Browsing by Author "Owor, Nicholas"
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Item Assessing Human Risk of Exposure to Plague Bacteria in Northwestern Uganda Based on Remotely Sensed Predictors(The American journal of tropical medicine and hygiene, 2010) Eisen, Rebecca J.; Apangu, Titus; Owor, Nicholas; Acayo, Sara; Acidri, Rogers; Mead, Paul S.Plague, a life-threatening flea-borne zoonosis caused by Yersinia pestis, has most commonly been reported from eastern Africa and Madagascar in recent decades. In these regions and elsewhere, prevention and control efforts are typically targeted at fine spatial scales, yet risk maps for the disease are often presented at coarse spatial resolutions that are of limited value in allocating scarce prevention and control resources. In our study, we sought to identify sub-village level remotely sensed correlates of elevated risk of human exposure to plague bacteria and to project the model across the plague-endemic West Nile region of Uganda and into neighboring regions of the Democratic Republic of Congo. Our model yielded an overall accuracy of 81%, with sensitivities and specificities of 89% and 71%, respectively. Risk was higher above 1,300 meters than below, and the remotely sensed covariates that were included in the model implied that localities that are wetter, with less vegetative growth and more bare soil during the dry month of January (when agricultural plots are typically fallow) pose an increased risk of plague case occurrence. Our results suggest that environmental and landscape features play a large part in classifying an area as ecologically conducive to plague activity. However, it is clear that future studies aimed at identifying behavioral and fine-scale ecological risk factors in the West Nile region are required to fully assess the risk of human exposure to Y. pestis.Item COVID-19 immune signatures in Uganda persist in HIV co-infection and diverge by pandemic phase(Nature Publishing Group, 2024-02) Cummings, Matthew J; Bakamutumaho, Barnabas; Lutwama, Julius J; Owor, Nicholas; Che, Xiaoyu; Astorkia, Maider; Postler, Thomas S; Kayiwa, John; Kiconco, Jocelyn; Muwanga, Moses; Nsereko, Christopher; wamutwe, Emmanuel; Nayiga, Irene; Kyebambe, Stephen; Haumba, Mercy; Bosa, Henry Kyobe; Ocom, Felix; Watyaba, Benjamin; TKikaire, Bernard; Tomoiaga, Alin S; Kisaka, Stevens; Kiwanuka, Noah; Lipkin, W Ian; O'Donnell, Max RLittle is known about the pathobiology of SARS-CoV-2 infection in sub-Saharan Africa, where severe COVID-19 fatality rates are among the highest in the world and the immunological landscape is unique. In a prospective cohort study of 306 adults encompassing the entire clinical spectrum of SARS-CoV-2 infection in Uganda, we profile the peripheral blood proteome and transcriptome to characterize the immunopathology of COVID-19 across multiple phases of the pandemic. Beyond the prognostic importance of myeloid cell-driven immune activation and lymphopenia, we show that multifaceted impairment of host protein synthesis and redox imbalance define core biological signatures of severe COVID-19, with central roles for IL-7, IL-15, and lymphotoxin-α in COVID-19 respiratory failure. While prognostic signatures are generally consistent in SARS-CoV-2/HIV-coinfection, type I interferon responses uniquely scale with COVID-19 severity in persons living with HIV. Throughout the pandemic, COVID-19 severity peaked during phases dominated by A.23/A.23.1 and Delta B.1.617.2/AY variants. Independent of clinical severity, Delta phase COVID-19 is distinguished by exaggerated pro-inflammatory myeloid cell and inflammasome activation, NK and CD8+ T cell depletion, and impaired host protein synthesis. Combining these analyses with a contemporary Ugandan cohort of adults hospitalized with influenza and other severe acute respiratory infections, we show that activation of epidermal and platelet-derived growth factor pathways are distinct features of COVID-19, deepening translational understanding of mechanisms potentially underlying SARS-CoV-2-associated pulmonary fibrosis. Collectively, our findings provide biological rationale for use of broad and targeted immunotherapies for severe COVID-19 in sub-Saharan Africa, illustrate the relevance of local viral and host factors to SARS-CoV-2 immunopathology, and highlight underemphasized yet therapeutically exploitable immune pathways driving COVID-19 severity. Less is known about SARS-CoV-2 infection in unstudied geographical areas such as sub-Saharan Africa. Here the authors use multi-omics to characterize the immune response to SARS-CoV-2 in Uganda and consider how people living with HIV immunologically differentially respond to the virus.Item Detection of urine lipoarabinomannan