Malaria Pathogenesis Milner, Jr, Danny A
Cold Spring Harbor perspectives in medicine,
01/2018, Letnik:
8, Številka:
1
Journal Article
Recenzirano
Odprti dostop
In the mosquito-human life cycle, the six species of malaria parasites infecting humans (
,
,
,
,
, and
) undergo 10 or more morphological states, replicate from single to 10,000+ cells, and vary in ...total population from one to many more than 10
organisms. In the human host, only a small number of these morphological stages lead to clinical disease and the vast majority of all malaria-infected patients in the world produce few (if any) symptoms in the human. Human clinical disease (e.g., fever, anemia, coma) is the result of the parasite preprogrammed biology in concert with the human pathophysiological response. Caveats and corollaries that add variation to this host-parasite interaction include parasite genetic diversity of key proteins, coinfections, comorbidities, delays in treatment, human polymorphisms, and environmental determinants.
Immunotherapy strategies targeting immune checkpoints such as the
and
(programmed cell death 1 ligand 1, PD-L1)/
(programmed cell death 1, PD-1) T-cell coreceptor pathways are revolutionising ...oncology. The approval of pembrolizumab use for solid tumours with high-level microsatellite instability or mismatch repair deficiency by the US Food and Drug Administration highlights promise of precision immuno-oncology. However, despite evidence indicating influences of exogenous and endogenous factors such as diet, nutrients, alcohol, smoking, obesity, lifestyle, environmental exposures and microbiome on tumour-immune interactions, integrative analyses of those factors and immunity lag behind. Immune cell analyses in the tumour microenvironment have not adequately been integrated into large-scale studies. Addressing this gap, the transdisciplinary field of molecular pathological epidemiology (MPE) offers research frameworks to integrate tumour immunology into population health sciences, and link the exposures and germline genetics (eg,
genotypes) to tumour and immune characteristics. Multilevel research using bioinformatics, in vivo pathology and omics (genomics, epigenomics, transcriptomics, proteomics and metabolomics) technologies is possible with use of tissue, peripheral blood circulating cells, cell-free plasma, stool, sputum, urine and other body fluids. This immunology-MPE model can synergise with experimental immunology, microbiology and systems biology. GI neoplasms represent exemplary diseases for the immunology-MPE model, given rich microbiota and immune tissues of intestines, and the well-established carcinogenic role of intestinal inflammation. Proof-of-principle studies on colorectal cancer provided insights into immunomodulating effects of aspirin, vitamin D, inflammatory diets and omega-3 polyunsaturated fatty acids. The integrated immunology-MPE model can contribute to better understanding of environment-tumour-immune interactions, and effective immunoprevention and immunotherapy strategies for precision medicine.
Evidence indicates that diet, nutrition, lifestyle, the environment, the microbiome, and other exogenous factors have pathogenic roles and also influence the genome, epigenome, transcriptome, ...proteome, and metabolome of tumor and nonneoplastic cells, including immune cells. With the need for big-data research, pathology must transform to integrate data science fields, including epidemiology, biostatistics, and bioinformatics. The research framework of molecular pathological epidemiology (MPE) demonstrates the strengths of such an interdisciplinary integration, having been used to study breast, lung, prostate, and colorectal cancers. The MPE research paradigm not only can provide novel insights into interactions among environment, tumor, and host but also opens new research frontiers. New developments-such as computational digital pathology, systems biology, artificial intelligence, and in vivo pathology technologies-will further transform pathology and MPE. Although it is necessary to address the rarity of transdisciplinary education and training programs, MPE provides an exemplary model of integrative scientific approaches and contributes to advancements in precision medicine, therapy, and prevention.
New Insights into Malaria Pathogenesis Moxon, Christopher A; Gibbins, Matthew P; McGuinness, Dagmara ...
Annual review of pathology,
01/2020, Letnik:
15, Številka:
1
Journal Article
Recenzirano
Malaria remains a major public health threat in tropical and subtropical regions across the world. Even though less than 1% of malaria infections are fatal, this leads to about 430,000 deaths per ...year, predominantly in young children in sub-Saharan Africa. Therefore, it is imperative to understand why a subset of infected individuals develop severe syndromes and some of them die and what differentiates these cases from the majority that recovers. Here, we discuss progress made during the past decade in our understanding of malaria pathogenesis, focusing on the major human parasite
Plasmodium falciparum
.
The murine model of experimental cerebral malaria (ECM) has been utilised extensively in recent years to study the pathogenesis of human cerebral malaria (HCM). However, it has been proposed that the ...aetiologies of ECM and HCM are distinct, and, consequently, no useful mechanistic insights into the pathogenesis of HCM can be obtained from studying the ECM model. Therefore, in order to determine the similarities and differences in the pathology of ECM and HCM, we have performed the first spatial and quantitative histopathological assessment of the ECM syndrome. We demonstrate that the accumulation of parasitised red blood cells (pRBCs) in brain capillaries is a specific feature of ECM that is not observed during mild murine malaria infections. Critically, we show that individual pRBCs appear to occlude murine brain capillaries during ECM. As pRBC-mediated congestion of brain microvessels is a hallmark of HCM, this suggests that the impact of parasite accumulation on cerebral blood flow may ultimately be similar in mice and humans during ECM and HCM, respectively. Additionally, we demonstrate that cerebrovascular CD8+ T-cells appear to co-localise with accumulated pRBCs, an event that corresponds with development of widespread vascular leakage. As in HCM, we show that vascular leakage is not dependent on extensive vascular destruction. Instead, we show that vascular leakage is associated with alterations in transcellular and paracellular transport mechanisms. Finally, as in HCM, we observed axonal injury and demyelination in ECM adjacent to diverse vasculopathies. Collectively, our data therefore shows that, despite very different presentation, and apparently distinct mechanisms, of parasite accumulation, there appear to be a number of comparable features of cerebral pathology in mice and in humans during ECM and HCM, respectively. Thus, when used appropriately, the ECM model may be useful for studying specific pathological features of HCM.
