Presentation: A 3 month-old male is referred for admission with a 2-day history of fever, having been diagnosed with pneumonia and prescribed a cephalosporin on the previous day. A blood culture obtained at that time is positive for coagulase negative Staphyloccocus. On exam, he is ill-appearing. He has bilateral conjunctivitis that spares the limbus, non-exudative pharyngitis, and a polymorphic truncal rash. There is no appreciable cervical lymphadenopathy or extremity involvement. A chest x-ray demonstrates a round infiltrate of the left upper lobe, and initial labs reveal a white blood count of 17.5, a C-reactive protein (CRP) of 23.9 mg/dL, and a normal comprehensive metabolic panel. His positive blood culture is deemed a contaminant, and antibiotic coverage for community-acquired pneumonia is given with ampicillin. Diagnostic evaluation: On day 5 of illness, his fevers persist despite broadened antibiotic coverage. Further work-up has ruled out viral respiratory pathogens and Epstein-Barr virus as a cause of persistent fevers. Incomplete Kawasaki disease is suspected due to continued fevers, the presence of three clinical criteria, and further increase in his CRP. He lacks other supplemental laboratory criteria, so an echocardiogram is obtained that shows mild dilation of the left anterior descending artery (LAD) of indeterminate significance. A repeat echocardiogram 2 days later reveals progressive dilation of left main coronary artery (LMCA), LAD, and right coronary artery (RCA). Diagnosis: Dilation of the LAD and RCA confirm a diagnosis of incomplete Kawasaki disease. Within 48 hours of treatment with IVIG and high-dose aspirin, the patient is afebrile with resolving symptoms and a declining CRP. He is discharged on the 9th day of illness on low dose aspirin and a cephalosporin to complete an antibiotic course for concurrent pneumonia. Conclusion & Discussion: This case illustrates the importance of maintaining a high index of suspicion for an incomplete presentation of Kawasaki disease, particularly among infants. The American Heart Association’s guidelines were updated in 2017 to improve recognition of incomplete Kawasaki disease, particularly among infants who are more likely to have an incomplete presentation, abnormalities of the coronary arteries, and a delayed diagnosis. The key to this patient’s diagnosis was the presence of a bilateral conjunctivitis that spared the limbus. A bilateral, non-exudative conjunctivitis that spares the limbus has been recognized as a feature suggestive of Kawasaki disease for the better part of four decades; our review of the literature suggests this feature is highly specific to the diagnosis of Kawasaki disease.

Given that neurocognitive impairment is a frequent complication of HIV-1 infection in Spanish-speaking adults, the limited number of studies assessing HIV-associated neurocognitive disorders (HAND) in this population raises serious clinical concern. In addition to being appropriately translated, instruments need to be modified, normed, and validated accordingly. The purpose of the current study was to examine the diagnostic utility of the HIV Dementia Scale (HDS) and International HIV Dementia Scale (IHDS) to screen for HAND in Spanish-speaking adults living with HIV infection. Participants were classified as either HAND (N = 47) or No-HAND (N = 53) after completing a comprehensive neuropsychological evaluation. Receiver operating characteristic analyses found the HDS (AUC =.706) was more sensitive to detecting HAND than the IHDS (AUC =.600). Optimal cutoff scores were 9.5 for the HDS (PPV = 65.2%, NPV = 71.4%) and 9.0 for the IHDS (PPV = 59.4%, NPV = 59.1%). Canonical Correlation Analysis found the HDS converged with attention and executive functioning. Findings suggest that while the IHDS may not be an appropriate screening instrument with this population, the HDS retains sufficient statistical validity and clinical utility to screen for HAND in Spanish-speaking adults as a time-efficient and cost-effective measure in clinical settings with limited resources.

