PhD, University of Cincinnati, 2023, Medicine: Epidemiology (Environmental Health)

Biological sex is a moderator of immune system responses; however, much remains unknown about the dynamics of the relationship between sex and infectious disease burden across different age groups, body systems and pathogens. The sex-specific epidemiology of viral infections common to childhood are particularly underdeveloped. This dissertation utilized data from the CDC-funded, multisite, New Vaccine Surveillance Network (NVSN) to define the associations between sex and disease burden of symptomatic, medically attended Acute Respiratory Infection (ARI) and Acute Gastroenteritis (AGE) in U.S. children. Incident ARI and AGE were enrolled in outpatient clinics, emergency departments and inpatient units. Healthy controls were enrolled in outpatient clinics during well-child visits. Stool and mid-turbinate nasal swabs were collected for pathogen testing. Multivariable binary logistic regression was used to determine the association between sex and all-cause ARI and AGE, pathogen positivity, clinical presentation and outcomes. Linear trend in the proportion of males by severity classification was assessed post-hoc using Cochran-Armitage Trend Test. ARI analyses included 28,155 children <10 years of age (23,807 ARI cases; 4,348 controls). AGE analyses included 27,207 children <18 years of age (17,487 AGE cases; 9,720 controls). All-cause ARI and all-cause AGE cases had 38% (p<0.0001) and 9% (p<0.0001) greater odds to be male, respectively, compared to controls. Adjusted odds ratios (aOR) for male sex associated with Influenza, Respiratory Syncytial Virus, Parainfluenza Virus, Human Metapneumovirus, Human Adenovirus Virus positive ARI (aORs of 1.22, 1.27, 1.38, 1.34, 1.38) were similar to the odds seen for all-cause ARI (aOR=1.38) compared to controls. Similarly, the aOR for male sex associated with Rotavirus positive AGE (aOR=1.08) was similar to all-cause AGE (aOR=1.09) compared to controls. There was a significant, linear association bet (open full item for complete abstract)

Committee: Ardythe Morrow Ph.D. (Committee Chair); Mary Staat M.D. (Committee Member); Susan Pinney Ph.D. (Committee Member); Liang Niu Ph.D. (Committee Member) Subjects: Epidemiology

Doctor of Philosophy in Regulatory Biology, Cleveland State University, 2016, College of Sciences and Health Professions

Pneumonia Virus of Mice (PVM) and Respiratory Syncytial Virus (RSV) are negative sense, single-stranded, enveloped RNA viruses from Pneumovirus genus, Paramyxoviridae family. RSV is the leading cause of respiratory diseases in infants. PVM causes similar respiratory illness in mice. PVM is used as an animal model to study RSV pathogenesis because of its similarity with RSV infection. Viral infection induces type I interferon (IFN) response as an antiviral strategy. PVM and RSV both have two non-structural (NS) proteins that are known to be IFN antagonists. While RSV can target different signaling components of IFN pathway, the mechanism of IFN suppression for PVM was unknown. We have identified that PVM can also target different signaling components of IFN pathway to circumvent the host immune system. Our observations showed that PVM NS proteins facilitate proteasome-mediated degradation of RIG-I, IRF3, STAT2 in IFN pathway by direct interactions with them. Production of several Interferon Stimulated Genes (ISGs) is the distal part of the IFN pathway. We have identified that NS proteins of PVM can also target a few of them such as TRAFD1, IFITM1, ISG20, and IDO for complete suppression of the host immune system. RSV NS proteins play a similar role to suppress IFN pathway by targeting TBK1, RIG-I, IRF3, IRF7, and STAT2. Our study has identified one ISG, OASL, that has antiviral properties against RSV and documented that to counteract this antiviral property of OASL, RSV NS proteins can degrade OASL in a proteasome-dependent way. These above observations help us to delineate the complete suppression mechanism for the whole Pneumovirus genus, both for PVM and RSV by providing the first experimental evidence of signaling components from the IFN pathway targeted by PVM to suppress the IFN response. PVM is a clinically relevant animal model that will help us to find new therapeutic strategies against Pneumovirus infection. RSV study with one of those important ISGs, OA (open full item for complete abstract)