is associated with proinflammatory innate immune activation, impaired host defense, and organ dysfunction in adults with severe HIV-associated tuberculosis in Uganda(JAIDS Journal of Acquired Immune Deficiency Syndromes, 2023) Matthew, J. Cummings; Bakamutumaho, Barnabas; Komal, Jain; Adam Price; Owor, Nicholas; Kayiwa, John; Namulondo, Joyce; Byaruhanga, Timothy; Muwanga, Moses; Nsereko, Christopher; Nayiga, Irene; Kyebambe, Stephen; Xiaoyu, Che; Stephen, Sameroff; Rafal, Tokarz; Wai, Wong; Thomas, S. Postler; Michelle, H. Larsen; W. Ian, Lipkin; Lutwama, Julius J.; Max, R. O’DonnellBackground: The immunopathology of disseminated HIV-associated tuberculosis (HIV/TB), a leading cause of critical illness and death among persons living with HIV in sub-Saharan Africa, is incompletely understood. Reflective of hematogenously disseminated TB, detection of lipoarabinomannan (LAM) in urine is associated with greater bacillary burden and poor outcomes in adults with HIV/TB. Methods: We determined the relationship between detection of urine TB-LAM, organ dysfunction, and host immune responses in a prospective cohort of adults hospitalized with severe HIV/TB in Uganda. Generalized additive models were used to analyze the association between urine TB-LAM grade and concentrations of 14 soluble immune mediators. Whole-blood RNA-sequencing data were used to compare transcriptional profiles between patients with high- vs. low-grade TB-LAM results. Results: Among 157 hospitalized persons living with HIV, 40 (25.5%) had positive urine TB-LAM testing. Higher TB-LAM grade was associated with more severe physiologic derangement, organ dysfunction, and shock. Adjusted generalized additive models showed that higher TB-LAM grade was significantly associated with higher concentrations of mediators reflecting proinflammatory innate and T-cell activation and chemotaxis (IL-8, MIF, MIP-1β/CCL4, and sIL-2Ra/sCD25). Transcriptionally, patients with higher TB-LAM grades demonstrated multifaceted impairment of antibacterial defense including reduced expression of genes encoding cytotoxic and autophagy-related proteins and impaired cross-talk between innate and cell-mediated immune effectors. Conclusions: Our findings add to emerging data suggesting pathobiological relationships between LAM, TB dissemination, innate cell activation, and evasion of host immunity in severe HIV/TB. Further translational studies are needed to elucidate the role for immunomodulatory therapies, in addition to optimized anti-TB treatment, in this often critically ill population.Item Development of a Novel Clinicomolecular Risk Index to Enhance Mortality Prediction and Immunological Stratification of Adults Hospitalized with Sepsis in Sub-Saharan Africa: A Pilot Study from Uganda(The American Journal of Tropical Medicine and Hygiene, 2023) Matthew, J. Cummings; Bakamutumaho, Barnabas; Komal, Jain; Adam, Price; Owor, Nicholas; Kayiwa, John; Namulondo, Joyce; Byaruhanga, Timothy; Muwanga, Moses; Nsereko, Christopher; Stephen, Sameroff; W. Ian, Lipkin; Lutwama, Julius J.; Max, R. O’DonnellThe global burden of sepsis is concentrated in sub-Saharan Africa (SSA), where epidemic HIV and unique pathogen diversity challenge the effective management of severe infections. In this context, patient stratification based on biomarkers of a dysregulated host response may identify subgroups more likely to respond to targeted immunomodulatory therapeutics. In a prospective cohort of adults hospitalized with suspected sepsis in Uganda, we applied machine learning methods to develop a prediction model for 30-day mortality that integrates physiology-based risk scores with soluble biomarkers reflective of key domains of sepsis immunopathology. After model evaluation and internal validation, whole-blood RNA sequencing data were analyzed to compare biological pathway enrichment and inferred immune cell profiles between patients assigned differential model-based risks of mortality. Of 260 eligible adults (median age, 32 years; interquartile range, 26–43 years; 59.2% female, 53.9% living with HIV), 62 (23.8%) died by 30 days after hospital discharge. Among 14 biomarkers, soluble tumor necrosis factor receptor 1 (sTNFR1) and angiopoietin 2 (Ang-2) demonstrated the greatest importance for mortality prediction in machine learning models. A clinicomolecular model integrating sTNFR1 and Ang-2 with the Universal Vital Assessment (UVA) risk score optimized 30-day mortality prediction across multiple performance metrics. Patients assigned to the high-risk, UVA-based clinicomolecular subgroup exhibited a transcriptional profile defined by proinflammatory innate immune and necroptotic pathway activation, T-cell exhaustion, and expansion of key immune cell