scholarly journals APOL1 renal risk variants have contrasting resistance and susceptibility associations with African trypanosomiasis

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Anneli Cooper ◽  
Hamidou Ilboudo ◽  
V Pius Alibu ◽  
Sophie Ravel ◽  
John Enyaru ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Human African Trypanosomiasis ◽  
Disease Risk ◽  
African Ancestry ◽  
Sub Saharan Africa ◽  
African Trypanosomiasis ◽  
African Trypanosomes ◽  
Risk Variants ◽  
Deleterious Alleles ◽  
Sub Saharan

Reduced susceptibility to infectious disease can increase the frequency of otherwise deleterious alleles. In populations of African ancestry, two apolipoprotein-L1 (APOL1) variants with a recessive kidney disease risk, named G1 and G2, occur at high frequency. APOL1 is a trypanolytic protein that confers innate resistance to most African trypanosomes, but not Trypanosoma brucei rhodesiense or T.b. gambiense, which cause human African trypanosomiasis. In this case-control study, we test the prevailing hypothesis that these APOL1 variants reduce trypanosomiasis susceptibility, resulting in their positive selection in sub-Saharan Africa. We demonstrate a five-fold dominant protective association for G2 against T.b. rhodesiense infection. Furthermore, we report unpredicted strong opposing associations with T.b. gambiense disease outcome. G2 associates with faster progression of T.b. gambiense trypanosomiasis, while G1 associates with asymptomatic carriage and undetectable parasitemia. These results implicate both forms of human African trypanosomiasis in the selection and persistence of otherwise detrimental APOL1 kidney disease variants.

APOL1 and Kidney Disease: From Genetics to Biology

2020 ◽  
Vol 82 (1) ◽  
pp. 323-342 ◽  
Author(s):  
David J. Friedman ◽  
Martin R. Pollak
Keyword(s):  
Kidney Disease ◽  
Genetic Variants ◽  
African Ancestry ◽  
Sub Saharan Africa ◽  
Natural Experiments ◽  
Lower Organism ◽  
Risk Alleles ◽  
Risk Variants ◽  
Sub Saharan ◽  
Models Of Disease

Genetic variants in the APOL1 gene, found only in individuals of recent African ancestry, greatly increase risk of multiple types of kidney disease. These APOL1 kidney risk alleles are a rare example of genetic variants that are common but also have a powerful effect on disease susceptibility. These alleles rose to high frequency in sub-Saharan Africa because they conferred protection against pathogenic trypanosomes that cause African sleeping sickness. We consider the genetic evidence supporting the association between APOL1 and kidney disease across the range of clinical phenotypes in the APOL1 nephropathy spectrum. We then explore the origins of the APOL1 risk variants and evolutionary struggle between humans and trypanosomes at both the molecular and population genetic level. Finally, we survey the rapidly growing literature investigating APOL1 biology as elucidated from experiments in cell-based systems, cell-free systems, mouse and lower organism models of disease, and through illuminating natural experiments in humans.

scholarly journals Chemotherapy of Human African Trypanosomiasis

2009 ◽  
Vol 2009 ◽  
pp. 1-5 ◽  
Author(s):  
Cyrus J. Bacchi
Keyword(s):  
Combination Chemotherapy ◽  
Human African Trypanosomiasis ◽  
Economic Loss ◽  
Chemotherapeutic Agents ◽  
Sub Saharan Africa ◽  
African Trypanosomiasis ◽  
Physical Suffering ◽  
Rural Clinics ◽  
Sub Saharan

Human Africa trypanosomiasis is a centuries-old disease which has disrupted sub-Saharan Africa in both physical suffering and economic loss. This article presents an update of classic chemotherapeutic agents, in use for >50 years and the recent development of promising non-toxic combination chemotherapy suitable for use in rural clinics.

scholarly journals No evidence for association between APOL1 kidney disease risk alleles and Human African Trypanosomiasis in two Ugandan populations

2018 ◽  
Vol 12 (2) ◽  
pp. e0006300 ◽  
Author(s):  
Magambo Phillip Kimuda ◽  
Harry Noyes ◽  
Julius Mulindwa ◽  
John Enyaru ◽  
Vincent Pius Alibu ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Human African Trypanosomiasis ◽  
Disease Risk ◽  
African Trypanosomiasis ◽  
Risk Alleles

scholarly journals Generation of neuroinflammation in human African trypanosomiasis