Committee: Sailen Barik Ph.D. (Advisor); Barsanjit Mazumder Ph.D. (Committee Member); Roman V Kondratov Ph.D. (Committee Member); Cornelia Bergmann Ph.D. (Committee Member); Aaron F Severson Ph.D. (Committee Member); Aimin Zhou Ph.D. (Committee Member) Subjects: Biology; Molecular Biology; Virology

MS, University of Cincinnati, 2004, Medicine : Epidemiology (Environmental Health)

This study examined infants' risk for developing upper respiratory symptoms (URS) in relation to their exposure to environmental tobacco smoke (ETS) and mold. Eligible infants (n=633) were identified by birth records and had one parent that was atopic by positive skin prick test (SPT). Exposure information was collected at the time of parent SPT, and the average age of the infants was seven months. Parents were asked to complete monthly diaries related to their infants' URS. Our analysis included two models, one using parental report of mold/mildew and a sub-analysis (n=342) using in-home assessor report of none, low or high mold exposure. When controlling for race, gender and socioeconomic status, multivariate logistic regression showed an increased risk of sinus infection with parental report of mold/mildew (OR 1.91; 95%CI 1.14-3.23) and exposure to >20 cigarettes/day (2.38; 1.26-4.49); in the in-home assessor report, high mold was even more significant (6.7; 2.27-19.79). Ear infection was also associated with assessor report of mold, in both the low (1.77; 1.17-2.67) and high (3.07; 1.32-7.12) categories. Rhinitis was significantly associated with parental report of mold/mildew (1.32; 1.31-1.47) and exposure to >20 cigarettes/day (1.74; 1.14-2.65). Although significant associations were not observed with allergic rhinitis, elevated odds ratios were observed with both parent and assessor report of mold. This analysis suggests that mold is a risk factor of sinus infection, ear infection and rhinitis, while ETS is a risk factor of sinus infections and rhinitis. This analysis suggests that mold exposure and not ETS is associated with ear infections in infants. The sub-analysis findings also may suggest that mold exposure is a stronger risk factor than ETS for sinus infection, while ETS may be more closely associated with rhinitis.

Committee: Dr. Grace LeMasters (Advisor) Subjects: Environmental Sciences

Doctor of Philosophy, The Ohio State University, 2011, Integrated Biomedical Science Graduate Program

Respiratory syncytial virus (RSV) infection of most cultured cell lines causes cell-cell fusion and death. Cell fusion is caused by the fusion (F) glycoprotein and is clearly cytopathic, but other aspects of RSV infection may also contribute to cytopathology. To investigate this possibility, we generated an RSV replicon that lacks all three of its glycoprotein genes and so cannot cause cell-cell fusion or virus spread. This replicon includes a green fluorescent protein gene and an antibiotic resistance gene to enable detection and selection of replicon-containing cells. Adaptive mutations in the RSV replicon were not required for replicon maintenance. Cells containing the replicon could be cloned and passaged many times in the absence of antibiotic selection, with 99% or more of the cells retaining the replicon after each cell division. Transient expression of the F and G (attachment) glycoproteins supported the production of virions that could transfer the replicon into most cell lines tested. Since the RSV replicon is not toxic to these cultured cells and does not affect their rate of cell division, none of the 8 internal viral proteins, the viral RNA transcripts, or the host response to these molecules or their activities are cytopathic. However, the level of replicon genome and gene expression is controlled in some manner, well below that of complete virus and, as such, might avoid cytotoxicity. RSV replicons could be useful for cytoplasmic gene expression in vitro and in vivo, and for screening compounds active against the viral polymerase.

Committee: Mark Peeples PhD (Advisor); Douglas McCarty PhD (Other); Michael Oglesbee PhD (Other); Jianrong Li PhD (Other) Subjects: Virology