subsets including regulatory and gamma-delta T cells. Clinicomolecular stratification of adults with suspected sepsis in Uganda enhanced 30-day mortality prediction and identified a high-risk subgroup with a therapeutically targetable immunological profile. Further studies are needed to advance pathobiologically informed sepsis management in SSA.Item Emergence, Epidemiology, and Transmission Dynamics of 2009 Pandemic A/H1N1 Influenza in Kampala, Uganda, 2009–2015(The American journal of tropical medicine and hygiene, 2018) Cummings, Matthew J.; Bakamutumaho, Barnabas; Yang, Wan; Wamala, Joseph F.; Kayiwa, John; Owor, Nicholas; Namagambo, Barbara; Byaruhanga, Timothy; Lutwama, Julius J.; Shaman, Jeffrey; O’Donnell, Max R.In sub-Saharan Africa, little is known about the epidemiology of pandemic-prone influenza viruses in urban settings. Using data from a prospective sentinel surveillance network, we characterized the emergence, epidemiology, and transmission dynamics of 2009 pandemic A/H1N1 influenza (H1N1pdm09) in Kampala, Uganda. After virus introduction via international air travel from England in June 2009, we estimated the basic reproductive number in Kampala to be 1.06–1.13, corresponding to attack rates of 12–22%. We subsequently identified 613 cases of influenza in Kampala from 2009 to 2015, of which 191 (31.2%) were infected with H1N1pdm09. Patients infected with H1N1pdm09 were more likely to be older adult (ages 35–64) males with illness onset during rainy season months. Urban settings in sub-Saharan Africa are vulnerable to importation and intense transmission of pandemic-prone influenza viruses. Enhanced surveillance and influenza pandemic preparedness in these settings is needed.Item Evaluation of Rodent Bait Containing Imidacloprid for the Control of Fleas on Commensal Rodents in a Plague-Endemic Region of Norther Uganda(Journal of medical entomology, 2010) Borchert, Jeff; Enscore, Russell E.; Eisen Rebecca J.; Atiku, Linda A.; Owor, Nicholas; Acayo, Sarah; Babi, Nackson; Montenieri, John A.; Gage, Kenneth L.In recent decades, the majority of human plague cases (caused by Yersinia pestis) have been reported from Africa. In an effort to reduce the risk of the disease in this area, we evaluated theefÞcacy of a host-targeted rodent bait containing the insecticide imidacloprid for controlling ßeas on house-dwelling commensal rodents in a plague-endemic region of northwestern Uganda. results demonstrated that the use of a palatable, rodent-targeted, wax-based bait cube was effective at reducing the prevalence of ßeas on commensal rodents and ßea burdens on these animals at day 7 postbait exposure, but lacked signiÞcant residual activity, allowing ßea populations to rebound in the absence of additional bait applications. Our results indicate the use of a palatable host-targeted bait block containing imidacloprid was an effective technique for quickly reducing ßea numbers on rodents in northwest Uganda and, thus, could be useful for lowering the potential risk of human ßea bite exposures during plague outbreaks if applied continuously during the period of riskItem Influenza-associated pneumonia hospitalizations in Uganda, 2013-2016(PLoS ONE, 2019) Emukule, Gideon O.; Namagambo, Barbara; Owor, Nicholas; Bakamutumaho, Barnabas; Kayiwa, John T.; Namulondo, Joyce; Byaruhanga,Timothy; Tempia, Stefano; Sandra, S. Chaves; Lutwama, Julius J.Background Influenza is an important contributor to acute respiratory illness, including pneumonia, and results in substantial morbidity and mortality globally. Understanding the local burden of influenza-associated severe disease can inform decisions on allocation of resources toward influenza control programs. Currently, there is no national influenza vaccination program in Uganda. Methods In this study, we used data on pneumonia hospitalizations that were collected and reported through the Health Management Information System (HMIS) of the Ministry of Health, Uganda, and the laboratory-confirmed influenza positivity data from severe acute respiratory illness (SARI) surveillance in three districts (Wakiso, Mbarara, and Tororo) to estimate the age-specific incidence of influenza-associated pneumonia hospitalizations from January 2013 through December 2016. Results The overall estimated mean annual rate of pneumonia hospitalizations in the three districts was 371 (95% confidence interval [CI] 323–434) per 100,000 persons, and was highest among children aged <5 years (1,524 [95% CI 1,286–1,849]) compared to persons aged ≥5 years (123 [95% CI 105–144]) per 100,000 persons. The estimated mean annual rate of influenza-associated pneumonia hospitalization was 34 (95% CI 23–48) per 100,000 persons (116 [95% CI 78–165] and 16 [95% CI 6–28] per 