Amelia K. Pinto, Ph.D.
Doisy Research Center
INTRODUCTION:Over half the world’s population is now at risk of contracting an arbovirus infection. Arboviruses, including West Nile (WNV), Chikungunya (CHIKV), Zika (ZIKV), and Dengue (DENV) are some of the best examples of this emerging global threat. With the resurgence of arbovirus infections in the last decade, there is a greater urgency to understand the host response to re-emerging pathogens. My laboratory explores how cytokines regulate the balance between virus and host during a viral infection. Utilizing innovative tools and small animal models my laboratory aims to improve our understanding of the immune response to arbovirus, so we can direct the development of new classes of vaccines, anti-virals, and anti-inflammatories to control this emerging global threat.
Animal models of arbovirus infections
Small animal models are important for understanding disease progression and for the early evaluation of vaccines, therapeutics, and anti-virals. For many arbovirus infections there are no small animal models that mimic human disease progression. In my postdoctoral work I used various mouse strains to replicate the human infections caused by WNV and DENV in mice. My laboratory is continuing to use small animal models to understand WNV and DENV disease progression, and evaluate novel therapeutics, vaccines, and antivirals against flaviviruses. We are also working to develop new animal models for the study diseases caused by other re-emerging arboviruses including CHIKV and ZIKV.
Cytokine regulation of immune responses
To effectively treat viral infections we must first understand how the protective immune response develops. Cytokines are critical during all stages of the immune response; alterations in cytokine signaling can lead to permanent immune dysfunction and viral pathogenesis. By blocking type I interferon (IFN) receptor signaling four days after infection I have demonstrated a unique role for type I IFNs in regulating the adaptive immune response to WNV. This observation forms the basis for the approaches we currently use to identify the specific mechanism(s) by which cytokines contribute to immune function, viral control, and viral pathogenesis. We are interested in exploring the role of cytokines, including type I IFNs, TNFα, and IL-6, in the development and maintenance of a protective immune response to arbovirus infections. The goal of this research is to understand the contribution of cytokines during the course of infection so that we may design cytokine-targeted therapeutics that will enhance the protective capacity of the cytokine-driven immune response.
Mouse models of viral sepsis
A common feature of viral infections is the ability of a virus to manipulate the host cytokine response. The cytokines that make up the family of type I IFNs are often targeted by viruses; by targeting the type I IFNs early during infection a virus is able to blunt the host immune response creating a cell intrinsic environment conducive to viral replication and spread. However, the consequences of this viral manipulation of the type I IFN signaling pathway for the host are only now being appreciated. I have demonstrated that the selective loss of type I IFN signaling on myeloid cells early in WNV infection leads to an increase in susceptibility of mice to infection. This enhanced susceptibility to WNV infection predisposes the mice to the development of viral sepsis and subsequent immune-mediated pathology. My laboratory is working with this model to explore the contribution of the cytokine response during viral sepsis, with the goal of understanding how to effectively target the acute inflammation associated with emerging pathogens.
Pinto AK*, Brien JD*, Chia-Ying KL, Johnson S, Chiang C, Hiscott J, Sarathy VV, Barett AD, Shresta S, Diamond MS. 2015. Defining New Therapeutics Using a More Immunocompetent Mouse Model of Antibody-Enhanced Dengue Virus Infection. MBio. 2015 September 15;6(5) (*co-first author)
Pinto AK, Williams G, Szretter K, White J, Proenca-Modena J, Liu G, Olejnik J, Brien JD, Ebihara H, Mühlberger E, Amarasinghe G, Diamond MS, and Boon A, 2015. Human and murine IFIT1 do not restrict infection of negative sense RNA viruses of the orthomyxoviridae, bunyaviridae, and filoviridae families. Journal of Virology. 2015 September 15;89(18):9465-76
Pinto AK, Ramos HJ, Wu X, Aggarwal S, Shrestha B, Gorman M, Kim KY, Suthar MS, Atkinson JP, Gale M, and Diamond MS. A loss of IFN signaling in myeloid cells results in a MAVS-dependent sepsis after viral infection. PLoS Pathogens 2014 Apr 17:10(4).
Kim, S, Pinto, AK*, Myers, NB, Weidanz, JA, Hildebrand, WH, Diamond, MS, and Hansen, TH, Use of a novel T cell receptor mimic to define cells that cross-present an immunodominant West Nile virus epitope in mice. European Journal of Immunology 2014 Jul;44(7):1936-46. (*co-first author)
Pinto AK, Richner J, Poore E, Patil P, Amanna I, Slifka M, and Diamond MS A hydrogen peroxide-inactivated virus vaccine elicits humoral and cellular immunity and protects against lethal West Nile virus infection in aged mice. Journal of Virology 2013 February; 87(4):1926-36.
Pinto AK, Daffis S, Brien JD, Gainey MD, Yokoyama WM, Sheehan KCF, Murphy KM, Schreiber RD, Diamond MS. A temporal role of type I interferon signaling in CD8+ T cell maturation during acute West Nile virus infection. PLoS Pathogens, 2011 December; 7(12).
Hensley SE, Pinto AK, Hickman HD, Kastenmayer RJ, Bennink JR, Virgin HW, Yewdell JW. Murine norovirus infection has no significant effect on adaptive immunity to vaccinia virus or influenza A virus. Journal of Virology 2009 July: 83(14):7357-60.