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Pathogens
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Pathology of Severe Malaria
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Pathology of Severe Malaria

A special issue of Pathogens (ISSN 2076-0817). This special issue belongs to the section "Parasitic Pathogens".

Deadline for manuscript submissions: closed (10 December 2022) | Viewed by 17267

Special Issue Editor

Dr. Julio Gallego-Delgado

E-Mail Website
Guest Editor
1. Department of Biology, Lehman College, City University of New York, Bronx, New York 10468, USA
2. PhD Program in Biology, The Graduate Center, City University of New York, New York, NY 10016, USA
Interests: malaria; severe malaria; renal injury; blood-brain-barrier; endothelial dysfunction

Special Issue Information

Dear colleagues,

Severe malaria still is one of the top five causes of death in children under five. After years of successful international efforts reducing the impact of this disease, we have reached a plateau, and the number of people, mostly children, dying of severe malaria has remained unchanged since 2015. Understanding the mechanisms leading to the different manifestations of severe malaria caused by different species of Plasmodium would help us to develop new therapeutic strategies specific to complicated malaria, as well as earlier and more accurate diagnostic tools. Studies in the areas described below can serve to delineate the strategies necessary to get us back on track to defeat malaria.

  • Identification of molecular mechanisms involved in severe malaria complications: cerebral malaria, renal failure, severe anemia, respiratory distress, hypoglycemia, acidosis, hyperparasitemia.
  • Histological studies of severe malaria caused not only by Plasmodium falciparum but by any of the other four Plasmodium infecting humans.
  • Identification of genetic polymorphisms associated with malaria severity.
  • Analysis of biomarkers that can be used as predictive and/or prognostic markers of severe malaria.
  • Use of animal models to understand the pathophysiological processes of severe malaria.
  • Follow-up studies evaluating potential sequalae in patients with a history of severe malaria.

Dr. Julio Gallego-Delgado
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pathogens is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cerebral malaria
  • malaria-induced acute kidney injury
  • severe anemia
  • respiratory distress
  • hyperparasitemia
  • hypoglycemia
  • acidosis
  • multiorgan failure

Published Papers (7 papers)

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Editorial

Jump to: Research

3 pages, 171 KiB  
Editorial
Pathology of Severe Malaria
by Julio Gallego-Delgado
Pathogens 2023, 12(12), 1389; https://doi.org/10.3390/pathogens12121389 - 25 Nov 2023
Viewed by 901
Abstract
Malaria, a devastating disease transmitted by mosquitoes, continues to plague many regions worldwide, affecting millions of lives annually [...] Full article
(This article belongs to the Special Issue Pathology of Severe Malaria)

