Anita A Koshy
- Assistant Professor, Neurology
- Assistant Professor, Immunobiology
- Assistant Professor, Evelyn F Mcknight Brain Institute
- Assistant Professor, BIO5 Institute
- Assistant Professor, Neuroscience - GIDP
- M.D. Medical Doctor
- Duke University, Durham, North Carolina, United States
- B.S. Biological Sciences
- Stanford University, Stanford, California, United States
- Assistant Professor, University of Arizona; Department of Immunobiology (2012 - Ongoing)
- Neuroscience Affiliate, Evelyn F. McKnight Brain Institute (2012 - Ongoing)
- Assistant Professor, University of Arizona; Department of Neurology (2012 - Ongoing)
- Assistant Research Scientist, University of Arizona; Bio5 Institute Member, GIDP (2012 - Ongoing)
- Instructor, Stanford University, Stanford, California (2010 - 2012)
- Postdoctoral Fellow, Infectious Disease, Stanford University (2006 - 2010)
- Engel Society
- Duke University Medical School, Fall 1997
- Howard Hughes Medical Institute Medical Student Fellowship
- Duke University Medical School, Fall 1997
- Outstanding Faculty Educator Award
- Department of Neurology, University of Arizona, Spring 2013
- Chief Fellow
- Division of Infectious Disease, Stanford University, Spring 2010
- AOA membership
- UCSF AOA chapter, Spring 2003
Licensure & Certification
- Diplomate, Neurology Boards, American Board of Psychiatry and Neurology, Diplomate, Neurology Boards, American Board of Psychiatry and Neurology (2006)
- Arizona Medical License, Arizona Medical License (2012)
- California Medical License (Retired status currently), California State Medical Board (2001)
No activities entered.
DissertationIMB 920 (Fall 2016)
Lab Presentations & DiscussionMCB 696A (Fall 2016)
Neuro+Rehab Med ClerkshpNEUR 813C (Fall 2016)
ResearchIMB 900 (Fall 2016)
ResearchMCB 900 (Fall 2016)
Scientific GrantsmanshipIMB 521 (Fall 2016)
DissertationIMB 920 (Spring 2016)
Honors ThesisNSCS 498H (Spring 2016)
Independent StudyBME 299 (Spring 2016)
Independent StudyMIC 399 (Spring 2016)
Introduction to ResearchMCB 795A (Spring 2016)
Neuro+Rehab Med ClerkshpNEUR 813C (Spring 2016)
ResearchIMB 900 (Spring 2016)
ResearchNRSC 900 (Spring 2016)
DissertationIMB 920 (Fall 2015)
Honors Independent StudyNSCS 499H (Fall 2015)
Honors ThesisNSCS 498H (Fall 2015)
Independent StudyBME 299 (Fall 2015)
Independent StudyMIC 399 (Fall 2015)
Introduction to ResearchMCB 795A (Fall 2015)
ResearchIMB 900 (Fall 2015)
ResearchNRSC 900 (Fall 2015)
DissertationIMB 920 (Spring 2015)
Independent StudyMIC 399 (Spring 2015)
ResearchIMB 900 (Spring 2015)
Independent StudyNSCS 499 (Fall 2014)
Introduction to ResearchMCB 795A (Fall 2014)
Methods In NeuroscienceNRSC 700 (Fall 2014)
ResearchIMB 900 (Fall 2014)
ResearchIMB 900 (Spring 2014)
Introduction to ResearchMCB 795A (Fall 2013)
ResearchIMB 900 (Fall 2013)
- Anderson, N. C., Koshy, A. A., & Roos, K. (2015). Infections of the Nervous System: Bacterial, Fungal, and Parasitic Diseases of the Nervous System. In Bradley’s Neurology in Clinical Practice. Elsevier.
- Koshy, A. A., Blackburn, B. G., & Singh, U. (2014). Free-Living Amebae. In Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases(pp 3059 – 3069). Elsevier.
