Multisystem Inflammatory Syndrome in Children (MISC-C) is a systemic inflammatory disorder associated with novel COVID-19. Children diagnosed with COVID-19 typically experience mild viral symptoms, however, in rare instances more severe disease will develop. Current epidemiology states <1% of children diagnosed with COVID will develop complications of MIS-C. Symptoms of MIS-C are varying, but in general include abnormal vital signs (tachycardia, tachypnea), Kawasaki-like symptoms, respiratory distress, cardiac involvement, and shock like symptoms. Abdominal pain, features of acute kidney injury, coagulopathy, and neurologic dysfunction have also been reported. It is currently recommended for children with any combination of the above symptoms to be hospitalized and treated for MIS-C, given the potential for severe consequences. This case presentation aims to highlight the neurologic symptoms that can occur with the diagnosis of MIS-C. Current estimations predict 20% of children with MIS-C will develop more severe central nervous system symptoms. Our patient presented with neuropsychiatric symptoms, which has little documentation in current medical literature. Initial presentation, differential diagnosis, hospital workup, and treatment of disease will be discussed. Our case is a previously healthy 8yo male with past medical history of ADHD. He presented to the Emergency room with chief complaints of fever, confusion, and visual and motor hallucinations 3 weeks after receiving a positive COVID test. Prior to the date of presentation, the patient’s only symptom of COVID 19 was rhinorrhea. ED workup revealed tachycardia, pallor and erythema/swelling of fingers, facial rash, abdominal pain, and leukocytosis. Initial differential diagnosis included sepsis secondary to urinary tract infection versus encephalopathic MIS-C. Labs at presentation showed CRP and D-dimer within normal limits, and treatment for UTI was initiated. For the first few days of hospital stay, patients condition was unchanged and inflammatory marker levels rose. The patient also showed sustained tachycardia, fever, widened pulse pressures, nocturnal incontinence, and one episode of bigeminy. Treatment targeting MIS-C with, IV ceftriaxone, vancomycin, IVIG, methylprednisone, and aspirin was begun. Inflammatory markers subsequently began to downtrend and patients condition began to improve. This case study highlights central nervous system features as a potential primary presenting symptom of MIS-C. Currently, there is little literature on COVID 19 associated psychosis. Further research is needed to assess the underlying potential inflammatory mechanisms responsible for our patient’s visual and motor hallucinations resulting from MIS-C.

Interventions for influenza virus infections are essential to minimize the worldwide annual morbidity, mortality, and economic loss caused by this highly contagious respiratory pathogen. Establishment of universal, long-lasting protection against epidemic and pandemic strains of the virus can potentially eradicate the necessity of annual reformulation and readministration of low-efficacious seasonal vaccines, increasing pandemic preparedness. The protective potential of Type 1 T helper (TH1)-polarized memory CD4+ T cells against Influenza A virus (IAV) infection and generation of secondary memory populations following viral clearance are well-characterized. To assess the potential of CD4+ T memory cells as a candidate for adoptive immunotherapy, here we validated and optimized cryopreserved IAV-specific memory CD4+ T cell-mediated protection against infection and evaluated their potential for subsequent memory formation. Donor-derived in vitro-generated memory CD4+ T cells were transferred into IAV-infected naïve mice following cryopreservation of these cells for 6-12 months and overnight activation with gamma-chain cytokines, interleukin (IL)-7 and IL-7+IL-2. Results showed that cytokine-cultured cryopreserved memory CD4+ T cells, compared to their non-cultured counterparts, controlled viral titer in the lung at the peak infection phase, decreased morbidity, expedited recovery, and formed increased secondary memory cells in the lung, the primary site of infection, including lung tissue-resident memory (TRM) CD4+ T cells. Phenotypic and functional analysis confirmed that donor-derived secondary memory CD4+ T cells retain a TH1-phenotype and produce cytokines associated with protection against IAV. These observations support that the protectiveness and memory-forming potential of host- and/or donor-derived memory CD4? T cells can be preserved and harnessed for future use. This T-cell based adoptive immunotherapy addresses some of the current challenges of available preventative and therapeutic options, such as low vaccine efficacy, availability of only early treatment drugs, lack of immunity against pandemic strains and effective memory cell generation.