Acute inflammatory response is caused by the rapid recruitment of leukocytes, mainly neutrophils and monocytes, from blood to the tissue site. Diverse agents, including invading pathogens, injured or dead cells, and other irritants, may stimulate this response. In the ensuing inflammatory response, the recruited leukocytes and their secreted molecules help in eliminating or containing the injurious agents and promoting tissue regeneration. But often this response is imprecise and can lead to bystander tissue damage. Unchecked neutrophil activation is implicated in the pathology of many inflammatory conditions. An in-depth understanding of the pathways regulating this response, therefore, becomes critical in identifying therapeutic targets for these diseases. In this study, we investigate the role of intestinal commensal bacteria in regulating the acute inflammatory response. Furthermore, we examine the mechanism by which Interleukin-1 (IL-1) controls the inflammatory response to sterile agents. Inflammatory responses have been studied in the context of host defense against pathogens. However, we report that the innate immune system needs to be primed by intestinal flora to enable neutrophil recruitment to diverse microbial or sterile inflammatory signals. This priming requires myeloid differentiation primary response gene (88) (MyD88) signaling. In antibiotic-treated mice, which have depleted intestinal flora, we show that neutrophils get released into the blood from the bone marrow, but have a specific defect in migration into the inflammed tissue. This deficiency can be restored by pre-stimulating the mice with a purified MyD88 ligand. Despite having reduced number of infiltrating neutrophils, antibiotic-treated mice make higher levels of pro-inflammatory cytokines in the tissue, after inflammatory challenge. This suggests that antibiotic-treated mice produce some anti-inflammatory molecule(s) that counteract the effect of the pro-inflammatory cytokines. However, this effect is not due to the overproduction of the anti-inflammatory cytokine, Interleukin-10 (IL-10). In summary, our findings highlight the role of commensals in the development of acute inflammatory responses to microbial and sterile particles. The inflammatory response to sterile dead cells has been shown to be critically dependent upon IL-1. However, several key aspects of the IL-1 signaling cascade including the source of IL-1 and the cellular target of IL-1 were unresolved. We find that in most cases, the injured cells are not a major contributor of IL-1 that is required to propagate the inflammatory signal. On the contrary, we demonstrate that both the isoforms of IL-1, IL-1α/IL-1β are generated by bone marrow-derived, tissue-resident responding cells, upon sensing the injury. We also sought to determine the identity of the cellular target of IL-1 signaling. Previous studies have shown that for cell death-induced neutrophil recruitment, interleukin-1 receptor (IL-1R) expression is required on parenchymal cells. To identify this parenchymal cell, we are currently in the process of making the conditional knockout mouse of IL-1R. The latter would facilitate the parenchymal tissue-specific deletion of IL-1R. In summary, this study reports our progress in unraveling key aspects of IL-1 signaling during sterile inflammation. Taken together, we have identified key modulators of the acute inflammatory response and their mechanisms of regulation. These findings would facilitate the development of new therapies for inflammatory diseases triggered by both microbe and sterile agents.

Mycobacterium tuberculosis infection is one of the leading causes of mortality worldwide. One third of the population is estimated to be infected, however only 5-10% of those individuals can transmit the disease. While T cell immunity initially limits mycobacterium growth, it is unclear why T cell immunity fails to sterilize the infection and prevent subsequent recrudescence. One hypothesis is T cell exhaustion is mediating the failure of T cell immunity late during infection. Here we show the development of T cell exhaustion during chronic infection, and that the inhibitory receptor T cell-immunoglobulin and mucin domain containing 3 (TIM3) mediates the development of T cell exhaustion. TIM3 accumulates on the surface of T cells throughout the course of infection and there is a subsequent decrease in effector cytokine production, such as IL-2, TNFα, and IFNγ. Furthermore, antibody blockade of TIM3 restores T cell function and improves bacterial control. Our results show that TIM3 is mediating T cell exhaustion during chronic TB infection and leading to suboptimal bacterial control.

Includes bibliographical references / Introduction: Tuberculosis (TB) notification in South Africa has increased six fold over the last two decades mainly because of the Human Immunodeficiency Virus (HIV) epidemic. Globally, it was estimated that 73% of the TB cases were co-infected with HIV with more than 25% of this global co-infection burden being in South Africa alone. In 2012, globally 1.3 million deaths occurred due to TB; moreover 0.3 million were HIV-associated TB death. In 2010 TB was the leading cause of natural deaths in the population aged 15 to 24 years accounting for 14% of the total deaths in South Africa. In 2013 the proportion of patients with TB who were co-infected with HIV was extremely high at 62%.The outcome of co-infected patients was poorer than the outcome of HIV negative TB patients. However, there is little information available on the risk factors associated with TB treatment outcomes and the influence of co-infection. Method: A cross sectional study analysed Electronic TB Register (ETR.net) data from the Metro East Geographic Service Area (GSA) of the Cape Town Metro district. The dataset included adult patients aged 15 years or more, who initiated TB treatment between 1st July 2011 and 30th June 2012. In the descriptive analysis we analysed death separately but for the regression we merged death with unfavourable treatment outcome. Relative risks were used for measures of association. Univariate and multivariate analyses were performed using a generalized linear regression model. Statistically significant variables in the univariate analysis were included in the multivariate analysis. Findings: TB case notification in Eastern GSA was 922 per 100 000 population. Of the 12672 TB patients registered, 50% were co-infected with HIV. The incidence of death in co-infected was 5% versus 3% in uninfected, treatment success 67% versus 73% and unfavourable treatment outcome 28% versus 24%. The Khayelitsha sub-district had the highest proportion of the TB burden (37%) and of co-infection (65%). Fourteen percent of patients had extra-pulmonary TB (EPTB), 66% of whom were co-infected with HIV. In the multivariate analysis HIV (RR 1.2), retreatment (RR 1.4) and sputum smear microscopy not done (RR 1.4) were significantly associated with unfavourable treatment outcome. The sub districts Eastern (RR 0.9) and Northern (RR 0.7) were less likely to develop unfavourable outcome compared to Khayelitsha. In the stratified analysis, retreatment (RR 1.3) and smear not done (RR 1.3) were significant risk factors for an unfavourable treatment outcome in co-infected patients. Amongst HIV negative patients retreatment (RR 1.6) and smear not done (RR 1.6) were significant risk factors for an unfavourable treatment outcome. Conclusions: The incidence of TB is extremely high in the Eastern GSA of Cape Town however the prevalence of co-infection varies across the sub-districts. Although treatment outcomes have been improving, co-infection, retreatment and smear microscopy not done pre-treatment were factors significantly associated with an unfavourable treatment outcome. Eastern and Northern sub-districts were significantly more likely to have favourable treatment outcomes compared to Khayelitsha, where both TB incidence and HIV co-infection were greatest.