Research

Jump to: Editorial

11 pages, 10943 KiB  
Article
Novel Experimental Mouse Model to Study Malaria-Associated Acute Kidney Injury
by Johanna Bensalel, Alexandra Roberts, Kiara Hernandez, Angelica Pina, Winifred Prempeh, Blessing V. Babalola, Pablo Cannata, Alberto Lazaro and Julio Gallego-Delgado
Pathogens 2023, 12(4), 545; https://doi.org/10.3390/pathogens12040545 - 1 Apr 2023
Cited by 1 | Viewed by 2273
Abstract
The impact of malaria-associated acute kidney injury (MAKI), one of the strongest predictors of death in children with severe malaria (SM), has been largely underestimated and research in this area has been neglected. Consequently, a standard experimental mouse model to research this pathology [...] Read more.
The impact of malaria-associated acute kidney injury (MAKI), one of the strongest predictors of death in children with severe malaria (SM), has been largely underestimated and research in this area has been neglected. Consequently, a standard experimental mouse model to research this pathology is still lacking. The purpose of this study was to develop an in vivo model that resembles the pathology in MAKI patients. In this study, unilateral nephrectomies were performed on wild-type mice prior to infection with Plasmodium berghei NK65. The removal of one kidney has shown to be an effective approach to replicating the most common findings in humans with MAKI. Infection of nephrectomized mice, compared to their non-nephrectomized counterparts, resulted in the development of kidney injury, evident by histopathological analysis and elevated levels of acute kidney injury (AKI) biomarkers, including urinary neutrophil gelatinase-associated lipocalin, serum Cystatin C, and blood urea nitrogen. Establishment of this in vivo model of MAKI is critical to the scientific community, as it can be used to elucidate the molecular pathways implicated in MAKI, delineate the development of the disease, identify biomarkers for early diagnosis and prognosis, and test potential adjunctive therapies. Full article
(This article belongs to the Special Issue Pathology of Severe Malaria)
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10 pages, 1575 KiB  
Article
Analysis of Fifty Years of Severe Malaria Worldwide Research
by Jose A. Garrido-Cardenas, Lilia González-Cerón, Federico García-Maroto, José Cebrián-Carmona, Francisco Manzano-Agugliaro and Concepción M. Mesa-Valle
Pathogens 2023, 12(3), 373; https://doi.org/10.3390/pathogens12030373 - 24 Feb 2023
Cited by 7 | Viewed by 2175
Abstract
This study analyzed fifty years of severe malaria research worldwide. Malaria is a parasitic disease that continues to have a significant impact on global health, particularly in sub-Saharan Africa. Severe malaria, a severe and often fatal form of the disease, is a major [...] Read more.
This study analyzed fifty years of severe malaria research worldwide. Malaria is a parasitic disease that continues to have a significant impact on global health, particularly in sub-Saharan Africa. Severe malaria, a severe and often fatal form of the disease, is a major public health concern. The study used different bibliometric indicators such as the number of publications, citations, authorship, and keywords to analyze the research trends, patterns, and progress made in the field of severe malaria. The study covers the period from 1974 to 2021 and includes articles from Scopus. The results of the study indicated that there has been a steady increase in the number of publications on severe malaria over the past fifty years, with a particular increase in the last decade. The study also showed that most of the publications are from USA and Europe, while the disease occurs in Africa, South-East Asia, and the Americas. The study also identified the most frequent keywords used in the publications, and the most influential journals and authors in the field. In conclusion, this bibliometric study provides a comprehensive overview of the research trends and patterns in the field of severe malaria over the past fifty years and highlights the areas that need more attention and research efforts. Full article
(This article belongs to the Special Issue Pathology of Severe Malaria)
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16 pages, 1099 KiB  
Article
A Retrospective Review on Severe Malaria in Colombia, 2007–2020
by Jaime Carmona-Fonseca, Mario J. Olivera and María F. Yasnot-Acosta
Pathogens 2022, 11(8), 893; https://doi.org/10.3390/pathogens11080893 - 9 Aug 2022
Cited by 3 | Viewed by 2776
Abstract
Background: Knowledge of severe malaria (SM) or complicated malaria is insufficient in all its components. The least known type is the one associated with Plasmodium vivax, compared to that caused by P. falciparum. The aim of this study was to provide [...] Read more.
Background: Knowledge of severe malaria (SM) or complicated malaria is insufficient in all its components. The least known type is the one associated with Plasmodium vivax, compared to that caused by P. falciparum. The aim of this study was to provide a general overview of epidemiological information about the burden of SM, obtained from the National Public Health Surveillance System (SIVIGILA) for the period 2007–2020 in Colombia. Methods: A descriptive, retrospective, and cross-sectional study of secondary information was performed via SIVIGILA. Results: There were 9881 SM cases among 1,060,950 total malaria cases in Colombia in 2007–2020: 9.31 SM cases per 1000 malaria cases. During this period, there were 7145 SM cases due to the following species: Plasmodium vivax, 57.6%; P. falciparum, 38.6%; severe mixed malaria, 3.2%; and P. malariae, 0.6%. The most compromised organ systems are the hematological system (54.9%), the liver (9.1%), the kidneys (4.2%), the lungs (1.9%) and the brain (1.6%). Conclusions: There has been a reduction in malaria incidence in Colombia in the last 10–15 years, but there has also been a strong increase in SM incidence. We suggest emphasizing the prevention of the onset of severe malaria, with the early and accurate diagnosis of plasmodial infection. Full article
(This article belongs to the Special Issue Pathology of Severe Malaria)
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12 pages, 1529 KiB  
Article
Characterization of Lymphocyte Subsets in Lymph Node and Spleen Sections in Fatal Pediatric Malaria
by Wilson L. Mandala, Steve Ward, Terrie E. Taylor and Samuel C. Wassmer
Pathogens 2022, 11(8), 851; https://doi.org/10.3390/pathogens11080851 - 28 Jul 2022
Cited by 2 | Viewed by 1667
Abstract
