The Acute Serum Cytokine Response to Norovirus Infection and Illness Open Access

Newman, Kira Laine S. (2015)

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Importance: Noroviruses (NoV) are a major cause of gastroenteritis worldwide. NoV have a low infectious dose and are environmentally persistent. NoV vaccine development has been limited, in part because human host immune factors that contribute to susceptibility to infection and symptoms are poorly understood.

Objective: This dissertation sought to determine whether immunocompetent adults develop NoV viremia, to describe the human serum cytokine response to experimental human NoV challenge, and to elucidate differences in immune activation as they corresponded to a variety of clinical response to NoV.

Methods: Using individuals from past NoV human challenge studies, we measured the frequency of NoV viremia among infected individuals. Combining two GI.1 NoV challenge studies, we assembled an age-matched population of 52 individuals, half of which had become infected post-challenge and of which had remained uninfected. We measured the concentrations of 16 serum cytokines and chemokines from pre-challenge and days 1-4 post-challenge for all subjects. We used a variety of statistical methods, including multivariable logistic regression and random effects models.

Results: Study 1: We did not detect viremia in any of the 20 subjects or 38 corresponding serum samples. Study 2: NoV infection post-challenge was associated with an elevation of Th1-type cytokines, Th2-type cytokines, and chemokines IL-8 and MCP-1, compared to individuals who remained uninfected post-challenge. Among infected individuals, most serum cytokines peaked on day 2 post-challenge, though IL-10 remained elevated through day 4 post-challenge. Study 3: Symptomatic NoV infection was associated with greater elevation of Th1-type cytokines, Th2-type cytokines, and IL-8, compared to asymptomatic infection. Elevated daily viral RNA titer was associated with increased IFN-γ, IL-6, IL-8, and TNF-α. Symptoms were not significantly associated with elevated viral RNA shedding.

Conclusions: Though NoV infection of healthy adults was not associated with viremia, infected individuals exhibited brief and broad cytokine responses coincident with the development of symptoms. Symptomatic infection was associated with greater immune activation than asymptomatic infection, though it was not associated with greater viral burden. This suggests that NoV elicits a broad anti-viral response and that symptoms may be partially due to immune-mediated damage. Further work should investigate the pathogenesis of NoV symptoms due to their epidemiologic importance.

Table of Contents

Chapter 1 : Introduction, Aims, and Hypotheses..... 1

Chapter 2: Literature Review: Norovirus immunology: Of Mice and Mechanisms..... 4

Chapter 3: Study 1: Immunocompetent Adults from Human Norovirus Challenge Studies do not Exhibit Norovirus Viremia..... 35

Chapter 4: Study 2: Human Norovirus Infection and the Acute Serum Cytokine Response...... 38

Chapter 5: Study 3: Norovirus in Symptomatic and Asymptomatic Individuals: Comparison of the Acute Cytokine Response..... 59

Chapter 6: Research Summary, Strengths, Limitations, Public Health Implications, Future Directions..... 85

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