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

Mendez, O. A., & Koshy, A. A. (2017). Toxoplasma gondii: Entry, association, and physiologic influences on the central nervous system. Plos Pathogens.
Christian, D. A., Koshy, A. A., Reuter, M. A., Betts, M. R., Boothroyd, J. C., & Hunter, C. A. (2014). Use of transgenic parasites and host reporters to dissect events that promote interleukin-12 production during toxoplasmosis. Infection and immunity, 82(10), 4056-67.

The intracellular parasite Toxoplasma gondii has multiple strategies to alter host cell function, including the injection of rhoptry proteins into the cytosol of host cells as well as bystander populations, but the consequence of these events is unclear. Here, a reporter system using fluorescent parasite strains that inject Cre recombinase with their rhoptry proteins (Toxoplasma-Cre) was combined with Ai6 Cre reporter mice to identify cells that have been productively infected, that have been rhoptry injected but lack the parasite, or that have phagocytosed T. gondii. The ability to distinguish these host-parasite interactions was then utilized to dissect the events that lead to the production of interleukin-12 p40 (IL-12p40), which is required for resistance to T. gondii. In vivo, the use of invasion-competent or invasion-inhibited (phagocytosed) parasites with IL-12p40 (YET40) reporter mice revealed that dendritic cell (DC) and macrophage populations that phagocytose the parasite or are infected can express IL-12p40 but are not the major source, as larger numbers of uninfected cells secrete this cytokine. Similarly, the use of Toxoplasma-Cre parasite strains indicated that dendritic cells and inflammatory monocytes untouched by the parasite and not cells injected by the parasite are the primary source of IL-12p40. These results imply that a soluble host or parasite factor is responsible for the bulk of IL-12p40 production in vivo, rather than cellular interactions with T. gondii that result in infection, infection and clearance, injection of rhoptry proteins, or phagocytosis of the parasite.

Han, S., Melichar, H. J., Coombes, J. L., Chan, S. W., Koshy, A. A., Boothroyd, J. C., Barton, G. M., & Robey, E. A. (2014). Internalization and TLR-dependent type I interferon production by monocytes in response to Toxoplasma gondii. Immunology and cell biology, 92(10), 872-81.

The classic anti-viral cytokine interferon (IFN)-β can be induced during parasitic infection, but relatively little is know about the cell types and signaling pathways involved. Here we show that inflammatory monocytes (IMs), but not neutrophils, produce IFN-β in response to T. gondii infection. This difference correlated with the mode of parasite entry into host cells, with phagocytic uptake predominating in IMs and active invasion predominating in neutrophils. We also show that expression of IFN-β requires phagocytic uptake of the parasite by IMs, and signaling through Toll-like receptors (TLRs) and MyD88. Finally, we show that IMs are major producers of IFN-β in mesenteric lymph nodes following in vivo oral infection of mice, and mice lacking the receptor for type I IFN-1 show higher parasite loads and reduced survival. Our data reveal a TLR and internalization-dependent pathway in IMs for IFN-β induction to a non-viral pathogen.

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.