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<p> Flaviviruses are a diverse group of emerging arboviruses capable of infecting an extraordinarily broad range of vertebrate and invertebrate hosts. Nearly half of the viruses in this rapidly expanding genus have been reported to be pathogenic for humans, as well as other vertebrates. The spectrum of human disease includes asymptomatic and febrile illnesses, rash, arthralgia, encephalitis and hemorrhagic fever. The recent outbreak of Zika virus (ZIKV) has uncovered pathology in the form of microcephaly and Guillain-Barr&eacute; syndrome, cementing the importance of flaviviruses as emerging human pathogens. All vector-borne flaviviruses studied thus far have to overcome type I interferon (IFN) antiviral responses in order to replicate and cause disease in vertebrates. The non-structural protein NS5 is a potent and specific antagonist of IFN signaling for human pathogenic flaviviruses such as dengue virus (DENV), yellow fever virus (YFV), West Nile virus (WNV), and tick-borne encephalitis viruses (TBEVs). Intriguingly, each of these viruses exhibits different mechanisms of IFN antagonism, highlighting the complicated evolutionary nature of flaviviruses. This thesis work presents novel insights into the NS5-mediated antagonism of IFN signaling for several underexamined flaviviruses. Notably, all NS5 proteins examined were able to inhibit IFN-induced gene expression in a mammalian system, indicating a functional conservation of IFN antagonism for flavivirus NS5 proteins. However, mechanistically NS5 function was diverse. Of great interest, ZIKV NS5 bound to the human, but not mouse, IFN-regulated transcriptional activator STAT2 and targeted it for proteasomal degradation. This phenomenon may explain the requirement for IFN deficiency in order to observe ZIKV pathogenesis in mice. Furthermore, the mechanism of ZIKV NS5 resembles that of DENV NS5, but not that of its closer relative Spondweni virus (SPOV). However, unlike DENV NS5, ZIKV NS5 did not require the E3 ubiquitin ligase UBR4 to induce STAT2 degradation. Consequently, flavivirus NS5 proteins exhibit a remarkable functional convergence in IFN antagonism, albeit by virus-specific mechanisms. The potent antagonism of human IFN responses by neglected flaviviruses such as SPOV and Usutu virus (USUV), coupled with similar ecologies to that of known human flavivirus pathogens, suggests their potential for broad emergence into the human population.</p><p>

<p> Bacterial strains from the <i>Mycobacterium tuberculosis</i> complex (MTBC) are functionally diverse and vary in both geographic distribution and potential to cause tuberculosis (TB) disease. <i>Mycobacterium africanum </i>&mdash;a lineage of the MTBC&mdash;is restricted to West Africa and causes slower progression to active tuberculosis (TB) after initial infection than other MTBC lineages. We hypothesized that this may be partly due to how bacterial strains from these lineages interact with the host immune response. Specifically, we predicted that <i>M. africanum</i> would induce less of the innate cytokine type I interferon because type I interferon has been shown to contribute to TB disease. Our studies focused on (1) whether diverse MTBC strains induce distinct levels of type I interferon in host cells, (2) the mechanism underlying differential type I interferon induction by diverse MTBC strains, and (3) the consequences of the type I interferon response during infection with diverse MTBC strains. We found that <i>M. africanum</i> induced less mitochondrial stress, less release of mitochondrial DNA and less cGAS- and STING-dependent type I interferon in macrophages than other <i> M. tuberculosis</i> strains. Furthermore, we found that <i> M. africanum</i> contained a polymorphism in the Esx-1 gene locus and was unable to secrete the virulence factor EspB through the Esx-1 secretion system, which may contribute to the reduced type I interferon induction by this strain. Finally, we found that type I interferon signaling was pathogenic during chronic <i>M. africanum</i> infection in mice, and thus that the ability to induce pathogenic levels of type I interferon is likely widespread in MTBC strains. Our data suggest that reduced mitochondrial stress and reduced type I interferon induction may contribute to the attenuation of <i> M. africanum</i>. Moreover, our data show that treatments that limit type I interferon induction could be effective in treating diverse mycobacterial infections. Therefore our studies provide insight into a mycobacterial virulence mechanism and highlight the importance of studying diverse clinical isolates of <i>M. tuberculosis</i>.</p><p>

<p> <i>Clostridium difficile</i> is an anaerobic, gram-positive bacterium that is responsible for the majority of hospital-associated gastrointestinal infections. It has been recognized as a pathogen since the 1970s but more recently has become an urgent threat to public health. <i>C. difficile </i> produces two powerful toxins that disrupt the integrity of the colonic epithelium and induce a strong inflammatory response. Susceptible individuals experience symptoms that range from mild, self-limiting diarrhea to fulminant pseudomembranous colitis and even death. However, most healthy individuals are protected from <i>C. difficile</i> infections so long as they are able to maintain a diverse population of commensal bacteria in their gut. Disruptions to these commensals, often from antibiotic therapy, provide the niche <i>C. difficile</i> spores need to germinate, produce toxins, and cause disease. Current first-line therapy for infections is additional antibiotics that lead to a high risk of relapse. In fact, we found that short course antibiotic therapy leaves mice susceptible to additional infections in the days and weeks that the commensal microbiota spends recovering to pre-antibiotic levels. Beyond requiring disruptions to the microbiota before colonization, <i>C. difficile</i> is composed of hundreds of different strain subtypes. The variability in disease severity induced by each of these different subtypes has been hampered by diverse sources of human patient data and has confused the literature for years. We found that the mouse model could be used successfully to quantify the differences in disease burden of phylogenetically diverse <i>C. difficile</i> clinical isolates. Our results demonstrate that differences in observed virulence have less to do with the amount of toxin each isolate produces and more to do with its tolerance to secondary bile acids like lithocholic acid. In addition, whole genome sequencing allows us to identify groups of genes that are associated with highly lethal strains. This work emphasizes the need to evaluate the impact of antibiotic therapy and infecting strain when assessing and treating <i>C. difficile</i> infections.</p><p>

Asthma is the most common chronic respiratory disease affecting young children and adults all over the world. An estimated 34.1 million Americans have reported asthma in their lifetime and the disease costs ∼US $56 billion dollars to treat each year. Current treatment is based on a paradigm of asthma as a non-infectious atopic condition whose root cause is inflammation. Chronically administered anti-inflammatory medications, primarily inhaled corticosteroids (ICS), ameliorate asthma symptoms in many patients. However, up to 50% of asthmatics, characterized by neutrophil infiltration, IL-17 secretion and increased risk of fatality are refractory to ICS treatment. Chlamydia pneumoniae , a ubiquitous, obligate intracellular pathogen with an innate propensity to persist and cause chronic infections, along with Mycoplasma pneumoniae have been implicated in the development of chronic, refractory asthma. C. pneumoniae infections are common in infants and young children, often coinciding with the development of early onset asthma in the population. These facts lead the Webley lab to evaluate the carriage of Chlamydia in pediatric respiratory disease patients and the work confirmed that respiratory infections caused by Chlamydia is a significant risk factor in asthma development and live Chlamydia was isolated from the lungs of children with chronic asthma. However, the exact mechanism underlying chlamydial involvement in the disease remained unknown and we believed that a better understanding could shed important light on expanded treatment options and mechanisms of this infectious asthma phenotype. The work presented here provides new insight into how (1) early life chlamydial infection can lead to asthma initiation and exacerbation (2) respiratory chlamydial infection induces cellular and chemical immune responses that support asthmatic inflammation (3) other respiratory pathogens (eg. Mycoplasma) can drive similar immunological responses resulting in significant lung pathology.

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