Browsing by Author "Lutwama, Julius J"

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    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 R
    Little 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.
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    Seroepidemiological investigation of Crimean Congo hemorrhagic fever virus in livestock in Uganda, 2017.
    (Public Library of Science, 2023-11) Nyakarahuka, Luke; Kyondo, Jackson; Telford, Carson; Whitesell, Amy; Tumusiime, Alex; Mulei, Sophia; Baluku, Jimmy; Cossaboom, Caitlin M; Cannon, Deborah L; Montgomery, Joel M; Lutwama, Julius J; Nichol, Stuart T
    Abstract Crimean-Congo Hemorrhagic fever (CCHF) is an important zoonotic disease transmitted to humans both by tick vectors and contact with fluids from an infected animal or human. Although animals are not symptomatic when infected, they are the main source of human infection. Uganda has reported sporadic human outbreaks of CCHF in various parts of the country since 2013. We designed a nationwide epidemiological study to investigate the burden of CCHF in livestock. A total of 3181 animals were sampled; 1732 cattle (54.4%), 1091 goats (34.3%), and 358 sheep (11.3%) resulting in overall livestock seropositivity of IgG antibodies against CCHF virus (CCHFV) of 31.4% (999/3181). Seropositivity in cattle was 16.9% and in sheep and goats was 48.8%. Adult and juvenile animals had higher seropositivity compared to recently born animals, and seropositivity was higher in female animals (33.5%) compared to male animals (24.1%). Local breeds had higher (36.8%) compared to exotic (2.8%) and cross breeds (19.3%). Animals that had a history of abortion or stillbirth had higher seropositivity compared to those without a history of abortion or stillbirth. CCHFV seropositivity appeared to be generally higher in northern districts of the country, though spatial trends among sampled districts were not examined. A multivariate regression analysis using a generalized linear mixed model showed that animal species, age, sex, region, and elevation were all significantly associated with CCHFV seropositivity after adjusting for the effects of other model predictors. This study shows that CCHFV is actively circulating in Uganda, posing a serious risk for human infection. The results from this study can be used to help target surveillance efforts for early case detection in animals and limit subsequent spillover into humans.
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    Severe morbidity and hospital-based mortality from Rift Valley fever disease between November 2017 and March 2020 among humans in Uganda
    (BMC, 2024-05) Anywaine, Zacchaeus; Hansen, Christian; Warimwe, George M; Abu-Baker Mustapher, Ggayi; Nyakarahuka, Luke; Balinandi, Stephen; Ario, Alex Riolexus; Lutwama, Julius J; Elliott, Alison; Kaleebu, Pontiano
    Abstract Background Rift Valley fever (RVF) is a zoonotic viral disease of increasing intensity among humans in Africa and the Arabian Peninsula. In Uganda, cases reported prior to 2016 were mild or not fully documented. We report in this paper on the severe morbidity and hospital-based mortality of human cases in Uganda. Methods Between November 2017 and March 2020 human cases reported to the Uganda Virus Research Institute (UVRI) were confirmed by polymerase chain reaction (PCR). Ethical and regulatory approvals were obtained to enrol survivors into a one-year follow-up study. Data were collected on socio-demographics, medical history, laboratory tests, potential risk factors, and analysed using Stata software. Results Overall, 40 cases were confirmed with acute RVF during this period. Cases were not geographically clustered and nearly all were male (39/40; 98%), median age 32 (range 11–63). The median definitive diagnosis time was 7 days and a delay of three days between presumptive and definitive diagnosis. Most patients (31/40; 78%) presented with fever and bleeding at case detection. Twenty-eight (70%) cases were hospitalised, out of whom 18 (64%) died. Mortality was highest among admissions in regional referral (11/16; 69%) and district (4/5; 80%) hospitals, hospitalized patients with bleeding at case detection (17/27; 63%), and patients older than 44 years (9/9; 100%). Survivors mostly manifested a mild gastro-intestinal syndrome with nausea (83%), anorexia (75%), vomiting (75%), abdominal pain (50%), and diarrhoea (42%), and prolonged symptoms of severe disease including jaundice (67%), visual difficulties (67%), epistaxis (50%), haemoptysis (42%), and dysentery (25%). Symptom duration varied between two to 120 days. Conclusion RVF is associated with high hospital-based mortality, severe and prolonged morbidity among humans that present to the health care system and are confirmed by PCR. One-health composite interventions should be developed to improve environmental and livestock surveillance, prevent infections, promptly detect outbreaks, and improve patient outcomes.