2019 ◽  
Vol 6 (6) ◽  
pp. e610 ◽  
Author(s):  
Jean Rodgers ◽  
Israel Steiner ◽  
Peter G. E Kennedy
Keyword(s):  
Human African Trypanosomiasis ◽  
Clinical Symptoms ◽  
Parasite Burden ◽  
Brain Inflammation ◽  
Sub Saharan Africa ◽  
African Trypanosomiasis ◽  
Peripheral Tissues ◽  
Neuroinflammatory Response ◽  
Proinflammatory Mediators ◽  
Sub Saharan

Human African trypanosomiasis (HAT) is caused by infection due to protozoan parasites of the Trypanosoma genus and is a major fatal disease throughout sub-Saharan Africa. After an early hemolymphatic stage in which the peripheral tissues are infected, the parasites enter the CNS causing a constellation of neurologic features. Although the CNS stage of HAT has been recognized for over a century, the mechanisms generating the neuroinflammatory response are complex and not well understood. Therefore a better understanding of the mechanisms utilized by the parasites to gain access to the CNS compartment is critical to explaining the generation of neuroinflammation. Contrast-enhanced MRI in a murine model of HAT has shown an early and progressive deterioration of blood-CNS barrier function after trypanosome infection that can be reversed following curative treatment. However, further studies are required to clarify the molecules involved in this process. Another important determinant of brain inflammation is the delicate balance of proinflammatory and counterinflammatory mediators. In mouse models of HAT, proinflammatory mediators such as tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and CXCL10 have been shown to be crucial to parasite CNS invasion while administration of interleukin (IL)-10, a counter inflammatory molecule, reduces the CNS parasite burden as well as the severity of the neuroinflammatory response and the clinical symptoms associated with the infection. This review focuses on information, gained from both infected human samples and animal models of HAT, with an emphasis on parasite CNS invasion and the development of neuroinflammation.

scholarly journals Slippery customers: How African trypanosomes evade mammalian defences

2009 ◽  
Vol 31 (4) ◽  
pp. 8-11
Author(s):  
Mark Carrington
Keyword(s):  
Cell Biology ◽  
Sub Saharan Africa ◽  
Mammalian Host ◽  
Tsetse Flies ◽  
Insect Vector ◽  
African Trypanosomiasis ◽  
Long Distance ◽  
African Trypanosomes ◽  
Endemic Areas ◽  
Sub Saharan

African trypanosomes are excellent parasites and can maintain an infection of a large mammalian host for months or years. In endemic areas, Human African Trypanosomiasis, also called sleeping sickness, has been largely unaffected by the advent of modern medicine, and trypanosomiasis of domestic livestock is a major restraint on productivity in endemic areas and is arguably the major contributor to the institutionalized poverty in much of rural sub-Saharan Africa1,2. A simple way of visualizing the effect of the livestock disease is to compare maps showing the distribution of livestock (www.ilri.org/InfoServ/Webpub/Fulldocs/Mappoverty/index.htm) and tsetse flies, the insect vector (www.fao.org/ag/AGAinfo/programmes/en/paat/maps.html): the lack of overlap is remarkable. Tsetse flies are only present in sub-Saharan Africa, and this probably restricted the spread of African trypanosomiasis until historical times. Livestock infections are now present in much of South Asia and South America, a product of long distance trade and adaptation of the trypanosomes to mechanical transmission3. The majority of research is on Trypanosoma brucei as this includes the human infective subspecies. This article provides a description of progress in the understanding the molecular details of how the trypanosome interacts with the mammalian immune system and how these studies have extended beyond this to fundamental aspects of eukaryotic cell biology.

scholarly journals Impaired renal function in a rural Ugandan population cohort

2019 ◽  
Vol 3 ◽  
pp. 149
Author(s):  
Robert Kalyesubula ◽  
Jeffrey P. Hau ◽  
Gershim Asiki ◽  
Billy Ssebunya ◽  
Sylvia Kusemererwa ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Serum Creatinine ◽  
Kidney Function ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Sub Saharan Africa ◽  
Population Cohort ◽  
The Mean ◽  
Sub Saharan ◽  
Ugandan Population