Secondary lymphoid tissues play a major role in the human immune response to P. falciparum infection. Previous studies have shown that acute falciparum malaria is associated with marked perturbations of the cellular immune system characterized by lowered frequency and absolute number of circulating [...] Read more.
Secondary lymphoid tissues play a major role in the human immune response to P. falciparum infection. Previous studies have shown that acute falciparum malaria is associated with marked perturbations of the cellular immune system characterized by lowered frequency and absolute number of circulating T cell subsets. A temporary relocation of T cells, possibly by infiltration to secondary lymphoid tissue, or their permanent loss through apoptosis, are two proposed explanations for this observation. We conducted the present study to determine the phenotype of lymphocyte subsets that accumulate in the lymph node and spleen during acute stages of falciparum malaria infection in Malawian children, and to test the hypothesis that lymphocytes are relocated to lymphoid tissues during acute infection. We stained tissue sections from children who had died of the two common clinical forms of severe malaria in Malawi, namely severe malarial anemia (SMA, n = 1) and cerebral malaria (CM, n = 3), and used tissue sections from pediatric patients who had died of non-malaria sepsis (n = 2) as controls. Both lymph node and spleen tissue (red pulp) sections from CM patients had higher percentages of T cells (CD4+ and CD8+) compared to the SMA patient. In the latter, we observed a higher percentage of CD20+ B cells in the lymph nodes compared to CM patients, whereas the opposite was observed in the spleen. Both lymph node and spleen sections from CM patients had increased percentages of CD69+ and CD45RO+ cells compared to tissue sections from the SMA patient. These results support the hypothesis that the relocation of lymphocytes to spleen and lymph node may contribute to the pan-lymphopenia observed in acute CM. Full article
(This article belongs to the Special Issue Pathology of Severe Malaria)
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11 pages, 2427 KiB  
Article
Treatment Reducing Endothelial Activation Protects against Experimental Cerebral Malaria
by Sabrina Mota, Johanna Bensalel, Do Hee Park, Sandra Gonzalez, Ana Rodriguez and Julio Gallego-Delgado
Pathogens 2022, 11(6), 643; https://doi.org/10.3390/pathogens11060643 - 2 Jun 2022
Cited by 7 | Viewed by 2329
Abstract
Cerebral malaria (CM) is the most severe neurological complication of malaria caused by Plasmodium falciparum infection. The available antimalarial drugs are effective at clearing the parasite, but the mortality rate remains as high as 20% of CM cases. At the vascular level, CM [...] Read more.
Cerebral malaria (CM) is the most severe neurological complication of malaria caused by Plasmodium falciparum infection. The available antimalarial drugs are effective at clearing the parasite, but the mortality rate remains as high as 20% of CM cases. At the vascular level, CM is characterized by endothelial activation and dysfunction. Several biomarkers of endothelial activation have been associated with CM severity and mortality, making the brain vascular endothelium a potential target for adjunctive therapies. Statins and Angiotensin II Receptor Blockers (ARBs) are drugs used to treat hypercholesterolemia and hypertension, respectively, that have shown endothelial protective activity in other diseases. Here, we used a combination of a statin (atorvastatin) and an ARB (irbesartan) as adjunctive therapy to conventional antimalarial drugs in a mouse experimental model of CM. We observed that administration of atorvastatin–irbesartan combination decreased the levels of biomarkers of endothelial activation, such as the von Willebrand factor and angiopoietin-1. After mice developed neurological signs of CM, treatment with the combination plus conventional antimalarial drugs increased survival rates of animals 3–4 times compared to treatment with antimalarial drugs alone, with animals presenting lower numbers and smaller hemorrhages in the brain. Taken together, our results support the hypothesis that inhibiting endothelial activation would greatly reduce the CM-associated pathology and mortality. Full article
(This article belongs to the Special Issue Pathology of Severe Malaria)
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13 pages, 1427 KiB  
Article
Pathophysiology of Acute Kidney Injury in Malaria and Non-Malarial Febrile Illness: A Prospective Cohort Study
by Michael T. Hawkes, Aleksandra Leligdowicz, Anthony Batte, Geoffrey Situma, Kathleen Zhong, Sophie Namasopo, Robert O. Opoka, Kevin C. Kain and Andrea L. Conroy
Pathogens 2022, 11(4), 436; https://doi.org/10.3390/pathogens11040436 - 3 Apr 2022
Cited by 9 | Viewed by 3559
Abstract
Acute kidney injury (AKI) is a life-threatening complication. Malaria and sepsis are leading causes of AKI in low-and-middle-income countries, but its etiology and pathogenesis are poorly understood. A prospective observational cohort study was conducted to evaluate pathways of immune and endothelial activation in [...] Read more.
Acute kidney injury (AKI) is a life-threatening complication. Malaria and sepsis are leading causes of AKI in low-and-middle-income countries, but its etiology and pathogenesis are poorly understood. A prospective observational cohort study was conducted to evaluate pathways of immune and endothelial activation in children hospitalized with an acute febrile illness in Uganda. The relationship between clinical outcome and AKI, defined using the Kidney Disease: Improving Global Outcomes criteria, was investigated. The study included 967 participants (mean age 1.67 years, 44.7% female) with 687 (71.0%) positive for malaria by rapid diagnostic test and 280 (29.1%) children had a non-malarial febrile illness (NMFI). The frequency of AKI was higher in children with NMFI compared to malaria (AKI, 55.0% vs. 46.7%, p = 0.02). However, the frequency of severe AKI (stage 2 or 3 AKI) was comparable (12.1% vs. 10.5%, p = 0.45). Circulating markers of both immune and endothelial activation were associated with severe AKI. Children who had malaria and AKI had increased mortality (no AKI, 0.8% vs. AKI, 4.1%, p = 0.005), while there was no difference in mortality among children with NMFI (no AKI, 4.0% vs. AKI, 4.6%, p = 0.81). AKI is a common complication in children hospitalized with acute infections. Immune and endothelial activation appear to play central roles in the pathogenesis of AKI. Full article
(This article belongs to the Special Issue Pathology of Severe Malaria)
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