NOV 06, 2019 06:00 AM PST

Understanding the Pathogenesis of Human Influenza Virus: A Systems Virology Approach

Presented At Influenza 2019
Speakers
  • Associate Professor, Laboratory of Molecular Virology, Department of Pediatric Infectious Diseases and Immunology, School of Medicine, Pontificia Universidad Catolica de Chile
    Biography
      Dr. Medina is Associate professor in the Department of Pediatric Infectious Diseases and Immunology at the School of Medicine at Pontificia Universidad Catolica de Chile in Santiago. His laboratory studies the molecular biology and ecology of Influenza virus encompassing three mayor areas of research: i) Translational studies to investigate molecular factors of the virus and the host that contribute to disease severity. This includes studying host-pathogens interactions, immune responses, elucidating pathogenesis factors and determining the role of the microbiome during respiratory IAV infection. ii) Characterization of the antigenic properties of the Hemagglutinin (HA) protein of IAV and its role in pathogenesis. This involves studying how specific changes in glycosylations affect the antigenicity and virulence of the virus, and their role in modulating innate, and humoral immune responses. These studies are aimed at contributing to better define epitopes with broad-spectrum antigenic characteristics, which might be relevant for vaccine development. iii) Investigate the ecology of emerging viruses in Chile and Antarctica. This includes developing improved diagnostic tools, sequencing pipelines and analyses platforms to perform long-term molecular epidemiology for the study of influenza virus in natural reservoirs. The overall aim is to gain a better understanding of the viral genetic pool in nature and the ecological niches that contribute to spill over events that generate outbreaks, epidemics and potentially pandemics. These overarching research themes provide an in depth and integrated approach to elucidate the viral and host molecular factors involved in infection and disease caused by emerging pathogens.

    Abstract:

    Multiple factors can affect and impact infection dynamics and virulence produced by influenza virus (IV) infections. Susceptibility factors and host responses can also have major effects in disease severity. It has become apparent that innate and adaptive immune responses can modulate clinical evolution to infection, which is directly and indirectly modulated by factors such as pre-existing conditions and host and virus genetic background. Thus, a major leap forward lies in understanding and integrating global virus-host interactions. To identify viral and host molecular markers of disease severity and outcome we investigated IV diversity and evolution and host responses to infection. Hence, we evaluated the status of the innate and adaptive immune responses, and established clinical parameters associated with poor outcome. A comprehensive multiscale analysis of clinical metadata and cytokine profiling, revealed that comorbidities such as arterial hypertension, chronic cardiovascular disease and obesity, together with early increased expression of pro-inflammatory cytokines, including of IL-6, 8 and the anti-inflammatory IL-10, were associated with severity. Additionally, we used next generation sequencing and developed bioinformatics tools to investigate viral diversity and to evaluate different IV variants obtained from severe individuals. We identified a number of transitional amino acid changes over time in functional sites. Notably, we found two novel mutations of epidemiological relevance in the viral glycoproteins. The I223M mutation on the Neuraminidase was found to confer resistance to the antiviral oseltamivir, whereas a K180Q residue change in a major antigenic site of the Hemagglutinin was found to contribute to the evasion of preexisting immunity (antibody responses). These changes occurred independently in severe subjects and were detected as mixed populations in sequential samples, indicating a dynamic change in the IV genome over time. Overall, our systematic approach suggests that early aberrant immune responses and increased viral diversity in susceptible individuals can play a crucial role in disease outcome. This translational virology approach allows us to interrogate complex biological systems in depth, to define and dissect the global molecular processes involved in viral infection and disease.
    FUNDING: FONDECYT 1121172, 1161791 and PIA-ACT 1408 from CONICYT, the Chilean Ministry of Economy, Development and Tourism, P09/016-F, the Center for Research in Influenza Pathogenesis (CRIP) HHSN272201400008C and grant U19AI135972 both from NIH-NIAID

    Learning Objectives:
    1. To identify what factors can contribute to disease severity during Influenza virus infection.
    2. To describe novel techniques and methodologies used to study viral-host interactions.

     


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