Indiana University-Purdue University Indianapolis (IUPUI) / Airway inflammation is the most common and important component of respiratory diseases, such as influenza and asthma. Severe influenza A virus infection typically triggers detrimental lung inflammation with massive immune cell infiltration and hyper-production of cytokines and chemokines. We identified a novel function for nuclear matrix protein 4 (NMP4), a zinc-finger-containing transcription factor known for its function in bone formation and spermatogenesis, in regulating antiviral immune responses and immunopathology. Nmp4-deficient mice are protected from influenza induced immunopathology and body weight loss. While having no effects on viral clearance or CD8/CD4 T cell or humoral immune responses, Nmp4 deficiency in either lung structural cells or hematopoietic cells significantly reduces the recruitment of neutrophils and monocytes to the lungs. Furthermore, NMP4 binds to the promoters and/or conserved non-coding sequences of the chemokine genes Ccl2 and Cxcl1 and upregulates their expression in mouse lung epithelial cells and macrophages. These chemokines attract monocytes and neutrophils to the airway, resulting in exaggerated airway inflammation and collateral lung damage. Another transcription factor forkhead box P3 (FOXP3) is critical for the development of regulatory T cells (Tregs) that function to control immune responses. Unlike human FOXP3 gene that encodes two major isoforms, a full length (FOXP3-FL) isoform and a short isoform lacking the exon 2 region (FOXP3-ΔE2), mouse Foxp3 gene only encodes Foxp3-FL isoform. We generate Foxp3-ΔE2 mice to study its function and find that Tregs expressing the Foxp3-ΔE2 isoform have intrinsic defects, thus allowing intensified adaptive immune responses without changes in innate immunity against influenza infection. In a model of chronic asthma, mice expressing only the Foxp3-ΔE2 isoform have significantly increased allergic airway inflammation and elevated production of allergen-specific IgE compared with mice expression the Foxp3-FL isoform. Mechanistically, Tregs expressing the Foxp3-ΔE2 isoform are less stable and prone to trans-differentiation into effector Th9-like cells, which are closely associated with the pathogenesis of asthma. These data suggest that the two Foxp3 isoforms have different functions in regulating airway immune responses. Overall, we have defined the important roles of both transcription factors NMP4 and FOXP3 in regulating airway inflammation. / 2022-08-17

Influenza is a seasonal acute respiratory infection, causing millions of illnesses worldwide on a yearly basis. A common subtype, the influenza A virus (IAV), is a single stranded RNA virus, that similarly to other subtypes, targets epithelial cells. The best way to protect against the virus is through vaccination. Vaccine induced protection is mediated through the generation of adaptive CD4 and CD8 T cells, as well as antibody producing B Cells. Although generally thought of as helper cells, previous research has highlighted additional roles of memory CD4 T cells in mediating protection against IAV beyond their helper function. More specifically they have been shown to enhance innate inflammatory responses and facilitate the recruitment of innate cell populations; including a recently discovered population of Innate Lymphoid Cells (ILC). Previous research has shown ILCs to have a key role in tissue repair and limiting tissue damage following infection. Whether memory cell response, during protective recall, modulates ILC repair function is currently not well understood. To better understand the possible regulation of ILCs by memory cells, we utilized a molecular technique called reverse transcription polymerase chain reaction (RT-qPCR), to assess select innate lymphoid cell associated protein expression following IAV challenge and rechallenge. We hypothesize, that memory cells drive differential expression of ILC associated repair proteins to assist in a faster and more efficient mobilization of repair processes following pathogenic invasion. Our goal is to highlight and better understand the regulatory and inflammatory responses memory cells provide following viral infection, as these may lead to key steps in the development of long lasting and efficacious vaccines.

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Excerpt: The recent study by Montejo, Richesson, Padilla, Zychowicz, and Hambley (2017) concluded that a multipronged occupational health education program to promote influenza vaccinations led to higher immunization rates among employees. However, this conclusion was not well supported by study data for two reasons: year-to-year differences in the experimental group and the nature of comparisons with the control group.

