or macrophages (but not those that had phagocytosed the parasite) to naïve mice potently induced CD4+ and CD8+ T cell responses, and conferred protection against challenge with virulent T. gondii. Collectively, these results point toward a critical role for actively infected host cells in initiating T. gondii-specific CD4+ and CD8+ T cell responses.

Lopez, J., Lomen-Hoerth, C., Deutsch, G. K., Kerchner, G. A., & Koshy, A. (2014). Influenza-associated global amnesia and hippocampal imaging abnormality. Neurocase, 20(4), 446-51.

The acute phase of influenza infection is rarely associated with significant cognitive dysfunction. We describe a case of a 24 year-old man who developed global amnesia in the acute phase of influenza A infection. His deficits resolved over the course of several weeks. Transient abnormalities of diffusion and T2-weighted imaging were seen in the bilateral hippocampi. We review cerebral complications of influenza and discuss the possible role of previously proposed mechanisms in our patient's case.

Konradt, C., Ueno, N., Christian, D. A., DeLong, J., Harms-Pritchard, G., Herz, J., Bzik, D. J., McGavern, D. B., Koshy, A. A., Lodoen, M. B., & Hunter, C. A. (2016). Endothelial cells as a replicative niche for pathway entry to the CNS. Nature Microbiology.
Blader, I. J., & Koshy, A. A. (2014). Toxoplasma gondii development of its replicative niche: in its host cell and beyond. Eukaryotic cell, 13(8), 965-76.

Intracellular pathogens can replicate efficiently only after they manipulate and modify their host cells to create an environment conducive to replication. While diverse cellular pathways are targeted by different pathogens, metabolism, membrane and cytoskeletal architecture formation, and cell death are the three primary cellular processes that are modified by infections. Toxoplasma gondii is an obligate intracellular protozoan that infects ∼30% of the world's population and causes severe and life-threatening disease in developing fetuses, in immune-comprised patients, and in certain otherwise healthy individuals who are primarily found in South America. The high prevalence of Toxoplasma in humans is in large part a result of its ability to modulate these three host cell processes. Here, we highlight recent work defining the mechanisms by which Toxoplasma interacts with these processes. In addition, we hypothesize why some processes are modified not only in the infected host cell but also in neighboring uninfected cells.