Background: Kidney disease is an important cause of morbidity and mortality globally. However, there are limited data on the prevalence of impaired kidney function in sub-Saharan Africa. We aimed to determine the prevalence of reduced kidney function and associated factors in a rural Ugandan population. Methods: We undertook a study of a representative sample of the General Population Cohort in South-western Uganda. We systematically collected data on cardiovascular disease risk factors, anthropometric measurements and blood tests including haemoglobin, HIV, HbA1c and serum creatinine.  The estimated glomerular filtration rate (eGFR) was calculated using the CKD-Epi equation, without the race component of the equation. Results: A total of 5,979/6,397 (93.5%) participants had valid creatinine results. The mean age was 39 years (Range:16-103 years) and 3,627 (60.7%) were female. HIV prevalence was 9.7% and about 40% of the population were pre-hypertensive or hypertensive. The mean serum creatinine level was 0.75 mg/dl (95% CI 0.74–0.75), and the average eGFR was 109.3 ml/min/1.73 m 2 (95% CI 108.8–109.9). The overall prevalence of eGFR <60 ml/min/1.73 m2 was 1.64% (98/5,979) (95% CI 1.34–1.99).  Additionally, 4,792(80.2%) were classified as normal eGFR (≥90 ml/min/1.73 m2), 1,089(18.2%) as low eGFR (60–89 ml/min/1.73 m2), 91(1.52%) as moderately reduced eGFR (30–59 ml/min/1.73 m2), 4(0.07%) as severely reduced eGFR (15-29 ml/min/1.73 m2), and 3(0.05%) classified as having kidney failure (eGFR<15 ml/min/1.73 m2).  When age-standardised to the WHO Standard Population the prevalence of eGFR<60 ml/min/1.73 m2 was 1.79%. Age above 35 years and the presence of hypertension (OR 2.86, 95% CI 1.15-7.08) and anaemia (OR 2.14, 95% CI 1.12-4.09) were associated with eGFR<60 ml/min/1.73 m2. Conclusion: In a systematic survey of people in rural Uganda, we found a substantial proportion had eGFR<60 ml/min/1.73 m2. More population based studies are needed to further characterize kidney disease in sub-Saharan Africa.

scholarly journals APOL1 kidney disease risk variants cause cytotoxicity by depleting cellular potassium and inducing stress-activated protein kinases

2015 ◽  
Vol 113 (4) ◽  
pp. 830-837 ◽  
Author(s):  
Opeyemi A. Olabisi ◽  
Jia-Yue Zhang ◽  
Lynn VerPlank ◽  
Nathan Zahler ◽  
Salvatore DiBartolo ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Protein Kinases ◽  
Intracellular Signaling ◽  
Cultured Cells ◽  
Disease Risk ◽  
African Ancestry ◽  
High Rate ◽  
Cell Swelling ◽  
Risk Variant ◽  
Risk Variants

Two specific genetic variants of the apolipoprotein L1 (APOL1) gene are responsible for the high rate of kidney disease in people of recent African ancestry. Expression in cultured cells of these APOL1 risk variants, commonly referred to as G1 and G2, results in significant cytotoxicity. The underlying mechanism of this cytotoxicity is poorly understood. We hypothesized that this cytotoxicity is mediated by APOL1 risk variant-induced dysregulation of intracellular signaling relevant for cell survival. To test this hypothesis, we conditionally expressed WT human APOL1 (G0), the APOL1 G1 variant, or the APOL1 G2 variant in human embryonic kidney cells (T-REx-293) using a tetracycline-mediated (Tet-On) system. We found that expression of either G1 or G2 APOL1 variants increased apparent cell swelling and cell death compared with G0-expressing cells. These manifestations of cytotoxicity were preceded by G1 or G2 APOL1-induced net efflux of intracellular potassium as measured by X-ray fluorescence, resulting in the activation of stress-activated protein kinases (SAPKs), p38 MAPK, and JNK. Prevention of net K+ efflux inhibited activation of these SAPKs by APOL1 G1 or G2. Furthermore, inhibition of SAPK signaling and inhibition of net K+ efflux abrogated cytotoxicity associated with expression of APOL1 risk variants. These findings in cell culture raise the possibility that nephrotoxicity of APOL1 risk variants may be mediated by APOL1 risk variant-induced net loss of intracellular K+ and subsequent induction of stress-activated protein kinase pathways.