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The consistent seasonal signal that characterizes annual influenza epidemics has long suggested a causal link between the physical environment and the transmission of influenza. Yet, despite considerable interest--dating as far back as Hippocrates--the environmental factors that facilitate the seasonal spread of influenza remain unclear. Historically, significant study of influenza seasonality was based almost exclusively on temperate regions,.due to a lack of high-quality influenza data in low-latitudes. In turn, although numerous hypotheses have been forwarded to explain the seasonal nature of influenza in temperate regions, few acknowledge the seasonal patterns in lower latitudes.This dissertation examines the scientific evidence for the seasonal mechanisms that potentially explain the complex seasonal patterns of influenza disease activity across the latitudinal gradient extending from temperate to tropical regions. I identified seasonal climatic variables that are potentially responsible for influenza seasonality from observational, experimental, ecological and anecdotal studies. I then used a global database of influenza seasonality to assess the consistency of relationships between influenza seasonality and the seasonality of relevant climatic variables. I determined that no single climatic variable is consistently correlated with seasonal influenza activity across temperate, subtropical and tropical regions.However, I did find a significant U-shaped relationship between specific humidity and influenza epidemics globally with epidemics becoming increasingly likely as specific humidity increases or decreases from approximately 12 g/kg. Further, I examined the temporal and spatial variation of influenza activity and specific humidity during the 2009 A/H1N1 pandemic across Mexico, which spans temperate, subtropical and tropical regions. I show that specific humidity may have modified the progression of three distinct waves of infection during the pandemic. These patterns are in agreement with the U-shaped relationship between specific humidity and seasonal influenza epidemics observed at a global scale. In all, this is the first time that relationships between climate and influenza (both seasonal and pandemic) activity have been successfully synthesized into a single parsimonious model across temperate, subtropical and tropical regions.

Recently researchers have recognized the potential effects of climate variability and climate change on infectious disease ecology. Mosquito-borne diseases are of considerable concern due to their reliance on temperature to regulate vector reproduction, survival, and vector and agent development. Precipitation is also influential because it helps maintain habitat for immature mosquitoes. The interactions between climate, vector, and agent are complex, however, and thus assessing the overall impact of climate on disease occurrence is difficult. Discerning the influence of climate on mosquito-borne diseases requires an interdisciplinary synthesis of knowledge about the relationships between components of the disease system and analysis techniques that account for the individual and interacting roles that each element contributes to the ecology of the disease. In this dissertation, climate and climate change influences on dengue fever and West Nile virus are identified through process based modeling to simulate changes in vector and viral transmission dynamics. Analysis of the literature pertaining to climate influences on dengue virus ecology reveals that climate variables often interact interdependently to influence dengue virus transmission. Statistical techniques correlating or modeling climate-dengue relationships are often inconsistent and location specific. Process based modeling has been employed to better simulate the intricacies and non-linear dynamics involved, but most models focus only on vector populations. Therefore, models should incorporate viral development and transmission components to better simulate dengue virus ecology. A model of West Nile virus vector dynamics across the southern United States reveals that impacts from climate change are very location and context-specific. While temperatures generally increase the season length of vector activity, changes in precipitation and evapotranspiration dynamics often lead to lower summer mosquito populations and limited population development in water-stressed areas. A simulation of dengue fever cases in San Juan County, Puerto Rico with a coupled vector-epidemiological model showed strong agreement when compared with reported case data (Willmott's d = 0.90 and r2 = 0.71). The model indicates that certain climate variables became disease limiting during specific times of the year. Temperature limits virus transmission during the winter by slowing viral development while lower precipitation limits spring transmission by suppressing vector populations.

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Many lines of evidence indicate that CD8+ T cells are important in the control of HIV-1 infection and this has led to much vaccine research focused at eliciting virus specific CTL. However to date, the few large-scale trials of HIV-1 vaccines designed to elicit CD8+ T cells have produced disappointing results. This has highlighted our incomplete knowledge of the factors that determine if such cells are capable of viral control. The aim of this thesis is to further characterise qualitative aspects of HIV-1 specific CTL that are associated with both good and bad anti-viral activity. HIV-1 specific CTL responses were investigated in three ways. Firstly, by longitudinally analysing an immunodominant HLA-B*08 restricted CD8+ T cell response in a single rapid progression patient. Secondly, HLA-B*40 restricted CTL responses to HIV-1 where characterised within a Chinese slow progressor cohort. Lastly, factors that affect the processing and presentation of certain overlapping HIV-1 specific CD8+ T cell epitopes were examined. The results of these studies reveal that subtle variations in both host and viral proteins can have a substantial impact on virus specific CTL and in turn may impact on the outcome of disease. The generation of HIV-1 specific CD8+ T cells is a complex process affected by many variables including the viral sequence of epitope flanking regions as well as polymorphisms in the proteins involved in antigen processing and presentation. To add a further layer of complexity, it appears that HIV-1 virus specific CTL can modulate their functionality throughout the course of infection. Such factors should therefore be taken into account during HIV-1 vaccine design.

