Attenuation of Interferon Responses in the Obese Host and Ramifications for Influenza Virus Evolution

<p>The most insidious pandemic of modern life does not arise from an infectious agent but rather from malnutrition. With its global incidence tripling over the past three decades, obesity is a major public health concern. Obesity’s rising prevalence has also illuminated its impact on communicable diseases. Following the 2009 H1N1 influenza A virus pandemic, obesity was identified as a risk factor for increased disease severity and mortality in infected individuals. Obesity causes a chronic state of meta-inflammation with systemic implications for immunity, including delayed antiviral responses to influenza virus infection, poor recovery, and impaired immunological memory. However, the majority of past work neglected the innate responses, especially the impact on the epithelium. To better understand the innate response to influenza infection, obese animal models and human respiratory epithelial cells were inoculated with influenza viruses to quantify the innate responses. In obese hosts, antiviral effector production, including type I and type III interferons, was consistently blunted across all model systems and linked to a highly oxidative, pro-inflammatory environment. This interferon-deficient state altered the host microenvironment in which influenza replicated, spread, and caused disease. Due to the inherent mutability and segmented nature of influenza virus, this altered microenvironment also had implications for the genetic drift and shift of the viral population. Compared to infection of lean hosts, minor variants rapidly emerged within the viral population in obese hosts which exhibited increased viral replication, enhanced virulence, and antiviral resistance. The delayed action of interferon also permitted greater rates of reassortment. Together, this suggested obesity permitted the emergence of novel, and potentially pathogenic, viral variants. Influenza viruses pose constant seasonal and pandemic threats with high morbidity and mortality suffered by overweight and obese patients. If current trends continue, nearly half of the worldwide population will be obese by 2050. This population will have growing impacts on both non-communicable and communicable diseases and may affect global evolutionary trends of influenza virus.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biomedical Sciences

Year dc:date.available

2020

Author dc:creator

• Honce, Rebekah Reed

Contributors dc:contributor

• Stacey Schultz-Cherry, PhD

• Evolution
• Influenza
• Interferon
• Obesity
• Quasispecies
• Reassortment
• Biochemical Phenomena, Metabolism, and Nutrition
• Diseases
• Medical Cell Biology
• Medical Sciences
• Medicine and Health Sciences
• Public Health
• Virus Diseases

Repository record dc:identifier

https://dc.uthsc.edu/dissertations/538

OAI identifier oai:identifier

oai:dc.uthsc.edu:dissertations-1536