This thesis is a biocultural analysis of the 1918 influenza pandemic among soldiers in the Polish army and the Canadian Expeditionary Force (CEF) training in Canada. Using an ethnographic epidemiological method and a variety of archival sources, I explore the 1918 influenza pandemic and focus on the first two pandemic waves which occurred between 1 January and 31 December 1918. This research examines the impact of influenza at the Polish army camp at Niagara-on-the-Lake, on soldiers treated in military hospitals across Ontario, and among recruits on troopships bound for Europe. The primary questions behind this thesis are: in what ways did the war effort intersect with pandemic influenza to affect soldiers in the Polish army camp at Niagara-on-the-Lake, across Ontario, and on troopships bound for Europe? What patterns of morbidity and mortality characterize the first two waves of the pandemic in Ontario’s military hospitals? Were all soldiers equally vulnerable to infection and death from influenza? These questions are addressed in this ‘sandwich thesis’ in three papers which are either published or have been submitted for publication. Pandemic influenza and the war effort in Canada were intimately linked. At the Polish army camp, crowding was prevalent in all aspects of the soldiers’ lives and facilitated the spread of airborne infectious diseases, including influenza. Soldiers continued to be sent to Canada from infected cities in the U.S. throughout the fall wave of the pandemic. Similar events played out on troopships bound for Europe in the summer of 1918 where epidemics of influenza occurred on board, in spite of regulations established in the summer of 1918 to prevent troopships from transporting soldiers sick with influenza. These findings support Humphries’s (2005, 2012) assertion that the war effort took precedence over the health of individual soldiers and the surrounding community. On the other hand, military authorities put the Polish army camp under quarantine in the fall of 1918 and great efforts were made to ensure that sick soldiers were cared for during the epidemic. This close examination of the epidemic in a particular location suggests that military management of the influenza pandemic was complicated and was mediated by a variety of local factors. Previous experience with the influenza virus, and the overarching social perceptions of the disease, also tempered the way in which military authorities managed the pandemic. I compare the way in which military doctors treated CEF soldiers hospitalized with influenza to those hospitalized with venereal disease. I argue that whereas influenza was understood to be a ‘normal’ or ‘everyday’ infection that rarely killed young people in the prime of life (being most deadly to the very young and old), other infectious diseases, such as venereal diseases, were treated with lengthy stays in hospital in spite of the need for soldiers overseas. This highlights the way the social perception of disease affected the ways in which the military handled sick soldiers. This research also confirms the presence of the first wave of influenza among soldiers of the CEF in the spring and summer of 1918. The Admission and Discharge (A&D) records for military hospitals confirm that the first wave of pandemic influenza circulated among soldiers training in Ontario’s military camps between March and May of 1918. The second wave occurred between September and December that year. Mortality during the second wave was more severe, with a case fatality rate of 4.7% among hospitalized soldiers, more than double the rate of 2.3% from March to May. However, not all soldiers were equally vulnerable to the 1918 influenza pandemic. Morbidity and mortality were concentrated in the military district headquarters, and during the second wave, new recruits were more vulnerable to both infection and death than seasoned soldiers. I hypothesize that this is the result of cross-protection between successive waves of the pandemic, whereby seasoned soldiers were less vulnerable during the fall wave by virtue of exposure to the first wave of the pandemic in the military. Since new recruits were most likely conscripts, this is another way in which the war effort in Canada was linked to soldier morbidity and mortality. / Thesis / Doctor of Philosophy (PhD)

A group of Influenza viruses, RNA containing viruses of the Orthomyxoviridae family, consists of Influenza virus types A-D and has been known to cause the Flu, a respiratory illness associated with numerous detrimental symptoms that can lead to death. Influenza A virus (IAV) is constantly changing and is capable of causing pandemics. Currently used diagnostic methods include virus culturing, immunoassays including rapid influenza detection tests (RIDTs), and molecular assays including those based on RT-PCR. Most of the methods can be only performed in the certified diagnostic laboratories equipped with sophisticated instrumentation and/or special biosafety facilities. The results using these methods are not available on a timely basis. RIDTs provide response within 15 minutes but are unable to differentiate between the IAV subtypes. New diagnostic technique, which allows reliable detection of the influenza virus infection and virus genotyping at point-of-care setting, are needed to prevent the spread of the virus and the occurrence of a pandemic. In this project, we propose to use split G-quadruplex (G4) peroxidase probes targeting a fragment of the IAV genome amplified using an isothermal RNA amplification reaction for the detection of IAV infection and virus genotyping. The probes selectively report the virus RNA target with a color change, which can be read by the naked eye. They are capable of differentiating the targets containing as little as a single-nucleotide variation in their sequences. This study aims to optimize the probes, test their selectivity, and calculate the detection limit.

Sialic acids (Sias) are receptors for influenza A viruses (IAVs). The influence of individual sialyltransferases on the Sias expressed is not understood. Also, sensitive methods to distinguish Sias on the cells are lacking. Our goals were to establish a method to detect Sias on the cell and to evaluate the importance of CMP-sialic acid transporter (SLC35A1) and ST6 beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1) for IAV infection. Aproximity ligation assay was established to detect and quantify Sias.

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