Streptococcus pneumoniae has a highly adaptable genome due at least in part to its natural transformability and its ability to recombine with other pneumococci and related species. The emergence of antibiotic resistant clones of S. pneumoniae presents an opportunity to investigate how the genome has altered, spread and diversified within a defined time frame. We postulated that the genomes of epidemic, resistant isolates of S. pneumoniae would carry evidence of the genetic mechanisms that have shaped their evolution. We investigated this using eight to fifteen isolates from each of three S. pneumoniae clones; two multiply resistant clones Spain 9V-3 and Taiwan 19F-14 and one clone that has not acquired multiple resistance, England 14-9. Genome diversity in each of the three clones was investigated using pulsed field gel electrophoresis and multilocus sequence typing. Polymorphisms identified as a result of changes in the size of restriction fragments were found to be caused mainly by genomic rearrangements rather than restriction site mutations. Several deletion/insertion events in addition to one large inversion were identified. A number of polymorphisms correlated with previously known variable regions. Database analysis of multilocus sequence data from all three clones showed that recombination leads to sequence divergence more frequently than de novo mutation, but was significantly less common in England 14-9. The lower frequency of recombination events in England14-9 was in line with a transformation deficiency observed in vitro, and may explain the rare occurrence of penicillin resistance in this clone. Analysis of competence and recombination gene sequences available from databases revealed a potential cause of transformation deficiency: a four amino acid deletion in CelA, involved in DNA uptake and transport. Recombination can act as a DNA repair mechanism, but the significantly low occurrence in England14-9 suggests other mechanisms act to repair severe damage. Although S. pneumoniae does not have a typical SOS response it does possess DNA polymerase IV, encoded by dinB, which is predicted to be involved in error-prone DNA replication and repair of double strand breaks. DinB knockout mutants were created to investigate the effect in isogenic backgrounds. DinB mutants presented a lower frequency of spontaneous rifampicin resistance mutations than wild type 3 isolates. DinB mutants were more sensitive to killing by three different DNA damaging agents as well as by hydrogen peroxide. Isolates of the natural dinB mutant clone Spain 9V-3 were also shown to be more sensitive to DNA damaging agents than clones England 14-9 and Taiwan 19F-14. It is concluded that genetic differences between the three clones investigated do influence their patterns of evolution, and may account for differences in their antibiotic resistance profiles. Furthermore DNA polymerase IV does function as an error prone repair polymerase capable of protecting pneumococci from DNA damage despite the lack of a coordinated SOS response in pneumococci, and the absence of the gene in one successful multi-resistant clone.

Cholera in Haiti has persisted since its introduction after the 2010 earthquake. The outbreak demonstrates how a combination of socioeconomic factors, mainly a lack of infrastructure, can cause an outbreak to become a much more serious epidemic and the current enduring endemic. Because cholera came to a previously unexposed nation through United Nations peacekeepers, the outbreak in Haiti offers a unique perspective on the impact of globalization on public health. In addition, it provides a deeper look into the disproportionate impact of diarrheal diseases on low-income countries. Several biological and socioeconomic factors have facilitated the outbreak. Biological risk factors include immunologically naïve populations, low gastric acidity, and blood type. In addition, socioeconomic factors include a lack of clean drinking water and sanitation as well as a fragile and over-taxed healthcare system. The persisting struggle surrounding water and sanitation combined with a lack of knowledge on cholera prevention have precipitated the outbreak into an epidemic and further into its current endemic status. Current efforts to battle cholera include water and sanitation improvements, a national vaccination campaign, as well as the mobilization of community health workers. However, without the construction of sustainable water and sanitation infrastructure, it is unlikely that cholera in Haiti can be eliminated.