The 2013–2015 West African epidemic of Ebola virus disease (EVD) reminds us of how little is known about biosafety level 4 viruses. Like Ebola virus, Lassa virus (LASV) can cause hemorrhagic fever ...with high case fatality rates. We generated a genomic catalog of almost 200 LASV sequences from clinical and rodent reservoir samples. We show that whereas the 2013–2015 EVD epidemic is fueled by human-to-human transmissions, LASV infections mainly result from reservoir-to-human infections. We elucidated the spread of LASV across West Africa and show that this migration was accompanied by changes in LASV genome abundance, fatality rates, codon adaptation, and translational efficiency. By investigating intrahost evolution, we found that mutations accumulate in epitopes of viral surface proteins, suggesting selection for immune escape. This catalog will serve as a foundation for the development of vaccines and diagnostics.
Display omitted
Display omitted
•Lassa virus is a life-threatening pathogen that is endemic in West Africa•Lassa virus has diverse and ancient origins in Nigeria•Viral strains from Nigeria and Sierra Leone differ in their translation efficiency•The virus evolves within hosts to evade immune-determined selection pressures
Sequencing analysis of ∼200 Lassa virus genomes reveals its ancient origins and distinct evolutionary features compared to the Ebola virus.
Correct use of statistical methods is important to ensure the reliability and value of the published experimental pathology literature. Considering increasing interest in the quality of statistical ...reporting in pathology, the statistical methods used in 10 recent issues of the American Journal of Pathology were reviewed. The statistical tests performed in the articles were summarized, with attention to their implications for contemporary pathology research and practice. Among the 195 articles identified, 93% reported using one or more statistical tests. Retrospective statistical review of the articles revealed several key findings. First, tests for normality were infrequently reported, and parametric hypothesis tests were overutilized. Second, studies reporting multisample hypothesis tests (eg, analysis of variance) infrequently performed post hoc tests to explore differences between study groups. Third, correlation, regression, and survival analysis techniques were underutilized. On the basis of these findings, a primer on relevant statistical concepts and tests is presented, including issues related to optimal study design, descriptive and comparative statistics, and regression, correlation, survival, and genetic data analysis.
Background
Before initiating cancer therapy, a diagnostic tumor tissue sample evaluated within a pathology laboratory by a pathologist is essential to confirm the malignancy type and provide key ...prognostic factors that direct the treatment offered.
Methods
Pathology evaluation includes multiple expensive reagents, complex equipment, and both laboratory and pathologist technical skills. By using breast cancer as an example, at a minimum, key tumor prognostic information required before the initiation of treatment includes subtype, tumor grade, tumor size, lymph node status when possible, and biomarker expression determined by immunohistochemistry for estrogen receptor. The additional determination of biomarker expression of progesterone receptor and human epidermal growth factor receptor (HER2) is the standard of care in high‐resource settings, but assays may not be affordable in low‐income and middle‐income countries.
Results
With positive tests, patients are eligible for either tamoxifen (for estrogen receptor‐positive/progesterone receptor‐positive cancers) or monoclonal antibody therapy (for HER2‐positive cancers). For settings in which endocrine therapy and/or HER2‐targeted therapy is unavailable, biomarker studies have no utility, and high‐resource setting standards for pathology evaluation and reporting are unachievable. Resource‐stratified pathology evaluation guidelines in cancer diagnosis have not been developed, in contrast to excellent comprehensive, resource‐stratified clinical guidelines for use in low‐income and middle‐income countries, and these are long overdue.
Conclusions
The challenges of pathology evaluation in the context of global health are being met by innovative solutions, which may change the face of pathology practice.
There is an urgent need for a set of resource‐stratified pathology evaluation guidelines to complement the current National Comprehensive Cancer Network resource‐stratified frameworks for diagnosis and treatment. Such guidelines are needed so that laboratories in lower resource settings can more practically meet globally acceptable standards appropriate to their resources and matched with stratified therapies available to the populations they serve.
Cerebral malaria (CM) is a major cause of mortality in African children and the mechanisms underlying its development, namely how malaria-infected erythrocytes (IEs) cause disease and why the brain ...is preferentially affected, remain unclear. Brain microhemorrhages in CM suggest a clotting disorder, but whether this phenomenon is important in pathogenesis is debated. We hypothesized that localized cerebral microvascular thrombosis in CM is caused by a decreased expression of the anticoagulant and protective receptors thrombomodulin (TM) and endothelial protein C receptor (EPCR) and that low constitutive expression of these regulatory molecules in the brain make it particularly vulnerable. Autopsies from Malawian children with CM showed cerebral fibrin clots and loss of EPCR, colocalized with sequestered IEs. Using a novel assay to examine endothelial phenotype ex vivo using subcutaneous microvessels, we demonstrated that loss of EPCR and TM at sites of IE cytoadherence is detectible in nonfatal CM. In contrast, although clotting factor activation was seen in the blood of CM patients, this was compensated and did not disseminate. Because of the pleiotropic nature of EPCR and TM, these data implicate disruption of the endothelial protective properties at vulnerable sites and particularly in the brain, linking coagulation and inflammation with IE sequestration.
•In cerebral malaria, IEs cause loss of protein C receptors and a highly localized microvascular coagulopathy.•Low cerebral constitutive expression of these receptors, EPCR and TM, may explain the brain's vulnerability to IE-dependent pathology.
PDF