- Cabral, C. M., Tuladhar, S., Dietrich, H. K., Nguyen, E., MacDonald, W. R., Trivedi, T., Devineni, A., & Koshy, A. A. (2016). Neurons are the primary target cell for the brain-tropic intracellular parasite Toxoplasma gondii.. PLoS Pathogens.
- 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).More infoThe 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.
- 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.More infoIntracellular 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.
- Cekanaviciute, E., Dietrich, H. K., Axtell, R. C., Williams, A. M., Egusquiza, R., Wai, K. M., Koshy, A. A., & Buckwalter, M. S. (2014). Astrocytic TGF-β signaling limits inflammation and reduces neuronal damage during central nervous system Toxoplasma infection. Journal of immunology (Baltimore, Md. : 1950), 193(1), 139-49.More infoThe balance between controlling infection and limiting inflammation is particularly precarious in the brain because of its unique vulnerability to the toxic effects of inflammation. Astrocytes have been implicated as key regulators of neuroinflammation in CNS infections, including infection with Toxoplasma gondii, a protozoan parasite that naturally establishes a chronic CNS infection in mice and humans. In CNS toxoplasmosis, astrocytes are critical to controlling parasite growth. They secrete proinflammatory cytokines and physically encircle parasites. However, the molecular mechanisms used by astrocytes to limit neuroinflammation during toxoplasmic encephalitis have not yet been identified. TGF-β signaling in astrocytes is of particular interest because TGF-β is universally upregulated during CNS infection and serves master regulatory and primarily anti-inflammatory functions. We report in this study that TGF-β signaling is activated in astrocytes during toxoplasmic encephalitis and that inhibition of astrocytic TGF-β signaling increases immune cell infiltration, uncouples proinflammatory cytokine and chemokine production from CNS parasite burden, and increases neuronal injury. Remarkably, we show that the effects of inhibiting astrocytic TGF-β signaling are independent of parasite burden and the ability of GFAP(+) astrocytes to physically encircle parasites.
- 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.More infoThe 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.
- 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.More infoDuring 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.
- 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.More infoThe 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.
- Koshy, A. A., & Cabral, C. M. (2014). 3-D imaging and analysis of neurons infected in vivo with Toxoplasma gondii. Journal of visualized experiments : JoVE.More infoToxoplasma gondii is an obligate, intracellular parasite with a broad host range, including humans and rodents. In both humans and rodents, Toxoplasma establishes a lifelong persistent infection in the brain. While this brain infection is asymptomatic in most immunocompetent people, in the developing fetus or immunocompromised individuals such as acquired immune deficiency syndrome (AIDS) patients, this predilection for and persistence in the brain can lead to devastating neurologic disease. Thus, it is clear that the brain-Toxoplasma interaction is critical to the symptomatic disease produced by Toxoplasma, yet we have little understanding of the cellular or molecular interaction between cells of the central nervous system (CNS) and the parasite. In the mouse model of CNS toxoplasmosis it has been known for over 30 years that neurons are the cells in which the parasite persists, but little information is available about which part of the neuron is generally infected (soma, dendrite, axon) and if this cellular relationship changes between strains. In part, this lack is secondary to the difficulty of imaging and visualizing whole infected neurons from an animal. Such images would typically require serial sectioning and stitching of tissue imaged by electron microscopy or confocal microscopy after immunostaining. By combining several techniques, the method described here enables the use of thick sections (160 µm) to identify and image whole cells that contain cysts, allowing three-dimensional visualization and analysis of individual, chronically infected neurons without the need for immunostaining, electron microscopy, or serial sectioning and stitching. Using this technique, we can begin to understand the cellular relationship between the parasite and the infected neuron.
- 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.More infoThe 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.
- 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.More infoToxoplasma 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.
- 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.More infoToxoplasma 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.