In summary, this study will be focused on Il-21 and its implications in the antibody response in influenza. The isotype classes primarily involved in this process will also be examined. This will be accomplished by looking at the serum of mice and analyzing the present influenza specific antibodies using ELISA. Another goal was to optimize the ELISA in order to make it sensitive enough to catch small differences in the results. This topic is important due to its implications for improving influenza vaccinations and preventions as current vaccines are not 100% effective. Influenza contributes to significant disease and death around the world every year and each piece of this puzzle is significant in order for the scientific community to be able to eventually make strides to improve the burden of this disease.

The eastern oyster Crassostrea virginica is an ecologically and commercially important species whose natural populations have been devastated by overharvesting, habitat destruction, and disease, but the rapid growth of oyster aquaculture has shown potential to restore the economic significance of this species. A key threat to the growth and sustainability of oyster aquaculture is the association of human-pathogenic Vibrio bacteria with product marketed for raw consumption. Two Vibrio species, Vibrio vulnificus and Vibrio parahaemolyticus, are the causes of the highest rates of seafood consumption-related mortality and gastrointestinal illness, respectively. Identification of the factors influencing V. vulnificus and V. parahaemolyticus prevalence and intensity in oysters is fundamental to better risk management. Within the oyster, these bacterial species interact with the same tissues as the prevalent oyster parasite, Perkinsus marinus, yet little is known about the effect of P. marinus infection on bacterial levels. Answering the fundamental question of whether P. marinus correlates with V. vulnificus and V. parahaemolyticus levels in oysters was the focus of this research. Oysters were deployed in the York River, Gloucester Point, VA, where both Vibrio species and P. marinus are endemic, and were sampled at five time points when levels of both P. marinus and Vibrio spp. were expected to be high in oysters. Abundance of all three organisms and pathogenic strains of V. parahaemolyticus were determined in individual oysters using molecular methods to investigate potential correlations between parasite and bacterial abundance. Additionally, the levels of V. vulnificus and V. parahaemolyticus in relation to histopathology associated with P. marinus infection and other conditions were determined. The following year, manipulation of P. marinus disease progression, which is slowed by lower salinities and favored by higher salinities, was attempted by deploying oysters at two additional sites of different salinities to gain insight into whether the timing of P. marinus infection emergence directly influences Vibrio levels. No correlation was observed between total abundance of P. marinus and either V. vulnificus or V. parahaemolyticus. Manipulation of P. marinus disease progression produced no effect on P. marinus emergence, so this yielded no insight into P. marinus-Vibrio interactions. Histopathological analyses did not reveal any correlations between P. marinus ranking, distribution, or associated tissue damage and Vibrio spp. levels. Though few in number, oysters infected by Haplosporidium nelsoni were characterized by higher levels of V. vulnificus, and oysters of peak gametogenic development had significantly higher levels of pathogenic strains of V. parahaemolyticus. The results with regard to H. nelsoni and gametogenic state warrant further study. The primary conclusion of this study is that oyster health has little influence on levels of human-pathogenic Vibrio species in oysters, inter-host variability in Vibrio levels is likely explained by other factors.

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2-ω-carboxyethylpyrrole (CEP) is a product of docosahexaenoic acid (DHA) oxidation, which forms covalent adducts with different proteins. CEP-modified proteins can interact with macrophage receptor, integrin αDβ2. This study aims to compare αDβ2 binding to its physiological ligand, fibrinogen, and CEP-modified fibrinogen, which is formed during inflammation. We hypothesize that modification of fibrinogen changes its ligand-binding properties to integrin αDβ2 which can affect macrophage migration and retention. Recombinant αD I-domain and αDβ2-transfected HEK293 cells were used for the experiments. Using biolayer interferometry, we found that the affinity of αD I-domain binding to fibrinogen-CEP was higher than fibrinogen and inhibited by the anti-CEP antibody. In agreement, αDβ2-transfected cells demonstrated stronger adhesion to fibrinogen-CEP and this adhesion was significantly inhibited by polyglutamic acid that mimics CEP-mediated binding. These findings suggest that αDβ2's interaction with DHA-modified extracellular matrix (ECM) proteins significantly increases macrophage adhesion and may serve for macrophage retention during chronic inflammation.