100,000 persons among children aged <5 years and those ≥5 years, respectively). Among children aged <5 years, the rate of hospitalized influenza-associated pneumonia was highest among those who were <2 years old (178 [95% CI 109–265] per 100,000 persons). Over the period of analysis, the estimated mean annual number of hospitalized influenza-associated pneumonia cases in the three districts ranged between 672 and 1,436, of which over 70% represent children aged <5 years. Conclusions The burden of influenza-associated pneumonia hospitalizations was substantial in Uganda, and was highest among young children aged <5 years. Influenza vaccination may be considered, especially for very young children.Item Phylogenomic analysis of Uganda influenza type-A viruses to assess their relatedness to the vaccine strains and other Africa viruses: a molecular epidemiology study(bioRxiv, 2021) Nabakooza, Grace; Owuor, David Collins; Laurent, Zaydah R. de; Owor, Nicholas; Kayiwa, John Timothy; Jjingo, Daudi; Nyaigoti Agoti, Charles; Nokes, David James; Kateete, David Patrick; Mulindwa Kitayimbwa, John; Frost, Simon David William; Lutwama, Julius JulianGenetic characterisation of circulating influenza viruses is essential for vaccine selection and mitigation of viral transmission. The current scantiness of viral genomic data and underutilisation of advanced molecular analysis methods on influenza viruses circulating in Africa has limited their extensive study and representation in the global influenza ecology. We aimed to sequence influenza type-A viruses (IAVs) that previously circulated in Uganda and characterised their genetic relatedness to the vaccine viruses and publicly available Africa IAVs. Methods: This was an observational study nested to the Uganda national influenza surveillance programme. We used Next-generation sequencing to locally generate genomes from 116 A(H1N1)pdm09 and 118 A(H3N2) viruses collected between 2010 and 2018 from 7 districts across Uganda. A total of 206 hemagglutinin (HA), 207 neuraminidase (NA), and 213 matrix protein (MP) sequences were genetically compared to the WHO-recommended vaccines and other viruses isolated from Africa since 1994. Viral temporal and spatial divergence and circulating genetic clades were characterised using phylogenetic methods. Findings: We successfully generated gene sequences for 91·9% (215/234) viruses. Uganda A(H1N1)pdm09 and A(H3N2) virus HA, NA, and MP proteins had 96·36-99·09%, 96·49-99·39%, and 97·48-99·95% amino acid similarity, respectively, to vaccines recommended from 2010 through 2020. The local viruses incorporated amino acid substitutions (AAS) in their antigenic, receptor binding, and glycosylation sites each year causing them to antigenically drift away from vaccines. For seasons when vaccine formulations differed, Uganda IAV antigenic sites had 1-2 extra AAS relative to the Southern than Northern hemisphere vaccine viruses. All Uganda IAVs carried the adamantine-resistance marker S31N but not the neuraminidase inhibitor (NAI) resistance markers H274Y and H275Y. However, some A(H1N1)pdm09 viruses had permissive substitutions V234I, N369K, and V241I typical of NAI-resistant viruses.Item Severe COVID-19 in Uganda across Two Epidemic Phases: A Prospective Cohort Study(The American journal of tropical medicine and hygiene, 2021) Bakamutumaho, Barnabas; Cummings, Matthew J.; Owor, Nicholas; Kayiwa, John; Namulondo, Joyce; Byaruhanga, Timothy; Muwanga, Moses; Nsereko, Christopher; Mutonyi, Roselyn; Achan, Josephine; wanyenze, Lucy; Ndazarwe, Alice; Nakanjako, Ruth; Natuhwera, Richard; Nsangi, Annet; Bosa, Henry Kyobe; Ocom, Felix; Kikaire, Bernard; Lutwama, Julius J.Among a prospective cohort of children and adults admitted to a national COVID-19 treatment unit in Uganda from March to December 2020, we characterized the epidemiology of and risk factors for severe illness. Across two epidemic phases differentiated by varying levels of community transmission, the proportion of patients admitted with WHO-defined severe COVID-19 ranged from 5% (7/146; 95% CI: 2–10) to 33% (41/124; 95% CI: 25–42); 21% (26/124; 95% CI: 14–29%) of patients admitted during the peak phase received oxygen therapy. Severe COVID-19 was associated with older age, male sex, and longer duration of illness before admission. Coinfection with HIV was not associated with illness severity; malaria or tuberculosis coinfection was rare. No patients died during admission. Despite low mortality, hospital incidence of severe COVID-19 during the first epidemic peak in Uganda was substantial. Improvements in vaccine deployment and acute care capacity, including oxygen delivery, are urgently needed to prevent and manage severe COVID-19 in sub-Saharan Africa.