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 Associate 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

Hidano, S., Randall, L. M., Dawson, L., Dietrich, H. K., Konradt, C., Klover, P. J., John, B., Harris, T. H., Fang, Q., Turek, B., Kobayashi, T., Hennighausen, L., Beiting, D. P., Koshy, A. A., & Hunter, C. A. (2016). STAT1 Signaling in Astrocytes Is Essential for Control of Infection in the Central Nervous System. mBio, 7(6).

The local production of gamma interferon (IFN-γ) is important to control Toxoplasma gondii in the brain, but the basis for these protective effects is not fully understood. The studies presented here reveal that the ability of IFN-γ to inhibit parasite replication in astrocytes in vitro is dependent on signal transducer and activator of transcription 1 (STAT1) and that mice that specifically lack STAT1 in astrocytes are unable to limit parasite replication in the central nervous system (CNS). This susceptibility is associated with a loss of antimicrobial pathways and increased cyst formation in astrocytes. These results identify a critical role for astrocytes in limiting the replication of an important opportunistic pathogen.

Coombes, J. L., Charsar, B. A., Han, S., Halkias, J., Chan, S. W., Koshy, A. A., Striepen, B., & Robey, E. A. (2013). Motile invaded neutrophils in the small intestine of Toxoplasma gondii-infected mice reveal a potential mechanism for parasite spread. Proceedings of the National Academy of Sciences of the United States of America, 110(21), E1913-22.

Toxoplasma gondii infection occurs through the oral route, but we lack important information about how the parasite interacts with the host immune system in the intestine. We used two-photon laser-scanning microscopy in conjunction with a mouse model of oral T. gondii infection to address this issue. T. gondii established discrete foci of infection in the small intestine, eliciting the recruitment and transepithelial migration of neutrophils and inflammatory monocytes. Neutrophils accounted for a high proportion of actively invaded cells, and we provide evidence for a role for transmigrating neutrophils and other immune cells in the spread of T. gondii infection through the lumen of the intestine. Our data identify neutrophils as motile reservoirs of T. gondii infection and suggest a surprising retrograde pathway for parasite spread in the intestine.

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.