scholarly journals Towards Point-of-Care Diagnostic and Staging Tools for Human African Trypanosomiaisis

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Enock Matovu ◽  
Anne Juliet Kazibwe ◽  
Claire Mack Mugasa ◽  
Joseph Mathu Ndungu ◽  
Zablon Kithingi Njiru
Keyword(s):  
Diagnostic Tests ◽  
Human African Trypanosomiasis ◽  
Point Of Care ◽  
Body Fluids ◽  
Accurate Diagnosis ◽  
Sub Saharan Africa ◽  
African Trypanosomiasis ◽  
Recent Advances ◽  
Sub Saharan ◽  
Unacceptable Toxicity

Human African trypanosomiasis is a debilitating disease prevalent in rural sub-Saharan Africa. Control of this disease almost exclusively relies on chemotherapy that should be driven by accurate diagnosis, given the unacceptable toxicity of the few available drugs. Unfortunately, the available diagnostics are characterised by low sensitivities due to the inherent low parasitaemia in natural infections. Demonstration of the trypanosomes in body fluids, which is a prerequisite before treatment, often follows complex algorithms. In this paper, we review the available diagnostics and explore recent advances towards development of novel point-of-care diagnostic tests.

scholarly journals Human African Trypanosomiasis: Ethnomedical and Biomedical Relationships

2000 ◽  
Vol 14 (1) ◽  
Author(s):  
Justin Brown
Keyword(s):  
Human African Trypanosomiasis ◽  
Explanatory Models ◽  
Sub Saharan Africa ◽  
World Health ◽  
African Trypanosomiasis ◽  
Sub Saharan ◽  
Biomedical Practitioners ◽  
Models Of Disease ◽  
Health Organization ◽  
The Relationship

Human African Trypanosomiasis (HAT) threatens more than 55 million people in sub-Saharan Africa. The focus of this paper is the relationship that exists between ethnomedical and biomedical practitioners regarding treatment of HAT. The relationship has been one of conflict. Biomedical practitioners have attempted to remove ethnomedicine from African society. This practice has been unsuccessful, especially in rural regions. Ethnomedical practitioners have adopted some aspects of biomedicine, but inadequate application and resources limit their efficacy. The biomedical community, including the World Health Organization, has not recognized the resource potential within ethnomedicine. An examination of the areas of conflict reveals differences in the explanatory models of disease causation and treatment methods. There has been some progress toward a cooperative model of healthcare, but most biomedical practitioners disregard ethnomedical techniques as primitive and ineffective. The conclusion of this paper presents a bleak future for the prevention and treatment of HAT in Africa. This future may be avoided with an increased level of cooperation and understanding between the two systems.

scholarly journals Community-driven citizen science approach to explore cardiovascular disease risk perception, and develop prevention advocacy strategies in sub-Saharan Africa: a programme protocol

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Kufre Joseph Okop ◽  
Kathy Murphy ◽  
Estelle Victoria Lambert ◽  
Kiya Kedir ◽  
Hailemichael Getachew ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Citizen Science ◽  
Risk Perceptions ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Data Gathering ◽  
Lessons Learned ◽  
Sub Saharan Africa ◽  
Rural And Urban ◽  
Sub Saharan

Abstract Background In sub-Saharan Africa (SSA), which experiences a disproportionately high cardiovascular disease (CVD) burden, population-based screening and prevention measures are hampered by low levels of knowledge about CVD and associated risk factors, and inaccurate perceptions of severity of risk. Methods This protocol describes the planned processes for implementing community-driven participatory research, using a citizen science method to explore CVD risk perceptions and to develop community-specific advocacy and prevention strategies in the rural and urban SSA settings. Multi-disciplinary research teams in four selected African countries will engage with and train community members living in rural and urban communities as citizen scientists to facilitate conceptualization, co-designing of research, data gathering, and co-creation of knowledge that can lead to a shared agenda to support collaborative participation in community-engaged science. The emphasis is on robust community engagement, using mobile technology to support data gathering, participatory learning, and co-creation of knowledge and disease prevention advocacy. Discussion Contextual processes applied and lessons learned in specific settings will support redefining or disassembling boundaries in participatory science to foster effective implementation of sustainable prevention intervention programmes in Low- and Middle-income countries.

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