- Koshy, A. A., Dietrich, H. K., Christian, D. A., Melehani, J. H., Shastri, A. J., Hunter, C. A., & Boothroyd, J. C. (2012). Toxoplasma co-opts host cells it does not invade. PLoS pathogens, 8(7), e1002825.More infoLike many intracellular microbes, the protozoan parasite Toxoplasma gondii injects effector proteins into cells it invades. One group of these effector proteins is injected from specialized organelles called the rhoptries, which have previously been described to discharge their contents only during successful invasion of a host cell. In this report, using several reporter systems, we show that in vitro the parasite injects rhoptry proteins into cells it does not productively invade and that the rhoptry effector proteins can manipulate the uninfected cell in a similar manner to infected cells. In addition, as one of the reporter systems uses a rhoptry:Cre recombinase fusion protein, we show that in Cre-reporter mice infected with an encysting Toxoplasma-Cre strain, uninfected-injected cells, which could be derived from aborted invasion or cell-intrinsic killing after invasion, are actually more common than infected-injected cells, especially in the mouse brain, where Toxoplasma encysts and persists. This phenomenon has important implications for how Toxoplasma globally affects its host and opens a new avenue for how other intracellular microbes may similarly manipulate the host environment at large.
- Koshy, A. A. (2016, Apr 25). Interrogating the CNS-Toxoplasma interaction in vivo. Seminar Series. Pittsburgh, PA: Department of Biological Sciences, University of Pittsburgh.
- Koshy, A. A. (2016, Mar 28). Interrogating the CNS-Toxoplasma interaction in vivo. Seminar Series. Hanover, NH: Department of Microbiology and Molecular Pathogenesis Program, Dartmouth University.
- Koshy, A. A. (2016, Mar 8). Using the Cre/loxP system to understand brain-parasite interactions. Conference. Tucson, Arizona: Neuroscience Datablitz, International Mendel Day, University of Arizona.
- Koshy, A. A. (2016, Oct 13). Toxoplasma gondii & the CNS: Frenemies- the crossroads of microbiology, immunology, & neuroscience. Seminar Series. Tucson, Arizona: Research Seminar Series, Department of Medicine, University of Arizona.
- Koshy, A. A. (2016, Oct 2). Toxoplasma gondii’s preference for neurons: location, location, location. Seminar Series. Philadelphia, PA: School of Veterinary Medicine, University of Pennsylvania.
- Koshy, A. A. (2015, Apr 21). Can a common brain parasite help find novel therapeutic targets for AD?. Seminar Series. Sun City, AZ: Banner Sun Health Research Institute.
- Koshy, A. A. (2015, Jul 24). Toxoplasma gondii & the CNS: Frenemies?. Seminar Series. Tucson, Arizona: Department of Neurology, University of Arizona.
- Koshy, A. A. (2015, Jun 12). Toxoplasma gondii & the CNS: Frenemies?. Seminar Series. Stanford, CA: Department of Neurology, Stanford University.
- Koshy, A. A. (2015, Mar 25). Using Toxoplasma gondii to understand brain immune capabilities. Seminar Series. Dallas, Texas: Department of Molecular Biology & Biochemistry,UC Irvine.
- Koshy, A. A. (2015, Sept 9). Redefining the CNS-Toxoplasma interaction. Seminar Series. Washington, DC: Department of Microbiology, Immunology & Tropical Medicine, George Washington University.
- Koshy, A. A. (2014, Nov 20). Changing the parasitic game: the new in vivo Toxoplasma-Cre model. Seminar. Irvine, CA: Department of Molecular Biology & Biochemistry,UC Irvine.
- Koshy, A. A. (2014, Oct 29). Toxoplasma-Cre: a new understanding of CNS-Toxoplasma interactions. Seminar Series. Tucson, Arizona: Dept of Cellular and Molecular Medicine; Dept of Molecular & Cellular Biology; Dept of Chemistry Biochemistry.